Conditions: Acute Coronary Syndrome
Keywords: Hyperlipidemia Atherosclerotic Cardiovascular Disease Hypercholesterolemia Lipid lowering therapies
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 400
Healthy volunteers: no

Brief summary:
The purpose of this study is to study the effectiveness of implementation of a systematic LDL-C management pathway including treatment with inclisiran in participants who have experienced a recent acute coronary syndrome (ACS) and have an increased LDL-cholesterol (≥70 mg/dL) despite being treated with a statin drug.

Detailed description:
This was a randomized, parallel-group, open-label, multicenter, 1-year (30-day Screening Period and 330-day Treatment Period) study comparing an LDL-C management strategy including inclisiran + usual care to usual care alone. Approximately 384 participants were planned to be randomized 1:1 to aggressive LDL-C management with inclisiran + usual care (intervention arm) (3 inclisiran doses) or usual care (control arm). Usual care could have included addition of ezetimibe, bempedoic acid, PCSK9-inhibiting monoclonal antibodies, and/or commercially available inclisiran

Arms:
arm 1: Inclisiran sodium 300 mg / 1.5 ml (equivalent to 284 mg of inclisiran) arm 2: Usual Care Alone

Interventions: intervention 1: Inclisiran
Intervention descriptions: intervention 1: Inclisiran sodium 300 mg / 1.5 ml (equivalent to 284 mg of inclisiran)

Protocol document:
Prot_000.pdf: 
Novartis Research and Development 
KJX839 
Clinical Trial Protocol CKJX839A1US01 / NCT04873934
A randomized, controlled, multicenter, open-label trial 
comparing a hospital post-discharge care pathway 
involving aggressive LDL-C management that includes 
inclisiran with usual care versus usual care alone in 
patients with a recent acute coronary syndrome 
(VICTORION-INCEPTION) 
Document type: 
Clinical Trial Protocol 
EUDRACT number: 
NA 
Version number: 
04 (Amended Protocol) (Clean) 
Clinical Trial Phase: 
IIIb 
Release date: 
20-Oct-2022
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020 


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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 04 ......................................................................................................................... 13 
Amendment 03 ......................................................................................................................... 14 
Amendment 02 ......................................................................................................................... 16 
Amendment 01 ......................................................................................................................... 18 
1 
Introduction ....................................................................................................................... 27 
1.1 
Background ............................................................................................................ 27 
1.1.1 
Atherosclerotic cardiovascular disease (ASCVD) ................................ 27 
1.1.2 
Mechanism of RNA Interference .......................................................... 28 
1.1.3 
Inclisiran ................................................................................................ 28 
1.1.4 
Non clinical studies ............................................................................... 29 
1.1.5 
Clinical Studies ..................................................................................... 29 
1.2 
Purpose .................................................................................................................. 29 
2 
Objectives, endpoints and estimands ................................................................................. 30 
2.1 
Primary estimands ................................................................................................. 32 
2.2 
Secondary estimands ............................................................................................. 33 
3 
Study design ...................................................................................................................... 33 
4 
Rationale ............................................................................................................................ 35 
4.1 
Rationale for study design ..................................................................................... 35 
4.1.1 
Rationale for choice of background therapy ......................................... 36 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 37 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 37 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 37 
4.5 
Risks and benefits .................................................................................................. 37 
4.6 
Rationale for Public Health Emergency mitigation procedures ............................ 38 
5 
Study Population ............................................................................................................... 38 
5.1 
Inclusion criteria .................................................................................................... 38 
5.2 
Exclusion criteria ................................................................................................... 39 
6 
Treatment ........................................................................................................................... 41 
6.1 
Study treatment ...................................................................................................... 41 


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6.1.1 
Investigational and control drugs .......................................................... 41 
6.1.2 
Additional study treatments .................................................................. 41 
6.1.3 
Treatment arms/group ........................................................................... 41 
6.1.4 
Treatment duration ................................................................................ 41 
6.2 
Other treatment(s) .................................................................................................. 41 
6.2.1 
Concomitant therapy ............................................................................. 41 
6.2.2 
Prohibited medication ........................................................................... 42 
6.3 
Participant numbering, treatment assignment, randomization .............................. 42 
6.3.1 
Participant numbering ........................................................................... 42 
6.3.2 
Treatment assignment, randomization .................................................. 43 
6.4 
Treatment blinding ................................................................................................ 43 
6.5 
Dose escalation and dose modification.................................................................. 43 
6.5.1 
Dose modifications ................................................................................ 43 
6.5.2 
Follow-up for toxicities ......................................................................... 44 
6.6 
Additional treatment guidance ............................................................................... 46 
6.6.1 
Treatment compliance ........................................................................... 46 
6.7 
Preparation and dispensation ................................................................................. 46 
6.7.1 
Handling of study treatment and additional treatment .......................... 46 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 47 
7 
Informed consent procedures ............................................................................................ 47 
8 
Visit schedule and assessments ......................................................................................... 48 
8.1 
Screening ............................................................................................................... 52 
8.1.1 
Information to be collected on screening failures ................................. 52 
8.2 
Participant demographics/other baseline characteristics ....................................... 52 
8.3 
Efficacy .................................................................................................................. 52 
8.3.1 
LDL-cholesterol .................................................................................... 54 
8.3.2 
Other lipoprotein measures ................................................................... 54 
8.3.3 
Appropriateness of efficacy assessments .............................................. 54 
8.4 
Safety ..................................................................................................................... 55 
8.4.1 
Laboratory evaluations .......................................................................... 56 
8.4.2 
Electrocardiogram (ECG) ..................................................................... 57 
8.4.3 
Pregnancy and assessments of fertility ................................................. 58 
8.4.4 
Other safety evaluations ........................................................................ 58 
8.4.5 
Appropriateness of safety measurements .............................................. 59 
8.5 
Additional assessments .......................................................................................... 59 
8.5.1 
Clinical Outcome Assessments (COAs) ............................................... 59 


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 59 
8.5.3 
Biomarkers ............................................................................................ 59 
 
 59 
9 
Study discontinuation and completion .............................................................................. 60 
9.1 
Discontinuation and completion ............................................................................ 60 
9.1.1 
Study treatment discontinuation and study discontinuation.................. 60 
9.1.2 
Withdrawal of informed consent ........................................................... 61 
9.1.3 
Lost to follow-up ................................................................................... 62 
9.1.4 
Early study termination by the sponsor ................................................. 62 
9.2 
Study completion and post-study treatment .......................................................... 62 
10 Safety monitoring and reporting ........................................................................................ 63 
10.1 
Definition of adverse events and reporting requirements ...................................... 63 
10.1.1 
Adverse events ...................................................................................... 63 
10.1.2 
Serious adverse events .......................................................................... 64 
10.1.3 
SAE reporting........................................................................................ 65 
10.1.4 
Pregnancy reporting .............................................................................. 66 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 66 
10.2 
Additional Safety Monitoring ................................................................................ 67 
10.2.1 
Liver safety monitoring ......................................................................... 67 
10.2.2 
Renal safety monitoring ........................................................................ 68 
10.2.3 
Steering Committee ............................................................................... 68 
11 Data Collection and Database management ...................................................................... 68 
11.1 
Data collection ....................................................................................................... 68 
11.2 
Database management and quality control ............................................................ 69 
11.3 
Site monitoring ...................................................................................................... 69 
12 Data analysis and statistical methods ................................................................................ 70 
12.1 
Analysis sets .......................................................................................................... 70 
12.2 
Participant demographics and other baseline characteristics ................................. 71 
12.3 
Treatments ............................................................................................................. 71 
12.4 
Analysis supporting primary objectives ................................................................ 71 
12.4.1 
Definition of primary endpoints ............................................................ 71 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 71 
12.4.3 
Handling of intercurrent events of primary estimand ........................... 73 
12.4.4 
Handling of missing values not related to intercurrent event ............... 73 
12.4.5 
Sensitivity analyses ............................................................................... 73 
12.4.6 
Supplementary analysis ......................................................................... 74 


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12.4.7 
Supportive analyses ............................................................................... 74 
12.5 
Analysis supporting secondary objectives ............................................................. 75 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) .................................... 75 
12.5.2 
Safety endpoints .................................................................................... 76 
12.5.3 
Pharmacokinetics .................................................................................. 77 
12.5.4 
DNA ...................................................................................................... 77 
12.5.5 
Biomarkers ............................................................................................ 77 
12.5.6 
PK/PD relationships .............................................................................. 77 
 
 77 
12.6 
Analysis of exploratory endpoints ......................................................................... 77 
12.7 
Interim analyses ..................................................................................................... 78 
12.8 
Sample size calculation.......................................................................................... 78 
12.8.1 
Primary endpoint(s) ............................................................................... 78 
12.8.2 
Secondary endpoint(s) ........................................................................... 79 
13 Ethical considerations and administrative procedures ...................................................... 79 
13.1 
Regulatory and ethical compliance ........................................................................ 79 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 79 
13.3 
Publication of study protocol and results............................................................... 80 
13.4 
Quality Control and Quality Assurance ................................................................. 80 
14 Protocol adherence ............................................................................................................ 80 
14.1 
Protocol amendments............................................................................................. 81 
15 References ......................................................................................................................... 82 
16 Appendices ........................................................................................................................ 85 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs ......................... 85 
16.2 
Appendix 2: Liver event and laboratory trigger definitions & follow-up 
requirements .......................................................................................................... 86 
16.3 
Appendix 3: Specific Renal Alert Criteria and Actions and Event Follow-up ...... 89 
16.4 
Appendix 4: Sampson Criteria for Diagnosing Anaphylaxis ................................ 91 
 
92 
 
 94 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 30 
Table 6-1 
Investigational and control drug ............................................................ 41 
Table 6-2 
Prohibited medication ........................................................................... 42 


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Table 6-3  
Guidance on specific clinical and diagnostic assessments which 
can be performed to rule out possible alternative causes of 
observed LFT abnormalities ................................................................. 45 
Table 6-4 
Dose and treatment schedule ................................................................. 47 
Table 8-1 
Assessment Schedule ............................................................................ 50 
Table 8-2 
Safety Assessment ................................................................................. 55 
Table 8-3 
Clinical Laboratory Assessments .......................................................... 57 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 67 
Table 12-1 
Sample size calculations for percent change from baseline in LDL-
C ............................................................................................................ 78 
Table 12-2 
Sample size calculations for achieving LDL-C < 70 mg/dL ................ 79 
Table 16-1 
Clinically notable vital signs ................................................................. 85 
Table 16-2 
Clinically notable laboratory abnormalities for selected tests .............. 85 
Table 16-3 
Liver event and laboratory trigger definitions ...................................... 86 
Table 16-4 
Follow up requirements for liver laboratory triggers with liver 
symptoms .............................................................................................. 86 
Table 16-5 
Follow up requirements for liver laboratory triggers ............................ 87 
Table 16-6 
Specific renal alert criteria and actions ................................................. 89 
Table 16-7 
Renal event follow-up ........................................................................... 90 
List of figures 
Figure 3-1 
Study Design ......................................................................................... 34 
 


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List of abbreviations 
ACS 
Acute coronary syndrome  
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ASCVD 
Atherosclerotic cardiovascular disease 
AST 
Aspartate Aminotransferase 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CHD 
Coronary heart disease 
CK 
Creatinine Kinase 
COA 
Clinical Outcome Assessment 
CQA 
Clinical Quality Assurance 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CV 
Cardiovascular 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
eGFR 
estimated Glomerular Filtration Rate 
EHR 
Electronic Health Record 
FDA 
Food and Drug Administration 
GalNAc 
N-acetylgalactosamine 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GLDH 
Glutamate Dehydrogenase 
GPP 
Good Pharmaceopidemiology Practice 
HBcAb 
Hepatitis B Core Antibody 
HBsAb 
Hepatitis B Surface Antibody 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B Virus 
hCG 
Human Chorionic Gonadotropin 
HCV 
Hepatitis C Virus 
HDL-C 
High Density Lipoprotein Cholesterol 
HEOR 
Health Economics & Outcomes Research  
HIV 
Human immunodeficiency virus 
HRQoL 
Health-Related Quality of Life 
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 


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IN 
Investigator Notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISR 
Injection Site Reaction 
IUD 
intrauterine device  
IUS 
intrauterine system 
LDH 
lactate dehydrogenase 
LDL-C 
low density lipoprotein cholesterol 
LFT 
Liver function test  
LLN 
lower limit of normal 
LNP 
lipid nanoparticle 
Lp(a) 
Lipoprotein(a)  
MACE 
Major adverse cardiovascular events  
 
 
MedDRA Medical dictionary for regulatory activities  
mg 
milligram(s) 
MI 
Myocardial Infarction 
mL 
milliliter(s) 
MMRM 
Mixed-effects model repeated measures  
mRNA 
Messenger RNA  
No. 
Number 
NOACs 
novel or non-Vitamin K oral anticoagulants 
NYHA 
New York Heart Association  
PD 
Pharmacodynamic(s) 
PFS 
Pre-Filled Syringe 
PK 
Pharmacokinetic(s) 
PRO 
Patient Reported Outcomes 
PT 
prothrombin time 
QMS  
Quality Management System 
RBC 
red blood cell(s) 
RISC 
RNA-Induced Silencing Complex  
RNAi 
Ribonucleic acid interference  
RU 
Resource Utilization 
s.c. 
subcutaneous 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
sCR 
serum creatinine 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
siRNA 
small interfering ribonucleic acid 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 


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TBL 
Total Bilirubin 
 
 
ULN 
upper limit of normal 
VLDL 
Very-Low-Density Lipoprotein 
WBC 
white blood cell(s) 
WHO 
World Health Organization  
WoC 
Withdrawal of Consent 


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Glossary of terms 
Additional 
treatment 
Medicinal products that may be used during the clinical trial as described in 
the protocol, but not as an investigational medicinal product (e.g. any 
background therapy) 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study participant  
Clinical Outcome 
Assessment (COA) 
A measure that describes or reflects how a participant feels, functions, or 
survives 
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 specific group of participants fulfilling certain criteria and generally treated 
at the same 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 paper source forms 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 or 
at a later point in time as defined by the protocol  
Enrollment 
Point/time of participant entry into the study at which informed consent must 
be obtained  
eSource (DDE) 
Electronic source (eSource) Direct Data Entry (DDE) refers to the capture of 
clinical study data electronically, at the point of care. eSource 
Platform/Applications combines source documents and case report forms 
(eCRFs) into one application, allowing for the real time collection of clinical 
trial information to sponsors and other oversight authorities, as appropriate 


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Estimand  
A precise description of the treatment effect reflecting the clinical question 
posed by the trial objective. It summarizes at a population-level what the 
outcomes would be in the same patients under different treatment conditions 
being compared. Attributes of an estimand include the population, variable (or 
endpoint) and treatment of interest, as well as the specification of how the 
remaining intercurrent events are addressed and a population-level summary 
for the variable. 
Healthy volunteer 
A person with no known significant health problems who volunteers to be a 
study participant  
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  
Off-site 
Describes trial activities that are performed at remote location by an off-site 
healthcare professional, such as procedures performed at the participant's 
home. 
Off-site healthcare 
Professional (OHP) 
A qualified healthcare professional, such as a nurse, phlebotomist or 
physician, who performs certain protocol procedures for the participant in 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) 
Part  
A sub-division of a study used to evaluate specific objectives or contain 
different populations. For example, one study could contain a single dose part 
and a multiple dose part, or a part in participants with established disease and 
in those with a newly diagnosed disease 
Participant 
A trial participant (can be a healthy volunteer or a patient) 
Participant number 
A unique number assigned to each participant upon signing the informed 
consent. This number is the definitive, unique identifier for the participant and 
should be used to identify the participant throughout the study for all data 
collected, sample labels, etc. 
Patient-Reported 
Outcome (PRO) 
A measurement based on a report that comes directly from the patient about 
the status of a participant's health condition without amendment or 
interpretation of the patient's report by a clinician or anyone else 
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. 
Premature 
participant 
withdrawal 
Point/time when the participant exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this time 
all study drug administration is discontinued, and no further assessments are 
planned 


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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 eSource 
Start of the clinical 
trial 
The start of the clinical trial is defined as the signature of the informed 
consent by the first participant 
Study treatment 
Any drug or combination of drugs   or intervention administered to the study 
participants as part of the required study procedures; includes investigational 
drug(s), control(s) or background therapy 
Study treatment 
discontinuation 
When the participant permanently stops taking any of the study drug(s) prior 
to the defined study treatment completion date (if any) for any reason; may or 
may not also be the point/time of study discontinuation  
Tele-visit 
Procedures or communications conducted using technology such as 
telephone or videoconference, whereby the participant is not at the 
investigative site where the investigator will conduct the trial. 
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 it might consist of an overall regimen involving a complex 
sequence of interventions. This is the treatment of interest used in describing 
the related clinical question of interest, which might or might not be the same 
as the study treatment. 
Variable (or 
endpoint) 
The variable (or endpoint) to be obtained for each participant that is required 
to address the clinical question. The specification of the variable might include 
whether the participant experiences an intercurrent event. 
Withdrawal of 
study consent 
(WoC) 
Withdrawal of consent from the study occurs only when a participant does not 
want to participate in the study any longer and does not allow any further 
collection of personal data   


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Amendment 04 
Amendment rationale  
The purpose of the clinical study amendment is to clarify the use of inclisiran, which is now 
commercially available as LEQVIO®. Exclusion criteria #11 and 15 has been modified. 
Similarly, the study design has been modified to reflect the same. The number of sites was 
increased from 40 to up to approximately 130. 
Changes to the protocol 
• Section 3 Study Design: Added “Commercially available inclisiran may be used for 
appropriate patients in the usual care arm at the sole discretion of the treating physician, 
without any influence from the PI.” Deleted “If and when…treating physician” 
• Section 5 Study Population: The number of sites was increased from 40 to up to 
approximately 130 
• Section 5.2  
o Exclusion criteria #15: Added “Treatment with monoclonal antibodies directed towards 
PCSK9 or inclisiran within 90 days of screening.” 
o Exclusion criteria #11: Added “Approved vaccines or vaccines used under Emergency Use 
Authorization  should not be considered part of this exclusion criteria. Patients can receive 
COVID vaccines during inclisiran trials. 
While use of COVID anti-viral therapies approved for use under  Emergency Use 
Authorization would need to adhere to the washout period outlined above prior to 
screening, they would not be considered as criteria for trial termination/discontinuation. 


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Amendment 03  
Amendment rationale  
The purpose of the clinical study amendment is to clarify the understanding of what is meant 
by patients being hospitalized for an acute coronary syndrome (ACS).  The term 
“hospitalization” applies to patients who are either admitted to the hospital as an in-patient or 
in an out-patient setting (i.e., not requiring admission for an overnight hospital stay).   
Some of the inclusion and exclusion criteria have been modified.  The criteria for glomerular 
filtration rate has been reduced from a calculated value greater than 30 ml/min to a value greater 
than 20 ml/min.  The exclusion criteria for heart failure (HF) has been changed from class III 
or IV HF to now only excluding participants with class IIIb or IV HF or a left ventricular 
ejection fraction less than 25%.  The exclusion criteria for The protocol amendment has also 
removed the requirement for participants to be randomized within 5 weeks of being discharged 
for an ACS.  Screening of participants needs to occur withing 5 weeks of an ACS but the site 
does not have to randomize the patient within the 5 week window as they still have 30 days 
following screening to randomize a participant into the trial. 
Changes to the protocol 
• Protocol Summary 
o Purpose and rationale:  added “… with a previous hospitalization (in-patient/out-
patient) for an ACS …” 
o Primary Objective:  added “… in participants with a recent hospitalization (in-
patient/out-patient) for an ACS ...” 
o Study population:  added “… with a recent hospitalization (in-patient/out-
patient) for an ACS …” 
o Inclusion criteria #2: Added “Recent ACS (in-patient/out-patient) within 5 
weeks of screening), …” 
o Inclusion criteria #3: Added “Serum LDL-C ≥70 mg/dL or non-HDL ≥100 
mg/dL” 
o Inclusion criteria #5: Modified “calculated glomerular filtration rate >20 ml/min 
…” 
o Inclusion criteria #7: Added “… following hospitalization (in-patient/out-
patient) for an ACS.” 
o Exclusion criteria #1: Modified “New York Heart Association (NYHA) class 
IIIb …” and  “… last known left ventricular ejection fraction <25%.” 
o Exclusion criteria #6: Modified “Treatment with monoclonal antibodies directed 
towards PCSK9 within 90 days of screening.” 
• Section 1.1 Background:  added “… with inclisiran in participants with a recent 
hospitalization (in-patient/out-patient) for an ACS …” 


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• Section 1.2 Purpose:  added “a recent ACS (in-patient/out-patient) within 5 weeks of 
screening.” and added “… initiation of inclisiran in participants with a recent 
hospitalization (in-patient/out-patient) for an ACS …” 
• Table 2-1  under Primary objectives:  added “initiation of inclisiran in participants with 
a recent hospitalization (in-patient/out-patient) …” 
• Section 2.1 Primary estimands:  removed “within 5 weeks” and added “… 
implementation pathway in participants following a recent ACS, …” 
• Section 3 Study Design:  deleted “and randomization” to now state: “Screening of 
participants must take place within 5 weeks after discharge.” 
• Section 4.1 Recruitment: added “… recently hospitalized for an ACS (in-patient/out-
patient), …” 
• Section 5 added “… with a recent hospitalization (in-patient/out-patient) for an ACS 
(within 5 weeks) …” 
 
• Section 5.1  
o Inclusion criteria #2: Added “Recent ACS (in-patient/out-patient) within 5 
weeks of screening, …” 
o Inclusion criteria #3: Added “Serum LDL-C ≥70 mg/dL or non-HDL ≥100 
mg/dL” 
o Inclusion criteria #5: Modified “…calculated glomerular filtration rate >20 
ml/min …” 
o Inclusion criteria #7: Removed “discharged” and added “in-patient/outpatient” 
to “Participants are required to be on statin therapy, or have documented statin 
intolerance, as determined by the investigator, following hospitalization (in-
patient/outpatient) …”. 
 
• Section 5.2  
o Exclusion criteria #3: Modified “New York Heart Association (NYHA) class 
IIIb …” and  “… last known left ventricular ejection fraction <25%.” 
o Exclusion criteria #15: Modified “Treatment with monoclonal antibodies 
directed towards PCSK9 within 90 days of screening.” 


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Amendment 02  
Amendment rationale  
The purpose of the clinical study amendment is to update the protocol in order to be aligned 
with other ongoing inclisiran Phase III studies with respect to the documentation of statin 
intolerance, definition of hyperglycemia-related events and assessment of injection site 
reactions.  The protocol has also removed any reference to the need to contact and obtain 
consent from the female partner of any male participant when the female partner becomes 
pregnant during the study in order to obtain pregnancy outcome information. 
This protocol amendment, finalized prior to study start, will be the initial protocol version 
submitted to regulatory authorities, including the FDA, and Site IRBs for study approval. 
Changes to the protocol 
• Updated list of abbreviations to include Injection Site Reaction  
• Protocol Summary 
o Data Analysis section updated efficacy variables being analyzed 
• Section 3 added language, “if and when inclisiran becomes commercially available” 
• Section 6.5.1 removed “not applicable” and provided guidance with respect to drug 
interruptions and/or drug discontinuation 
• Section 6.5.2 
o Removed not applicable  
o Added Section 6.5.2.1 follow up on potential drug-induced liver injury (DILI) 
cases  
• Section 6.7.1.1 removed language that participants will be asked to return all unused 
study medication 
• Section 7 removed pregnant partner information 
• Section 8  
o Included language for required 8 hour fasting prior to laboratory evaluations 
o Included language that blood donations are prohibited during study participation 
• Table 8-1 
o Added “Medical History: Statin Intolerance” 
o Added footer for “Weight” to be captured at visits 3, 4 and 5 
o Updated “Pulse Rate” and “Blood Pressure” to be captured at visits 3 and 4 
o Added “prior or” to concomitant medications   
o Added “Surgical / Medical procedures” 


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o Added “Injection Site Reaction Assessment”  
o Updated footer numbers   
o Provided clarification of biobanking collection at Visits 2-5  
• Section 8.2 removed “date of birth” 
• Table 8-3 removed “Lactate” from full serum chemistry  
• Section 8.4.4 added “Injection site reactions” and “Hyperglycemia-related events” 
information  
• 
  
• Section 8.5.3  
o Added analysis of proteins.  
o Updated language to indicate all measures of Lp(a) and hsCRP are blinded to 
participants and staff and to allow for any lab measures from the biobank 
samples to be analyzed during or after study close  
• Section 10.1.4 removed the word “pregnancies” at the start of the paragraph and 
pregnant partner information   
• Section 10.2 removed “not applicable” 
• Section 10.2.1 removed test for unexplained increases in transaminases or total 
bilirubin, as well as instructions on follow-up, as this is now captured in section 6.5.2.1, 
Appendix 2 and in the remainder of the paragraph 
• Section 11.1 removed Integrated data acquisition approach, Direct EHR Data Capture 
and Linked Pharmacy & Medical Claims Data information 
• Section 12.5.1 updated efficacy variables being analyzed 
 


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Amendment 01  
Amendment rationale  
The purpose of the clinical study amendment is to modify the protocol to be in alignment with 
it being a Phase IIIb trial instead of a Phase IV.  As a result, the protocol is now more closely 
aligned with the other Phase III studies with inclisiran, particularly with respect to the timing 
and frequency of some of the laboratory assessments.       
The protocol amendment also added two new exclusion criteria in the protocol to clearly define 
the situation regarding a recurrent ACS event and the scheduling or occurrence of a coronary 
revascularization procedure.   
The patient reported outcomes to be used in the study have been updated to remove the Belief 
about Medication Questionnaire (BMQ).   
The protocol updated the sections with respect to the capture of EHR and claims data into the 
database to state that it may not be possible in all patients. 
The protocol was also updated according to the most recent version (4.0) of the clinical trial 
protocol template, issued on 15-Feb-2021.   
Changes to the protocol have also been made to align with another ongoing Phase IIIb clinical 
study with inclisiran (KJX839A1US02). Other changes to the protocol included the addition of 
a study name and other necessary spelling and grammatical corrections. 
Changes to the protocol 
• Title page study name “VICTORION-INCEPTION” added to title. 
• List of abbreviations were updated to include EHR, GPP, HBcAb, HBsAb, hCG, HDL-
C, VLDL, 
 
• Glossary of terms were updated to include Clinical Outcomes Assessment (COA), 
Clinical Trial Team, Coded Data, Discontinuation from study, Discontinuation from 
study treatment, off-site, off-site healthcare professional (OHP), Patient-Reported 
Outcomes (PRO), Randomization, Re-screening, Remote and Tele-visit.  
• Glossary of terms were updated to remove cycles and run-in failure  
• Protocol Summary 
o Full title “VICTORION-INCEPTION” was added 
o Clinical Phase was updated to Phase IIIb 
o Study type was updated to interventional 
o Key Exclusion criteria was added.  
 Recurrent ACS event within 2 weeks prior to randomization. 
 Coronary angiography and revascularization procedure (percutaneous 
coronary intervention (PCI) or coronary artery bypass grafting (CABG) 








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new studies. No analysis will be performed using post-baseline data. Thus, there is no 
need to adjust the level of significance for such interim analysis of baseline data.”  
• Section 12.8.1 added “trial since changes in lipid-lowering therapy are allowed in both 
treatment groups.”  
• Section 15 updated references  
 
 
Other typographical corrections were also included. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes described 
in this amended protocol require IRB/IEC and Health Authority approval according to local 
regulations prior to implementation.  
 
 


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Protocol summary 
Protocol 
number 
CKJX839A1US01 
Full Title 
A randomized, controlled, multicenter, open-label trial comparing a hospital post-
discharge care pathway involving aggressive LDL-C management that includes 
inclisiran with usual care versus usual care alone in patients with a recent acute 
coronary syndrome(VICTORION-INCEPTION) 
Brief title 
Management of LDL-cholesterol with inclisiran + usual care compared to usual 
care alone in participants with a recent acute coronary syndrome 
Sponsor and 
Clinical Phase 
Novartis, Phase IIIb 
Investigation 
type 
Drug  
Study type 
Interventional clinical trial 
Purpose and 
rationale 
The purpose of this study is to study the effectiveness of implementation of a 
systematic LDL-C management pathway including treatment with inclisiran in 
participants who have experienced a recent acute coronary syndrome (ACS) 
and have an increased LDL-cholesterol (≥70 mg/dL) despite being treated with a 
statin drug. 
In this context, we aim to assess the LDL-C lowering effects of aggressive LDL-C 
management with inclisiran on top of usual care in patients with a previous 
hospitalization (in-patient/out-patient) for an ACS compared to patients receiving 
usual, care without inclisiran.  
Primary 
Objective(s)  
The primary objective of this study is to assess the effect on LDL-C of 
implementation of an LDL-C management care pathway that includes initiation 
of inclisiran on top of usual care in participants with a recent hospitalization (in-
patient/out-patient) for an ACS with LDL-C ≥70 mg/dL despite being on statin 
therapy compared to usual care without inclisiran at Day 330.  
Secondary 
Objectives 
The secondary objectives in this study include the following:  
To assess (1) the absolute change from baseline in LDL-C level at Day 330, and 
(2) average of absolute and percent changes from baseline in LDL-C levels to 
each post-baseline visit, in the inclisiran + usual care group compared to usual 
care group at Day 330  
To assess the proportion of participants reaching pre-specified LDL-C targets in 
the inclisiran + usual care group compared to usual care group at Day 330 
To assess plasma lipoproteins and triglycerides in the inclisiran + usual 
care group compared to usual care group at Day 330 
To assess changes in and adherence to background lipid-lowering therapy in the 
inclisiran + usual care group compared to usual care group at Day 330 
To assess overall safety and tolerability of inclisiran 
Study design 
The study design will be a randomized, parallel-group, open-label, controlled, 
multicenter study comparing an LDL-C management strategy including inclisiran 
with usual care. 
Study 
population 
Male or female participant’s ≥18 years of age with a recent hospitalization (in-
patient/out-patient) for an ACS and elevated LDL-C (≥70 mg/dL) despite being 


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treated with statin therapy by their health care practitioner. We plan to 
randomize approximately 384 participants at up to approximately 130 US sites. 
Key Inclusion 
criteria 
Participants eligible for inclusion in this study must meet all of the following 
criteria: 
1. Males and females ≥18 years of age 
2. Recent ACS (in-patient/out-patient) within 5 weeks of screening, defined as: 
Ischemic symptoms with unstable pattern, occurring at rest or minimal 
exertion within 24 hours of an unscheduled hospital admission or 
emergency department visit, due to presumed or proven obstructive 
coronary disease AND at least one of the following: 
a. Elevated cardiac biomarkers (cardiac troponin (cTn ) or the MB fraction 
of creatinine kinase (CKMB)) with at least one value above the 99th 
percentile of the upper reference limit (URL) or defined by the local 
laboratory MI diagnosis cut-off values OR 
b. Resting ECG changes consistent with ischemia or infarction AND 
additional evidence of obstructive coronary disease 
3. Serum LDL-C ≥70 mg/dL or non-HDL ≥100 mg/dL 
4. Fasting triglycerides <4.52 mmol/L (<400 mg/dL) at screening 
5. Calculated glomerular filtration rate >20 mL/min by estimated glomerular 
filtration rate (eGFR) 
6. Participants must be willing and able to give informed consent before 
initiation of any study related procedures and willing to comply with all 
required study procedures 
7. Participants are required to be on statin therapy, or have documented statin 
intolerance, as determined by the investigator, following hospitalization (in-
patient/out-patient) for an ACS. Statin intolerant patients are eligible if they 
had intolerable side effects on at least 2 different statins, including one at 
the lowest standard dose. 
Key Exclusion 
criteria 
• 
New York Heart Association (NYHA) class IIIb or IV heart failure or last 
known left ventricular ejection fraction <25%. 
• 
Significant cardiac arrhythmia within 3 months prior to randomization that is 
not controlled by medication or via ablation at the time of screening. 
• 
Severe concomitant non-cardiovascular disease that carries the risk of 
reducing life expectancy to less than 2 years. 
• 
Treatment with other investigational products or devices within 30 days or 
five half˗lives of the screening visit, whichever is longer. 
• 
Planned use of other investigational products or devices during the course 
of the study. 
• 
Treatment with monoclonal antibodies directed towards PCSK9 or with 
inclisiran within 90 days of screening.  
• 
Recurrent ACS event within 2 weeks prior to randomization.  
• 
Coronary angiography and revascularization procedure (percutaneous 
coronary intervention (PCI) or coronary artery bypass grafting (CABG) 
surgery) performed within 2 weeks prior to the randomization visit or 
planned after randomization.   
• 
Approved vaccines or vaccines used under Emergency Use Authorization  
should not be considered part of this exclusion criteria. Patients can receive 
COVID vaccines during inclisiran trials. 
While use of COVID anti-viral therapies approved for use under Emergency 
Use Authorization for would need to adhere to the washout period outlined 




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2. Average percent change from baseline in LDL-C levels to each post-
baseline visit 
3. Average absolute change from baseline in LDL-C levels to each post-
baseline visit 
4. Achieving LDL-C < 100 mg/dL (yes, no) (among the subset of participants 
with LDL-C ≥ 100 mg/dL at baseline) 
5. Achieving ≥ 50% reduction from baseline in LDL-C (yes, no) 
6. Achieving LDL-C < 55 mg/dL (yes, no) 
7. Percent change from baseline in apoB 
8. Absolute change from baseline in apoB 
9. Percent change from baseline in VLDL 
10. Absolute change from baseline in VLDL 
11. Percent change from baseline in non-HDL-C 
12. Absolute change from baseline in non-HDL-C 
13. Percent change from baseline in total cholesterol 
14. Absolute change from baseline in total cholesterol 
15. Percent change from baseline in Lp(a) 
16. Absolute change from baseline in Lp(a) 
17. Percent change from baseline in HDL-C 
18. Absolute change from baseline in HDL-C 
19. Percent change from baseline in triglycerides 
20. Absolute change from baseline in triglycerides 
21. Intensity of lipid-lowering therapy (decrease in dose, no change in dose, 
increase in dose) 
22. Proportion of days covered (total number of days on either statin, ezetimibe, 
or PCSK9 inhibiting monoclonal antibody therapies divided by total number 
of study days) 
23. Discontinuation of statin therapy (i.e., no statin use ≥ 30 days before the 
end-of-study visit) (yes, no) 
Analyses of secondary efficacy variables 1 and 7 - 20 will be similar to the primary 
analysis of primary efficacy variable 1 (using MMRM, but with a two-sided 95% 
confidence interval for the treatment difference). 
Secondary efficacy variables 2, 3, and 22 will be analyzed using a linear model 
with treatment and baseline LDL-C as explanatory variables.  
Secondary efficacy variables 4 - 6 and 23 will be analyzed at each post-baseline 
visit using a logistic regression model with treatment and baseline LDL-C as 
explanatory variables.  
Secondary efficacy variable 21 will be analyzed at each post-baseline visit using 
a proportional odds model with treatment and baseline LDL-C as explanatory 
variables. 
Key words  
Hyperlipidemia, Acute Coronary Syndrome (ACS), Secondary Cardiovascular 
Prevention, Atherosclerotic Cardiovascular Disease (ASCVD), 
Hypercholesterolemia, Lipid lowering therapies 


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1 
Introduction 
1.1 
Background 
Inclisiran is a novel synthetic small interfering ribonucleic acid (siRNA) therapeutic for 
subcutaneous (SC) injection for the treatment of hypercholesterolemia. Inclisiran has been 
shown to lower low density lipoprotein cholesterol (LDL-C) by 50% or more in patients with 
stable established atherosclerotic cardiovascular disease (ASCVD) who are treated with 
maximally tolerated statin therapy (Ray et al 2020). It is not known, however, if participants 
who have had a recent acute coronary syndrome (ACS) would have similar effects on LDL-C, 
with respect to the use of inclisiran, since these patients were excluded from participation in the 
Phase III registration trials. 
The purpose of this trial is to assess the LDL-C lowering effects of aggressive LDL-C 
management with inclisiran in participants with a recent hospitalization (in-patient/out-patient) 
for an ACS and have an LDL-C ≥70 mg/dL while receiving statin therapy. 
This study will be conducted in compliance with Good Clinical Practices (GCP) and Good 
Pharmacoepidemiology Practices (GPP), including the Declaration of Helsinki and all 
applicable regulatory requirements. 
1.1.1 
Atherosclerotic cardiovascular disease (ASCVD) 
Patients who have experienced an ASCVD event, including patients with coronary heart disease 
(CHD), are at a higher risk of having another cardiovascular (CV) event (Grundy et al 2019). 
Lowering of low density lipoprotein cholesterol (LDL-C) is one of the most important treatment 
strategies to help prevent a recurrent CV event (Baigent et al 2010). CHD patients, including 
those who experienced an ACS, should receive long-term intensive lipid lowering therapy 
starting with a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) as 
reductions in LDL-C have demonstrated significant reductions in CV morbidity and mortality 
both in patients with stable ASCVD and in those with a recent ACS (Mills et al 2011; 
Cannon et al 2004; Collins et al 2016). 
The most recent treatment guidelines by the American Heart Association and the American 
College of Cardiology now recommend initiating a high intensity statin (atorvastatin (40 mg) 
or rosuvastatin (20 mg)) as early as possible (1-4 days) after the diagnosis of ACS has been 
made with a goal of achieving at least 50% reduction in LDL-C (Grundy et al 2019). In those 
same patients whose LDL-C remains ≥70 mg/dL, use of other non-statin therapies are 
recommended for additional reductions in LDL-C.  
A more aggressive reduction in LDL-C in ACS patients was associated with further reductions 
in CV morbidity and mortality but data is limited when evaluating the efficacy of various lipid 
lowering therapies when added to statin therapy (Wilson et al 2019). Aggressive LDL-C targets 
are not easy to achieve in patients following an ACS with statin therapy alone 
(Rosenblit 2019; Koskinas et al 2019). The risk of recurrent CV events is lower in patients 
receiving more intensive LDL-C lowering with the addition of non-statin therapies (e.g., 
ezetimibe and PCSK9-inhibition) in patients already on maximally tolerated statin therapy but 
requires 
a 
structured 
step-wise 
approach 
to 
achieve 
target 
goals 
(Cannon et al 2015; Sabatine et al 2017; Schwartz et al 2018). Reasons for poor LDL-C 


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control rates in ACS patients can be attributed to multiple factors including: the inability to 
titrate statins to higher doses due to tolerability issues at higher doses, lack of a therapeutic 
target or goal to achieve for LDL-C with no regular assessment of LDL-C levels, and poor 
adherence to lipid lowering therapy (Lambert-Kerzner et al 2015; Anderson et al 2018). 
Employing a guideline directed medical therapy plan in ACS patients with a LDL-C goal of 
<70 mg/dL can be achieved. However, it requires the use of high-intensity statins at maximally 
tolerated doses and the use of add-on non-statin therapies (Cannon et al 2017).  
1.1.2 
Mechanism of RNA Interference 
Ribonucleic acid interference (RNAi) is a naturally occurring cellular mechanism for regulating 
gene expression that is mediated by small interfering ribonucleic acids (siRNAs). Typically, 
synthetic siRNAs are 19-base to 25-base pair double-stranded oligonucleotides in a staggered 
duplex with a two- to four-nucleotide overhang at one or both of the 3’ ends. Such siRNAs can 
be designed to target an endogenous messenger RNA (mRNA) transcript of a given gene. When 
introduced into cells, the guide (or antisense) strand of the siRNA loads into an enzyme complex 
called the RNA-Induced Silencing Complex (RISC). This enzyme complex subsequently binds 
to its complementary mRNA sequence, mediating cleavage of the target mRNA and the 
suppression of the target protein encoded by the mRNA (Elbashir et al 2001). 
Since unmodified siRNAs are rapidly eliminated and do not achieve significant tissue 
distribution upon systemic administration (Soutschek et al 2004), various formulations are 
currently used to target their distribution to tissues, and to facilitate uptake of siRNAs into the 
relevant cell type. One approach that has been used successfully in vivo, in animal models 
(including in rodents and nonhuman primates) and humans employs intravenous delivery of 
siRNA 
in 
lipid 
nanoparticle 
(LNP) 
formulations 
(Soutschek et al 2004; Morrissey et al 2005; Geisbert et al 2006; Zimmermann et al 2006; Coe
lho et al 2020; Tabernero et al 2013). Another approach for liver-specific gene silencing is 
subcutaneously administered siRNA conjugated to an N-acetylgalactosamine (GalNAc) 
carbohydrate ligand (Ashwell and Morell 1974). Conjugation of a triantennary GalNAc ligand 
to a siRNA enables hepatocyte binding and subsequent cellular uptake via the 
asialoglycoprotein receptor, resulting in engagement of the RNAi pathway and down regulation 
of hepatic proteins.  
1.1.3 
Inclisiran 
Inclisiran is a chemically synthesized, subcutaneously administered, double-stranded siRNA, 
conjugated on the sense strand with triantennary GalNAc to facilitate uptake specifically by 
hepatocytes. In hepatocytes, inclisiran utilizes the RNAi mechanism and directs catalytic 
breakdown of mRNA for PCSK9. This increases LDL-C receptor recycling and expression on 
the hepatocyte cell surface, which increases LDL-C uptake and lowers LDL-C levels in the 
circulation (Nishikido and Ray 2018). Inclisiran was approved by the FDA on December 22nd, 
2021, approved under the name Leqvio and is indicated as an adjunct to diet and maximally 
tolerated statin therapy for the treatment of adults with heterozygous familial 
hypercholesterolemia or clinical ASCVD who require additional lowering of LDL-C. (reference 
USPI). 


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1.1.4 
Non clinical studies 
Inclisiran was specifically designed with molecular and biochemical characteristics to minimize 
untoward side effects which are reflected by the absence of dose limiting toxicities in preclinical 
models. For example, GalNAc ligands were added to the RNA strands in order to target 
inclisiran to receptors on hepatocytes, thereby greatly reducing uptake by heterologous tissue 
with tissue distribution being primarily localized in the liver (Nishikido and Ray 2018). In 
addition, once inclisiran is inside the cell, there is a low likelihood of off-target binding because 
inclisiran is sequestered within RISC and guided to its complementary mRNA sequence. 
Inclisiran was well tolerated in all non-clinical studies (Ray et al 2020). The most common 
findings were related to the expected pharmacological effects of inclisiran on lipid profiles and 
histopathological findings of vacuolation in hepatocytes of rats and lymph node macrophages 
of monkeys and the presence of basophilic granules in hepatocytes of monkeys and kidneys of 
rats. These microscopic findings are not considered adverse effects because they are not 
associated with changes in clinical pathology parameters. Liver function enzymes were only 
minimally to mildly increased, and were reversible following treatment-free periods, and there 
were no changes in urinalysis or urine chemistry parameters. 
1.1.5 
Clinical Studies 
Inclisiran lowers LDL-C for sustained periods while only requiring twice yearly injections 
resulting in effective reductions in LDL-C (50% or more) in stable ASCVD patients in as soon 
as 3 months after the first injection. In the double-blind, placebo-controlled, multicenter Phase 
III ORION trials, involving 3,655 patients (about half of which received inclisiran, n=1,833), 
after the initial administration of inclisiran, LDL-C levels were quickly reduced with more than 
65% of patients (placebo controlled) reaching an LDL-C <70 mg/dL when used on top of a 
maximally tolerated statin (Ray et al 2020). Adverse events in the Phase III trials were 
generally similar in the inclisiran and placebo groups, although injection-site adverse events 
were more frequent with inclisiran than with placebo; such reactions were generally mild, and 
none were severe or persistent. The phase III studies with inclisiran, however, were performed 
in stable ASCVD patients and did not include those who had a recent ACS event. 
1.2 
Purpose 
Given the importance of achieving LDL-C targets in ACS patients and the unique LDL-C 
lowering properties of inclisiran a study is needed to better assess the effects of having inclisiran 
part of the care management pathway in participants who have a recent ACS (in-patient/out-
patient) within 5 weeks of screening. Implementation of a systematic LDL-C management 
pathway including treatment with inclisiran in patients who have experienced an ACS and have 
an LDL-C ≥70 mg/dL despite being on statin therapy could increase the proportion of patients 
who reach acceptable LDL-C levels and thereby lower their risk of recurrent ischemic events. 
The Phase III trials with inclisiran provided high-quality evidence supporting the efficacy and 
safety/tolerability of inclisiran, however, the highly controlled conditions under which these 
double-blind, placebo-controlled registration trials were conducted limit their ability to reflect 
the complexity and diversity of actual clinical practice. For example, adherence to lipid 
lowering medication that rely on patient self-administration, including statins, in clinical trials 


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is often higher than in real-world clinical practice, in part due to the better monitoring of the 
patient. In addition, in order to meet the inclusion criteria of the inclisiran Phase III trials, 
participants needed to be on stable lipid-lowering therapy without plans to switch therapy 
during the follow-up period, while switches in lipid lowering therapy (statin and non-statin) 
therapy are common in routine clinical practice. 
In summary, the purpose of this study is to assess the effect on LDL-C of implementation of an 
LDL-C management care pathway that includes initiation of inclisiran in participants with a 
recent hospitalization (in-patient/out-patient) for an ACS with LDL-C ≥70 mg/dL despite 
receiving statin therapy compared to usual care without inclisiran. 
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 assess the effect on LDL-C of implementation of an 
LDL-C management care pathway that includes 
initiation of inclisiran in participants with a recent 
hospitalization (in-patient/out-patient) for an ACS with 
LDL-C ≥70 mg/dL despite receiving statin therapy 
compared to usual care without inclisiran at Day 330 
• 
Percent change from baseline in 
LDL-C 
• 
Achieving LDL-C < 70 mg/dL 
(yes, no) 
Secondary objective(s) 
Endpoint(s) for secondary 
objective(s) 
• 
To assess (1) the absolute change from baseline in 
LDL-C level by visit, and (2) average of percent and 
absolute changes from baseline in LDL-C levels to 
each post-baseline visit, in the inclisiran + usual 
care group compared to usual care group at Day 330  
• 
Absolute change from baseline in 
LDL-C 
• 
Average percent change from 
baseline in LDL-C levels to each 
post-baseline visit 
• 
Average absolute change from 
baseline in LDL-C levels to each 
post-baseline visit 
• 
To assess the proportion of participants reaching pre-
specified LDL-C targets in the inclisiran + usual care 
group compared to usual care group at Day 330 
• 
Achieving ≥ 50% reduction from 
baseline in LDL-C (yes, no) 
• 
Achieving LDL-C < 100 mg/dL 
(yes, no) (among the subset of 
participants with LDL-C ≥ 100 
mg/dL at baseline) 
• 
Achieving LDL-C < 55 mg/dL 
(yes, no) 
• 
To assess plasma lipoproteins and triglycerides in the 
inclisiran + usual care group compared to usual care 
group at Day 330 
• 
Percent change and absolute 
change from baseline in apoB 
• 
Percent change and absolute 
change from baseline in VLDL 


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Objective(s) 
Endpoint(s) 
• 
Percent change and absolute 
change from baseline in non-
HDL-C 
• 
Percent change and absolute 
change from baseline in total 
cholesterol 
• 
Percent change and absolute 
change from baseline in Lp(a) 
• 
Percent change and absolute 
change from baseline in HDL-C 
• 
Percent change and absolute 
change from baseline in 
triglycerides 
• 
To assess changes in and adherence to background 
lipid-lowering therapy in the inclisiran + usual 
care group compared to usual care group at Day 330 
• 
Intensity of lipid lowering therapy 
(decrease in dose, no change in 
dose, increase in dose) 
• 
Proportion of days covered (total 
number of days on either statin, 
ezetimibe, or PCSK9 inhibiting 
monoclonal antibody therapies 
divided by total number of study 
days) 
• 
Discontinuation of statin therapy 
(i.e., no statin use ≥ 30 days 
before the end-of-study visit) 
(yes, no) 
• 
To assess overall safety and tolerability of inclisiran 
• 
Adverse events 
Exploratory objective(s) 
Endpoint(s) for exploratory 
objective(s) 


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Objective(s) 
Endpoint(s) 
• 
To assess major adverse cardiovascular events 
(MACE) (investigator determination) in the inclisiran + 
usual care group compared to usual care group at Day 
330 
• 
Cardiovascular death (yes, no) 
• 
Non-fatal MI (yes, no) 
• 
Resuscitated cardiac arrest (yes, 
no) 
• 
Non-fatal ischemic stroke (yes, 
no) 
• 
Composite MACE (cardiovascular 
death, non-fatal MI, resuscitated 
cardiac arrest, or non-fatal 
ischemic stroke) (yes, no) 
2.1 
Primary estimands 
The estimand is the precise description of the treatment effect and reflects strategies to address 
events occurring during the trial conduct which could impact the interpretation of the trial 
results (e.g., premature discontinuation of treatment).   
The primary clinical question of interest in this study is to evaluate the effect on LDL-C of 
implementation of an LDL-C management care pathway with inclisiran versus usual care in 
participants who are discharged after an ACS on statin therapy or have documented statin 
intolerance and do not have their LDL-C at the target level. The justification for the primary 
estimand is that it will evaluate the LDL-C lowering effect of inclisiran on both the percent 
change in LDL-C and the achievement of the target LDL-C (<70 mg/dL) compared to a usual 
care of implementation pathway in participants following a recent ACS, including potential 
changes in concomitant therapy. Further details can be found in Section 12.  
Primary estimand 1: The primary analysis of primary efficacy variable 1 (percent change from 
baseline in LDL-C) to address the primary objective will be based on the following estimand: 


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• Population: Defined through appropriate inclusion/exclusion criteria to reflect the 
targeted population 
• Variable: Percent change from baseline in LDL-C [The primary analysis time point is 
at Day 330.] 
• Treatment: Inclisiran + usual care or usual care  
•  
• Remaining intercurrent events: 1. Potential use of inclisiran by participants in the usual 
care group. This intercurrent event will be ignored in the analysis, as the design of the 
trial allows for participants in the usual care group to potentially use inclisiran. 2. 
Discontinuation of study treatment.  This intercurrent event will be ignored in the 
analysis. 
• Summary measure: Least-squares mean difference between inclisiran + usual care 
group and usual care group 
Primary estimand 2: The primary analysis of primary efficacy variable 2 (achieving LDL-C < 
70 mg/dL) to address the primary objective will be based on the following estimand: 
• Population: Defined through appropriate inclusion/exclusion criteria to reflect the 
targeted population 
• Variable: Achieving LDL-C < 70 mg/dL (yes, no) [The primary analysis time point is 
at Day 330.] 
• Treatment: Inclisiran + usual care or usual care  
• Remaining intercurrent events: 1. Potential use of inclisiran by participants in the usual 
care group. This intercurrent event will be ignored in the analysis, as the design of the 
trial allows for participants in the usual care group to potentially use inclisiran. 2. 
Discontinuation of study treatment.  This intercurrent event will be ignored in the 
analysis. 
• Summary measure: Odds ratio of inclisiran + usual care to usual care for achieving 
LDL-C < 70 mg/dL 
2.2 
Secondary estimands 
Not applicable. 
3 
Study design 
This is a randomized, parallel-group, open-label, multicenter study comparing an LDL-C 
management strategy including inclisiran plus usual care with usual care  A total of 
approximately 384 participants will be randomized 1:1 to aggressive LDL-C management with 
inclisiran plus usual care (intervention arm) and usual care (control arm). Identification of 
participants will take place during hospitalization or in the weeks following discharge with 
screening soon thereafter. Screening of participants must take place within 5 weeks after 
discharge. 
Potential participants who are discharged after an ACS on statin therapy (which is considered 
routine care) or have documented statin intolerance will be screened and receive an LDL-C test 


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within 5 weeks post-discharge (to allow for the realization of the full effect of statin therapy). 
After the LDL-C test, participants with an LDL-C ≥70 mg/dL are eligible for the trial as long 
as they meet all other inclusion criteria. Participants will be randomized to inclisiran + usual 
care or usual care. All participants will be maintained on statin therapy during inclisiran 
treatment, but concomitant lipid-lowering therapy and LDL-C assessments will be at the 
discretion of the treating (primary) physician, mimicking real-world clinical decision-making 
and enabling the evaluation of inclisiran compared to usual care in patients with a recent ACS. 
Usual care may therefore include addition of ezetimibe, PCSK9-inhibiting monoclonal 
antibodies and/or commercially available inclisiran (Note: participants treated with inclisiran 
should not be treated with PCSK9-inhibiting monoclonal antibodies). After randomization, the 
treating physician will not have access to LDL-C values obtained as part of the study but will 
be able to perform LDL-C assessments at their discretion, to mimic usual care. The rationale of 
not providing the treating physician the LDL-C values obtained as part of the study is that those 
results might influence decisions made by him/her and could therefore undermine “usual care”. 
Commercially available inclisiran may be used for appropriate patients in the usual care arm at 
the sole discretion of the treating physician, without any influence from the PI.  LDL-C 
measurement and assessment of lipid lowering medications at each visit will be performed to 
assess adherence to background statin therapy. 
The collection of data from trial sites through eCRFs may also be complemented with EHR 
data and claims data (e.g., lipid measurements and concomitant medications), if available. 
While study visits will be preferentially performed in-person at the study sites, phone 
or virtual home-visits are an acceptable alternative if in-person visits are not permitted or 
impractical (e.g., due to a public health emergency). Site or home health nursing service may 
be used to assist with blood draws and/or study medication administration if required at these 
visits. Informed consent forms will be available in English and Spanish. 
Figure 3-1 
Study Design 
 


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Remote 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 according to Table 8-1 Assessment schedule performed at a remote location. 
Procedures will be performed remotely under the oversight of the Investigator, who retains 
accountability for the oversight and all efficacy and safety decisions with delegation of tasks to 
an off-site healthcare professional.  
If allowable by a local Health Authority and depending on operational capabilities, phone calls, 
virtual contacts (e.g. tele consult) or visits by site or 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. Any off-site healthcare professionals utilized during the trial 
must be agreed with Novartis before use. In addition to procedures performed by the off-site 
healthcare professional, the on-site staff will perform certain procedures remotely using tele-
visits. 
4 
Rationale 
4.1 
Rationale for study design 
Following an ACS, patients are at increased risk of recurrent ischemic events. Lowering LDL-
C reduces the risk of recurrent events in patients with ASCVD, with a magnitude of clinical 
benefit that is proportional to the reduction in LDL-C levels. In view of the high risk of recurrent 
events in patients with a recent ACS, early initiation of aggressive lipid-lowering therapy, 
including non-statin therapies, is particularly beneficial. 
Clinical care pathways for patients with a recent ACS, as endorsed by clinical treatment 
guidelines, include discharge on high-intensity statin therapy and follow-up with LDL-C 
measurement four to twelve weeks post-discharge, and consideration of non-statin therapies 
(e.g., ezetimibe and/or a PCSK9 inhibiting monoclonal antibody) if a patient has a less-than 
50% reduction in LDL-C or an LDL-C ≥70 mg/dL.  Despite these treatment options only a 
minority of patients who are eligible actually receive non-statin therapies in current clinical 
practice and as a result, most patients will not reach their target LDL-C level.  The poor 
management of blood cholesterol is partly a consequence of clinical inertia and partly a 
consequence of limitations of currently available non-statin therapies (i.e., ezetimibe has a 
limited LDL-C lowering effect and PCSK9 inhibiting monoclonal antibodies require patient 
self-administration by injection every 2 to 4 weeks). The one-year study duration of this trial 
will enable comparison of LDL-C lowering strategies in participants following an ACS using 
inclisiran compared to usual care. 
Additional important considerations of the study design include: 
• Recruitment: Potentially eligible participants, recently hospitalized for an ACS (in-
patient/out-patient), will be identified by the primary investigator and be invited to contact 
the research site for screening and inclusion. Eligible participants will need to consent to 
having health records made available as part of the collection of medical and pharmacy 
claims in order to assess healthcare resource utilization during the study. 


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• Responsibilities of principal investigator: Study visits will be done by the principal 
investigator while routine care is performed by the participant's own treating physician. As 
a consequence, the treating physician will not see participants more frequently due to trial 
participation and will not be aware of the laboratory assessments performed in the context 
of the study (routine or usual care laboratory tests and changes in therapy are at their 
discretion).  
• Open label: The study will be performed as an open-label study to mimic decision 
making in usual care, following from the primary objective of the study. For example, if 
the study would have been performed as a double-blind placebo-controlled study, it would 
not be possible to study the effect of inclisiran treatment on statin discontinuation as 
participants and investigators would not be aware of treatment allocation. 
• Duration of study period: The study is designed as a one-year trial with a total of three 
inclisiran doses. The Phase III trials of inclisiran had a follow-up duration of 18 months. 
In the Phase II trial (ORION-1), it was shown that the second dose at Day 90 lowers LDL-
C to a slightly greater level then after the initial administration (Ray et al 2017). Based on 
these trials, the maximum reduction in LDL-C is achieved approximately 4 to 5 months 
after initiation of therapy. Prior studies have shown that approximately one-third of 
patients discontinue statin therapy in the three years following initiation of therapy 
(Khunti et al 2018). A follow-up duration of one year enables: 1) observation of the 
steady-state LDL-C lowering effect of inclisiran, 2) observation of a meaningful 
difference in statin discontinuations, should such a difference exist, and 3) observation of 
potential differences in variables that likely require longer-term treatment of inclisiran to 
become apparent, such as patient reported outcomes. 
Implementation of a systematic LDL-C management pathway including treatment with 
inclisiran in participants who have experienced an ACS and have an LDL-C ≥70 mg/dL, despite 
receiving  statin therapy, could increase the proportion of participants who reach acceptable 
LDL-C levels and thereby lower the risk of recurrent ischemic events in these 
participants.  Inclisiran has not been previously evaluated in patients with a recent ACS. In this 
context, we aim to assess the LDL-C lowering effects of aggressive LDL-C management with 
inclisiran in patients with a previous hospitalization for an ACS. 
4.1.1 
Rationale for choice of background therapy 
Participants are required to be receiving statin therapy, or have documentation of statin 
intolerance, at the time of identification and screening (~2-5 wks following an ACS) without 
plans to adjust lipid lowering therapy at that point in time. Adjustments in lipid-lowering 
therapy other than inclisiran during the study will occur at the discretion of the treating 
(primary) health care practitioner in both treatment groups, mimicking real-world clinical 
decision-making. Inclisiran will not be excluded from the usual care group post-approval – it is 
assumed based on historical and anticipated product uptake shortly after launch that potential 
inclisiran treatment in the usual care group will be minimal and thus will not significantly 
interfere with the study. Participants receiving inclisiran during the trial should not be 
simultaneously treated with a PCSK9 inhibiting monoclonal antibody. 


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4.2 
Rationale for dose/regimen and duration of treatment 
Previous studies have shown that a 300 mg dose of inclisiran sodium is well tolerated and 
provides maximum efficacy (i.e., doses higher than 300 mg did not provide additional efficacy 
in LDL-C lowering). The 300 mg dose of inclisiran will be administered on Day 0, Day 90 and 
Day 270, consistent with the dose and dosing regimen that was studied in the Phase III trials. 
Modelling and simulation have demonstrated that the 300 mg dose of inclisiran results in 
sustained reductions in LDL-C (Ray et al 2017). A treatment duration of one year will be 
sufficient to assess changes in LDL-C due to inclisiran and changes in concomitant lipid-
lowering therapy. 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
Not applicable. 
4.4 
Purpose and timing of interim analyses/design adaptations 
 After all participants complete their baseline visit, the demographic and baseline characteristics 
may be summarized to help design new studies. 
4.5 
Risks and benefits 
Appropriate eligibility criteria and specific dose-limiting toxicity definitions, as well as specific 
dose modification and stopping rules, are included in this protocol. The risk to participants in 
this trial may be minimized by compliance with the eligibility criteria and study procedures, as 
well as close clinical monitoring, and stopping rules. 
Participants taking part in this clinical study will receive statin therapy and/or other LDL-C 
lowering therapies as considered necessary by their treating physician and consistent with 
standard of care. Reduction of LDL-C has been associated with reduced CV risk both by 
epidemiology and in controlled clinical trials. Modification of concomitant therapy is at the 
discretion of the participants’ treating physician. Additionally, study assessments and frequent 
visits will provide close monitoring of participants’ conditions and may provide information 
that may benefit post-ACS patients in the future. 
Support for the planned administration of inclisiran to participants with elevated LDL-C is 
provided by the following: 
• Inclisiran has been studied in a Phase III program for the patient population eligible 
for this study.  
• Injection site reaction is the only adverse event known to be attributed to inclisiran 
treatment. To date, all injection site reactions were localized, predominantly mild or 
occasionally moderate, transient, and resolved without sequelae. 
• The potential for immunogenicity of inclisiran was shown to be low. 
• Reduction of LDL-C has been associated with reduced CV risk both by epidemiology 
and in controlled clinical trials.  
 


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Women of child-bearing potential and sexually active males 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. 
4.6 
Rationale for Public Health Emergency mitigation procedures 
During a Public Health emergency as declared by Local or Regional authorities, i.e. pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity 
are listed in relevant sections. 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 
This study will include male or female participants ≥18 years of age with a recent 
hospitalization (in-patient/out-patient) for an ACS (within 5 weeks) and elevated LDL-C (≥70 
mg/dL) despite being treated with statin therapy by their health care practitioner. We plan to 
randomize approximately 384 participants at up to approximately 130 US sites. 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Males and females ≥18 years of age 
2. Recent ACS (in-patient/out-patient) within 5 weeks of screening, defined as: 
Ischemic symptoms with unstable pattern, occurring at rest or minimal exertion within 24 
hours of an unscheduled hospital admission or emergency department visit, due to 
presumed or proven obstructive coronary disease AND at least one of the following: 
a. Elevated cardiac biomarkers (cardiac troponin (cTn) or the MB fraction of creatinine 
kinase  (CKMB)) with at least one value above the 99th percentile of the upper 
reference limit (URL) or defined by the local laboratory MI diagnosis cut-off 
values  OR 
b. Resting ECG changes consistent with ischemia or infarction AND additional evidence 
of obstructive coronary disease 
3. Serum LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL 
4. Fasting triglycerides <4.52 mmol/L (<400 mg/dL) at screening 
5. Calculated glomerular filtration rate >20 mL/min by estimated glomerular filtration rate 
(eGFR) 
6. Participants must be willing and able to give informed consent before initiation of any 
study related procedures and willing to comply with all required study procedures 
7. Participants are required to be on statin therapy, or have documented statin intolerance, as 
determined by the investigator, following hospitalization (in-patient/outpatient) for an 
ACS. Statin intolerant patients are eligible if they had intolerable side effects on at least 2 
different statins, including one at the lowest standard dose. 


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5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. Any uncontrolled or serious disease, or any medical or surgical condition, that may either 
interfere with participation in the clinical study, and/or put the participant at significant 
risk (according to investigator’s [or delegate] judgment) if he/she participates in the 
clinical study. 
2. An underlying known disease, or surgical, physical, or medical condition that, in the 
opinion of the investigator (or delegate) might interfere with interpretation of the clinical 
study results. 
3. New York Heart Association (NYHA) class IIIb or IV heart failure or last known left 
ventricular ejection fraction <25%. 
4. Significant cardiac arrhythmia within 3 months prior to randomization that is not 
controlled by medication or via ablation at the time of screening. 
5. Uncontrolled severe hypertension: systolic blood pressure >180 mmHg or diastolic blood 
pressure >110 mmHg prior to randomization (assessed at screening visit) despite 
antihypertensive therapy. 
6. Recurrent acute coronary syndrome event within 2 weeks prior to randomization.  
7. Coronary angiography and revascularization procedure (PCI or CABG surgery) performed 
within 2 weeks prior to the randomization visit or planned after randomization.   
8. Severe concomitant non-cardiovascular disease that carries the risk of reducing life 
expectancy to less than 2 years. 
9. History of malignancy that required surgery (excluding local and wide-local excision), 
radiation therapy and/or systemic therapy during the three years prior to randomization. 
10. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using basic methods of contraception during dosing of 
investigational drug. Basic contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow up hormone level assessment 
• Male sterilization (at least 6 months prior to screening). For female participants on the 
study, the vasectomized male partner should be the sole partner for that subject 
• Barrier methods of contraception: Condom or Occlusive cap (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) 


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In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking investigational drug. 
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy), total hysterectomy or 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. 
11. Treatment with other investigational products or devices within 30 days or five half˗lives 
of the screening visit, whichever is longer. 
a. Approved vaccines or vaccines used under Emergency Use 
Authorization  should not be considered part of this exclusion criteria. 
Patients can receive COVID vaccines during inclisiran trials. 
b. While use of COVID anti-viral therapies approved for use under 
Emergency Use Authorization would need to adhere to the washout period 
outlined above, prior to screening, they would not be considered as criteria 
for trial termination/discontinuation. 
12. History of hypersensitivity to any of the study treatments or its excipients or to drugs of 
similar chemical classes. 
13. Planned use of other investigational products or devices during the course of the study. 
14. Any condition that according to the investigator could interfere with the conduct of the 
study, such as but not limited to: 
a. Participants who are unable to communicate or to cooperate with the 
investigator. 
b. Unable to understand the protocol requirements, instructions and study-related 
restrictions, the nature, scope, and possible consequences of the study 
(including participants whose cooperation is doubtful due to drug abuse or 
alcohol dependency). 
c. Unlikely to comply with the protocol requirements, instructions, and study-
related restrictions (e.g., uncooperative attitude, inability to return for follow-
up visits, and improbability of completing the study). 
d. 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. 
e. Persons directly involved in the conduct of the study. 
15. Treatment with monoclonal antibodies directed towards PCSK9 or inclisiran within 90 
days of screening. 
16. Active liver disease defined as any known current infectious, neoplastic, or metabolic 
pathology of the liver or (ii) alanine aminotransferase (ALT) elevation >3x ULN, aspartate 
aminotransferase (AST) elevation >3x ULN, or total bilirubin elevation >2x ULN (except 


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patients with Gilbert’s syndrome) at screening confirmed by a repeat measurement at least 
one week apart. 
6 
Treatment 
6.1 
Study treatment 
All eligible participants will be randomized to receive either inclisiran + usual care or usual 
care (standard of care per treating physician). The following study treatment will be provided: 
Inclisiran (KJX839), 284 mg, 1.5 ml Liquid in a single-use prefilled syringe (PFS) for s.c. 
administration. 
6.1.1 
Investigational and control drugs 
Table 6-1 
Investigational and control drug 
Investigational/ 
Control Drug  
(Name and 
Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Sponsor (global 
or local) 
Inclisiran, 
KJX839 284 mg 
1.5 ml  
PFS, Liquid for 
injection 
 s.c. 
Inclisiran sodium 
300 mg / 1.5 ml 
(equivalent to 284 
mg of inclisiran) 
Sponsor (local) 
6.1.2 
Additional study treatments 
No other treatment beyond investigational drug and usual care are included in this trial. 
6.1.3 
Treatment arms/group 
Participants will be assigned  at Visit 2/Baseline to one of two treatment groups (inclisiran + 
usual care and usual care) in a ratio of 1:1 to require approximately 384 participants (192 
participants per treatment group) to be randomized. 
6.1.4 
Treatment duration 
The planned duration of treatment is 330 days from randomization. Participants may be 
discontinued from treatment at any time due to adverse events, disease progression and/or at 
the discretion of the investigator or the participant.  
6.2 
Other treatment(s) 
Not applicable 
6.2.1 
Concomitant therapy 
All prior cardiovascular medications (e.g., antiplatelets (aspirin, thienopyridines), non-vitamin 
K oral anticoagulants (NOACs), beta-blockers, ACE-inhibitors or ARBs, other 
antihypertensives, antidiabetics, and lipid lowering therapies) administered before the 


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participant is enrolled in the study but still receiving must be recorded in the appropriate Case 
Report Forms, or where applicable, sourced from the EHR and mapped into the clinical study.  
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the participant is enrolled into the study must be recorded 
on the appropriate Case Report Forms. 
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. 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
Not applicable 
6.2.2 
Prohibited medication 
The treatments displayed in the table below are not allowed to be used simultaneously with 
inclisiran in the treatment arm.  No modifications of therapy is required or recommended in the 
usual care arm. 
Table 6-2 
Prohibited medication 
Medication 
Prohibition period 
Action to be taken 
Alirocumab (Praluent) 
Participants randomized to 
inclisiran: monoclonal 
antibodies directed against 
PCSK9 are prohibited for the 
full duration of the study  
Discontinue PCSK9 inhibitor 
Evolocumab (Repatha) 
Participants randomized to 
inclisiran: monoclonal 
antibodies directed against 
PCSK9 are prohibited for the 
full duration of the study  
Discontinue PCSK9 inhibitor 
6.3 
Participant numbering, treatment assignment, randomization 
6.3.1 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. 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 to the site. 


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6.3.2 
Treatment assignment, randomization 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and investigator staff. A 
participant randomization list will be produced by the IRT system 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 groups, which in 
turn are linked to medication numbers. A separate medication list will be produced by or under 
the responsibility of Novartis Drug Supply Management using a validated system that 
automates the random assignment of medication numbers to the package containing the 
investigational drug(s).  
At Visit 2/Baseline, all eligible participants will be randomized via Interactive Response 
Technology (IRT) to one of the two treatment groups in 1:1 ratio (inclisiran + usual care vs 
usual care). 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 group and 
will specify a unique medication number for the first package of study treatment to be dispensed 
to the participant. 
The randomization scheme for participants will be reviewed and approved by a member of the 
Novartis Biometrics group. 
6.4 
Treatment blinding 
This is an open-label study and study treatment is not blinded, thus treatments will be known to 
participants, investigator staff, including persons performing the study assessments. 
6.5 
Dose escalation and dose modification 
Dose interruptions for the investigational study medication (inclisiran) are not permitted. 
If a planned dose is missed by less than 3 months, administer inclisiran and maintain dosing 
according to the participant’s original schedule. If a planned dose is missed by more than 3 
months, start a new dosing schedule - administer inclisiran initially, again at 3 months, and 
followed by dosing, thereafter, every 6 months.  
Dose interruptions must be recorded on the inclisiran Dose Administration case report form for 
the investigational study drug. 
6.5.1 
Dose modifications 
Study drug administration of inclisiran [inclisiran (KJX839), 284 mg liquid in PFS, 1.5 ml] 
should be temporarily interrupted or permanently discontinued in participants with: 
1. Intolerable AEs, or if the investigator believes that continuing dosing will be detrimental 
to the participant’s mental or physical health.  This includes severe or serious reactions 
at the injection site and any anaphylactic type reactions. 
2. Liver laboratory values meeting the study drug interruption criteria listed in Table 16-4 
and Table 16-5.   


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3. Unexplained creatine kinase (CK) values >5 x ULN confirmed by repeat test when the 
CK elevation is associated with muscle pain, muscle tenderness and/or muscle 
weakness, or new onset renal dysfunction. 
Study treatment may be restarted at the discretion of the investigator, if the reason for 
discontinuation has resolved. 
The dose interruptions must be recorded on an appropriate eCRF. 
6.5.2 
Follow-up for toxicities 
6.5.2.1 
Follow up on potential drug-induced liver injury (DILI) cases 
 Participants with transaminase increase combined with total bilirubin increase may be 
indicative of potentially severe DILI, and should be considered as clinically important events 
and assessed appropriately to establish the diagnosis. The required clinical information, as 
detailed below, should be sought to obtain the medical diagnosis of the most likely cause of the 
observed laboratory abnormalities. 
The threshold for potential DILI may depend on the participant’s baseline AST/ALT and total 
bilirubin value; participants meeting any of the following criteria will require further follow-up 
as outlined below: 
• For participants with normal ALT and AST and total bilirubin value at baseline: AST or 
ALT > 3.0 x ULN combined with total bilirubin > 2.0 x ULN 
• For participants with elevated AST or ALT or total bilirubin value at baseline: [AST or 
ALT > 2 x baseline] OR [AST or ALT >300 U/L] whichever occurs first combined with 
[total bilirubin > 2 x baseline AND > 2.0 x ULN 
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered and their role clarified before DILI is assumed as the cause of liver injury. 
A detailed history, including relevant information such as review of ethanol consumption, 
concomitant medications, herbal remedies, supplement consumption, history of any pre- 
existing liver conditions or risk factors, should be collected. 
Laboratory tests should include ALT, AST, total bilirubin, direct and indirect bilirubin, gamma- 
glutamyl transferase (GGT), glutamate dehydrogenase (GLDH), prothrombin time 
(PT)/International Normalized Ratio (INR), alkaline phosphatase (ALP), albumin, and CK. 
Perform relevant examinations (Ultrasound or Magnetic resonance imaging (MRI), Endoscopic 
retrograde cholangiopancreatography (ERCP)) as appropriate, to rule out an extrahepatic cause 
of cholestasis. Cholestasis (is defined as an ALP elevation > 2.0 x ULN with R value < 2 in 
participants without bone metastasis, or elevation of the liver-specific ALP isoenzyme in 
participants with bone metastasis). Note: The R value is calculated by dividing the ALT by the 
ALP, using multiples of the ULN for both values. It denotes whether the relative pattern of ALT 
and/or ALP elevation is due to cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and 
< 5) liver injury. For children, there are caveats to calculating the R-ratio as normal levels of 
ALP are higher than in adults with standard ranges varying by developmental age. In clinical 
situations where it is suspected that ALP elevations are from an extrahepatic source, the GGT 


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can be used if available. GGT may be less specific than ALP as a marker of cholestatic injury, 
since GGT can also be elevated by enzyme induction or by ethanol consumption. It is more 
sensitive than ALP for detecting bile duct injury (https://livertox.nih.gov/rucam.html). 
Table 6-3 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 6-3  
Guidance on specific clinical and diagnostic assessments which can 
be performed to rule out possible alternative causes of observed LFT 
abnormalities 
Disease 
Assessment 
Hepatitis A, B, C, E 
IgM anti-HAV; HBsAg, IgM & IgG anti-HBc, HBV 
DNA; anti-HCV, HCV RNA, IgM & IgG anti-HEV, 
HEV RNA 
CMV, HSV, EBV infection 
IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & 
IgG anti-EBV 
Autoimmune hepatitis 
ANA & ASMA titers, total IgM, IgG, IgE, IgA 
Alcoholic hepatitis 
Ethanol history, GGT, MCV, CD-transferrin 
Nonalcoholic steatohepatitis 
Ultrasound or MRI 
Hypoxic/ischemic hepatopathy 
Medical history: acute or chronic CHF, 
hypotension, hypoxia, hepatic venous occlusion. 
Ultrasound or MRI 
Biliary tract disease 
Ultrasound or MRI, ERCP as appropriate 
Wilson disease (if <40 yrs old) 
Caeruloplasmin 
Hemochromatosis 
Ferritin, transferrin 
Alpha-1-antitrypsin deficiency 
Alpha-1-antitrypsin 
Other causes should also be considered based upon participants’ medical history 
(hyperthyroidism / thyrotoxic hepatitis – T3, T4, TSH; CVD / ischemic hepatitis – ECG, prior 
hypotensive episodes; T1D / glycogenic hepatitis). 
Following appropriate causality assessments, as outlined above, the causality of the treatment 
is estimated as “probable” i.e. >50% likely, if it appears greater than all other possible causes 
of liver injury combined. The term “treatment-induced” indicates probably caused by the 
treatment, not by something else, and only such a case can be considered a DILI case and should 
be reported as an SAE. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified, should be considered as “medically 
significant,” and thus, meet the definition of SAE and should be reported as SAE using the term 
“potential treatment-induced liver injury.” All events should be followed up with the outcome 
clearly documented. 


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6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
Compliance will be ensured by the investigator and/or study personnel at each dosing visit. This 
information should be captured in the source document at each visit. Study drug (inclisiran) 
accountability will also be determined by the site monitor while performing routine site visits 
and at the completion of the study. 
Duration of study drug exposure will be calculated based upon the dates recorded in the eCRF. 
6.7 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section (Section 6.1.1). 
A unique medication number is printed on the study medication label. 
Investigator staff will identify the study medication kits to dispense to the participant by 
contacting the IRT and obtaining the medication number(s). The study medication has a 2-part 
label (base plus tear-off label), immediately before 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. 
All kits of study treatment assigned by the IRT will be recorded in the IRT system. 
As per Section 4.6, during a Public Health emergency that limits or prevents on-site study visits, 
a home health nurse is permitted to administer the study medication at a participant's home (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. The dispatch of study medication from the site to the participant’s home remains 
under the accountability of the Investigator. 
6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
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 US Quality Assurance representative. 
Medication labels 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 
monitors during site visits or remotely and at the completion of the trial.  


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At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the 
investigator folder at each site. 
6.7.2 
Instruction for prescribing and taking study treatment 
Packaging and Labeling 
Investigational product [Inclisiran (KJX839), 284 mg Liquid PFS, 1.5 ml] will be provided by 
the sponsor. Medication labels will comply with regulatory requirements. The storage 
conditions will be described on the medication label. 
The container closure system for the prefilled syringe consists of a Type I glass syringe with a 
stainless steel 27G 1/2" staked needle covered by a removable rigid needle shield and Flurotech 
covered bromobutyl plunger. 
Table 6-4 
Dose and treatment schedule 
Investigational / Control Drug 
(Name and Strength) 
Dose 
Frequency and/or Regimen 
Inclisiran (KJX839), 284 mg 
Liquid in PFS, 1.5 mL 
Inclisiran sodium 300 mg/1.5 
mL (equivalent to 284 mg 
inclisiran), s.c. use 
Initially, 90 days later, 180 days 
after the second dose 
Participants will be administered a single SC injection of 300 mg Inclisiran sodium for injection 
at predefined time points as described in the Schedule of Assessments (Table 8-1). 
Investigational product injection will be administered by qualified clinical study site staff under 
the supervision of the investigator or designee. The site of injection is the abdomen, arm or 
thigh. Do not inject into areas of active skin disease or injury such as sunburns, skin rashes, 
inflammation, tattoos or skin infections.  
All kits of study treatment assigned by the IRT will be recorded in the IRT system. 
7 
Informed consent procedures 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 
If applicable, in cases where the 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 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 GCP guidelines and regulatory requirements and is considered 




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Participants will have to comply with the following restrictions during the study: 
• Participants need to fast for at least 8 hours for all visits (measurement of 
lipids/lipoproteins and blood glucose requires participants to be fasting).  If the 
participant has not fasted, the collection of laboratory evaluations must be rescheduled. 
• Blood donation will not be allowed at any time during the study 
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. 
As per Section 4.6, during a Public Health emergency 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. 
If a public health emergency limits or prevents on-site study visits, alternative methods of 
providing continuing care may be implemented. Virtual visits [e.g., phone calls, video visits 
(preferred)] or visits by site staff/home nursing service to the participant´s home depending on 
local regulations and capabilities, can replace on-site study visits, for the duration of a public 
health emergency until it is safe for the participant to visit the site again. 
Unscheduled Visits 
Participants may be seen at any time for an unscheduled visit, e.g., if they experience 
deterioration or AEs that in the opinion of the Investigator/qualified site staff requires closer 
monitoring. The assessment(s) performed at an unscheduled visit must include at a minimum: 
an assessment of concomitant medications, vital signs, and an AE/SAE assessment. Any 
additional assessments performed are at the Investigator/qualified site staff’s discretion.  






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8.1 
Screening 
A participant’s eligibility for the study will be assessed during the 30 day screening period (Day 
-30 to Day -1). Screening is flexible in duration based on the time required for participants to 
be evaluated for eligibility. It is permissible to re-screen a participant if s/he fails the initial 
screening; however, each case must be discussed and agreed with the Sponsor on a case-by-
case basis. 
8.1.1 
Information to be collected on screening failures 
Participants who sign an informed consent form and subsequently found to be ineligible will be 
considered a screen failure. It is permissible to re-screen a participant if he/she fails the initial 
screening; however, each case must be discussed and agreed with the Sponsor on a case-by-
case basis. If the re-screen is approved, a new participant number will be allocated to the 
participant and he/she will need to re-perform all Visit 1 procedures. A participant may be re-
screened once. The participant must provide new written informed consent before they are re-
screened. 
The reason for screen failure should be entered on the applicable Case Report Form. The 
demographic information, informed consent, and Inclusion/Exclusion pages must also be 
completed for screen failure participants. No other data will be entered into the clinical database 
for participants who are screen failures, unless the participant experienced a serious adverse 
event during the screening phase (see SAE section for reporting details). If the participant fails 
to be randomized, the IRT must be notified within 2 days of the screen failure that the participant 
was not randomized. 
Participants who are randomized and fail to start treatment (e.g., participants randomized in 
error) will be considered an early terminator. The reason for early termination should be 
recorded on the appropriate Case Report Form. 
8.2 
Participant demographics/other baseline characteristics 
Participant demographic and baseline characteristic data to be collected on all participants 
include age, sex, race, ethnicity, and source of patient referral. Any relevant medical history 
including surgical/medical procedures, protocol solicited medical history, and/or current 
medical conditions before obtaining informed consent will be recorded in the Medical History 
eCRF.  A detailed medical history (including cardiovascular and other conditions relevant to 
the study population to be enrolled) and current medical conditions present, including the 
presentation and management of index MI event will also be recorded.  Where possible, 
diagnoses and not symptoms, will be recorded. All medications and relevant medical histories 
will be recorded on the corresponding eCRFs. 
8.3 
Efficacy 
The primary efficacy variables are the following: 
1. Percent change from baseline in LDL-C 
2. Achieving LDL-C < 70 mg/dL (yes, no) 






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8.4 
Safety 
Safety assessments will consist of monitoring and recording of all adverse events and serious 
adverse events, evaluation of hematology, blood chemistry and urine values, regular 
measurement of vital signs and the performance of physical examinations. 
As per Section 4.6, during a Public Health emergency that limits or prevents on-site study visits 
regular phone or virtual calls should occur for safety monitoring and discussion of the 
participant´s health status until the participant can again visit the site. If a participant cannot 
visit the site to have pregnancy tests done, a home urine pregnancy test kit may be used. 
Participants can perform the urine pregnancy test at home at the time of the scheduled visit and 
report the result to the site, or a communication process should be established with the 
participant so that the site is informed of the pregnancy test results. If a visit by site staff or 
home nursing staff is arranged, 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.  
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed. 
For details on AE collection and reporting, refer to AE section. Please consult the Investigator's 
Brochure for the specific (non-routine) safety assessments. 
Table 8-2 
Safety Assessment 
Assessment 
Specification 
Physical  
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. 
A short physical exam will include the 
examination of general appearance and vital 
signs (blood pressure [SBP and DBP] and 
pulse). A short physical exam will be at all visits 
starting from visit 3 except where a complete 
physical examination is required (see above).  
Information for all physical examinations must 
be included in the source documentation at the 
study site. Clinically relevant findings that are 
present prior to signing informed consent must 
be recorded on the appropriate CRF that 
captures medical history. Significant findings 
made after signing informed consent which meet 
the definition of an Adverse Event must be 
recorded as an adverse event. 


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Vital signs 
Vital signs include 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 will be measured three times using a 
validated device, e.g. standard 
sphygmomanometer or an automated BP 
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 in the Assessment Schedule (Table 8-1). 
A central laboratory will be used for analysis of all specimens collected, with the exception of 
urine pregnancy tests and urine dipstick tests, which will be done locally at the site (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. 
In case of abnormal dipstick urinalysis results, microscopy and other assessments (e.g. serum 
albumin and serum total protein) will be performed at the local laboratory and the abnormality 
recorded as an AE. 
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse events as appropriate. 
Clinically notable laboratory findings are defined in Section 16.1 
Local laboratory assessments may be performed on an as-needed basis for unscheduled visits. 
Laboratory values that exceed the boundaries of a notable laboratory abnormality must be 
commented on by the investigator on the source document and additional laboratory evaluations 
should be performed, as judged appropriate by the investigator. If the laboratory abnormality 
induces clinical signs or symptoms, or requires therapeutic intervention, then the diagnosis or 
medical condition must be entered on the patient's AE eCRF. If the laboratory abnormality is 
the primary reason for an unforeseen hospitalization or otherwise fulfills the seriousness 
category of an AE, then the procedure for rapid notification of SAEs must be followed. 
Likewise, if the laboratory abnormality leads to discontinuation from the study drug 
(temporarily or permanently), the patient must be followed until the abnormality resolves or 
until it is judged to be permanent. This investigation may include continued monitoring by 
repeat laboratory testing or by performing additional laboratory tests as deemed necessary by 
the investigator or the Novartis medical monitor. 


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As per Section 4.6, during a Public Health emergency that limits or prevents on-site study visits, 
if a visit by site staff/home nursing staff is arranged, specimen samples should be collected 
during the visit and processed and handled in line with the study laboratory manual. 
Table 8-3 
Clinical Laboratory Assessments 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, MCH, MCHC, MCV, 
Platelet count,  White blood cell count with 
Differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils, Bands, 
Other)  
Chemistry 
Full serum chemistry:  Albumin, Alkaline 
phosphatase (ALP), ALT, AST, Gamma-
glutamyl-transferase (GGT), Lactate 
dehydrogenase (LDH), Bicarbonate, Calcium, 
Magnesium, inorganic Phosphate, Chloride, 
Sodium, Potassium, Creatinine, estimated 
Glomerular Filtration Rate (eGFR), Creatine 
kinase (CK), Direct Bilirubin, Indirect Bilirubin, 
Total Bilirubin (TBL), Total Cholesterol, LDL-C 
(direct), VLDL, HDL-C. Apolipoprotein B, Total 
Protein, Triglycerides, Blood Urea Nitrogen 
(BUN) or Urea, Uric Acid, Amylase, Lipase, 
Hemoglobin A1C, Glucose (fasting) and 
glycated hemoglobin (HbA1C) 
Limited serum chemistry (ONLY):  AST, ALT, 
ALP, GGT, TBL, CK, creatinine, eGFR, fasting 
glucose and HbA1C 
Coagulation 
Prothrombin Time (PT), International Normalized 
Ratio (INR) and Activated Partial 
Thromboplastin Time (aPTT) 
Urinalysis 
Macroscopic Panel (Dipstick) (Color, Bilirubin, 
Red Blood Cells/Erythrocytes, Glucose, 
Ketones, White Blood Cells/Leukocytes, Nitrite, 
pH, Protein, Specific Gravity, Urobilinogen) 
Microscopic Panel (only performed in the event 
of abnormalities) (Red Blood Cells, White Blood 
Cells, Casts, Crystals, Bacteria, Epithelial cells) 
Hepatitis markers 
HBV-DNA, HBsAg, HBsAb, HBcAb, HCV RNA-
PCR (polymerase chain reaction) (screening 
visit) 
Additional tests 
Lipoprotein(a) (Lp(a)) 
 
Pregnancy Test 
Serum / Urine pregnancy test 
8.4.2 
Electrocardiogram (ECG) 
A standard 12 lead ECG will be performed at Visit 1. Interpretation of the tracing must be made 
by a qualified physician and documented on the ECG section of the eCRF. Each ECG tracing 
should be labeled with the study, participant number and date and kept in the source documents 
at the study site. 


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Clinically significant abnormalities must be recorded on the CRF as either medical 
history/current medical conditions or adverse events as appropriate. 
8.4.3 
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have a serum pregnancy test 
(hCG) performed at Visit 1 (central lab). In addition, these participants will have a urine 
pregnancy test conducted at the local site for Visits 2, 3, 4 and 5. If any of these tests are positive 
at Visits 1 and 2, the participant should not be enrolled in the trial. If a participant should become 
pregnant during the trial, the participant may remain in the trial for follow-up visits but cannot 
continue to receive inclisiran injections if randomized to the inclisiran arm. 
During a Public Health emergency that limits or prevents on-site study visits, a urine home 
pregnancy test kit may be used. Relevant participants can perform the urine pregnancy test at 
home and report the result to the site. If a visit by site staff/home nursing staff is arranged, it is 
important that participants perform the urine pregnancy test first, and only if the test result is 
negative, proceed with the administration of the study treatment. 
8.4.4 
Other safety evaluations 
Injection site reactions 
Injection site reactions (ISR) should be monitored at each visit from the Randomization (Day 
1) visit onwards (Table 8-1) and through additional contacts with the participant between visits 
as needed.  ISR including individual signs or symptoms at the injection site following study 
treatment administration should be recorded on an appropriate eCRF page.  Every effort should 
be made to follow-up with the participant until resolution of the ISR. 
Anaphylactic reactions 
Potential anaphylactic reactions should be assessed by Sampson criteria in Section 16.4 
(Appendix 4).  
Hyperglycemia-related events 
Laboratory results and newly added concomitant medications should be checked for potential 
hyperglycemia-related AEs.   
‘New onset of diabetes’ should be reported as AE on the eCRF in participants with no medical 
history of diabetes when: 
• HbA1c becomes ≥6.5% and/or 
• Two consecutive values of FPG are ≥126 mg/dL (7.0 mmol/L) 
• If a new concomitant medication for control of plasma glucose is added, further 
information to assess for a diagnosis of new onset diabetes will need to be collected  
‘Worsening of glycemic control’ should be reported as AE on the eCRF in participants with a 
medical history of diabetes (HbA1c ≥6.5% at baseline) when: 
• HbA1c increases from baseline >0.5% 






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If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s premature discontinuation of study 
treatment and record this information. 
Participants who discontinue study treatment or who decide they do not wish to participate in 
the study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see 'Withdrawal of Informed Consent' section). Where possible, they should 
return for the assessments indicated in the Assessment Schedule. If they fail to return for 
these assessments for unknown reasons, every effort (e.g., telephone, e-mail, letter) should be 
made to contact the participant/pre-designated contact as specified in the lost to follow-up 
section. This contact should preferably be done according to the study visit schedule.  Unless a 
participant withdraws informed consent, personal and coded data are able to be collected in 
accordance with the informed consent form. 
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the 
participant. This telephone contact should preferably be done according to the study visit 
schedule. 
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact: 
• New / concomitant treatments 
• Adverse Events / Serious Adverse Events 
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 
9.1.2 
Withdrawal of informed consent 
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a participant: 
• Does not want to participate in the study anymore, 
and 
• Does not want any further visits or assessments 
and 
• Does not want any further study related contacts 
In this situation, the investigator should make a reasonable effort (e.g., telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw his/her consent and 
record this information. 
Study treatment for participants in the inclisiran + usual care treatment group must be 
discontinued with no more inclisiran injections planned. In both the inclisiran + usual care and 
the usual care group no further assessments are to be 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. 


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All efforts should be made to complete the assessments prior to study discontinuation. A final 
evaluation at the time of the participant’s study discontinuation should be made as detailed in 
the assessment table. 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation. 
9.1.3 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the participant, e.g., dates of 
telephone calls, registered letters, etc. A participant should not be considered as lost to follow-
up until due diligence has been completed or until the end of the study. 
9.1.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time. 
Reasons for early termination, include 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 prematurely withdrawn participant. The investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the participant’s interests. The investigator or sponsor depending on local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial.  
9.2 
Study completion and post-study treatment 
At the study completion/end of study visit, including participants who are prematurely 
withdrawn from the study, the referring or primary physician will continue to provide ongoing 
medical care. When the participant has completed all scheduled study assessments, the 
investigator must call the IRT to record the participant completion in the IRT. 
Study completion is defined as when the last participant finishes their Study Completion visit 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the investigator or, in the event of an early study termination decision, the date 
of that decision (e.g., each participant will be required to complete the study in its entirety and 
thereafter there will be no further study treatments provided (i.e., no further inclisiran injections 
will be conducted). 
For study participants who have successfully completed the study, further guidance will be 
provided separately concerning continuation of treatment and access to investigational 
drug.  This guidance will be provided to sites prior to the completion visit of the first patient 


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(first patient last visit). For study participants who terminate prior to the end of the study or who 
withdraw from treatment, continuing treatment should be managed by the investigator and/or 
referring or primary physician 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
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 adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments.  
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. The severity grade  
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e., progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant 
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported 
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. Action taken regarding study treatment. 


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All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 
• Dose not changed 
• Dose Reduced/increased 
• Drug interrupted/withdrawn 
6. Its outcome (i.e., recovery status or whether it was fatal) 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g., continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB). 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of reference ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participants 
with the underlying disease. Alert ranges for laboratory abnormalities are included in 
Section 16.1 (Appendix 1). 
10.1.2 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 


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• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
- routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
- elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
- social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
- treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g., defined as an event that jeopardizes the participant or 
may require medical or surgical intervention to prevent one of the outcomes listed 
above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met 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 serious adverse 
event 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 30 days after the last study visit must be reported to 
Novartis safety within 24 hours of learning of its occurrence. Detailed instructions regarding 
the submission process and requirements are to be found in the investigator folder provided to 
each site. 
SAEs occurring after the participant has provided informed consent until the time the participant 
is deemed a Screen Failure must be reported to Novartis. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 


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different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
Any SAEs experienced after the 30 day period after the last study visit should only be reported 
to Novartis Safety if the investigator suspects a causal relationship to study treatment. 
10.1.4 
Pregnancy reporting 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
trial participant must be asked to read and sign pregnancy consent form to allow the Study 
Doctor ask about her pregnancy. To ensure participant safety, each pregnancy occurring after 
signing the informed consent must be reported to Novartis within 24 hours of learning of its 
occurrence. The pregnancy should be followed up 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 Chief Medical 
Office and Patient Safety (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 and 
any pregnancy outcome. Any SAE experienced during pregnancy must be reported. 
10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness. 


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Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
CRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with 
an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
10.2 
Additional Safety Monitoring 
10.2.1 
Liver safety monitoring 
To ensure 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 Appendix 2 (Section 16-2) for complete definitions of liver laboratory triggers. 
Once a participant is exposed to study treatment, every liver event defined in Table 16-3 should 
be followed up by the investigator or designated personnel at the trial site, as summarized 
below. Additional details on actions required in case of liver events are outlined in Table 16-4 
and Table 16-5. Repeat liver chemistry tests (i.e., ALT, AST, TBL, PT/INR, ALP and GGT) to 
confirm elevation. 
• These liver chemistry repeats will be performed using the central laboratory. If results 
will not be available from the central laboratory, then the repeats can also be 
performed at a local laboratory to monitor the safety of the participant. If a liver event 
is subsequently reported, any local liver chemistry tests previously conducted that are 
associated with this event should have results recorded on the appropriate CRF. 
• 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 can include based on investigator's discretion:  
- serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history 
of concomitant drug use, exclusion of underlying liver disease 
All follow-up information and procedures performed must be recorded as appropriate in the 
eCRF. 


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10.2.2 
Renal safety monitoring 
To ensure participant safety and enhance reliability in determining the nephrotoxicity potential 
of an investigational drug, a standardized process for identification, monitoring and evaluation 
of renal events has to be followed. Every renal laboratory trigger or renal event as defined 
in Table 16-6 in Appendix 3 (Section 16.3) should be followed up by the investigator or 
designated personnel at the trial site as summarized in Table 16-7 in Appendix 3 (Section 16.3). 
10.2.3 
Steering Committee 
A Steering Committee (SC) for this study will be established comprising medical experts and/or 
clinical investigators participating in the trial and Novartis representatives from the Clinical 
Trial Team. The SC will ensure transparent management of the study according to the protocol 
through recommending and approving modifications as circumstances require. The SC will 
provide input to the clinical study protocol and potential amendments to the clinical study 
protocol. Together with the clinical trial team, the SC will also develop recommendations for 
publications of study results including authorship rules. 
11 
Data Collection and Database management 
Efforts should be made to collect all data that are relevant to support a statistical analysis aligned 
with the estimands of interest. If the estimands that are required to support regulatory decision 
making do not require the collection of the variable after an intercurrent event, then the benefits 
of collecting such data for other estimands should be weighed against any complications and 
potential drawbacks of the collection. 
11.1 
Data collection 
Electronic CRF Collection 
Designated investigator staff will enter some or all of the data required by the protocol into the 
Electronic Case Report Forms (eCRF). The eCRFs have been built using fully validated secure 
web-enabled software that conforms to 21 CFR Part 11 requirements. Investigator site staff will 
not be given access to the EDC system until they have been trained in the use of the EDC system 
and data entry guidelines. Automatic validation program checks for data discrepancies in the 
eCRFs will be applied allowing modification and/or verification of the entered data by the 
investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on CRFs), (entered 
into CRF) 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 all 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. 


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11.2 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Dates of screenings, randomizations, screen failures and study completion, as well as 
randomization codes and data about inclisiran injections administered to the participant will be 
tracked using an Interactive Response Technology (IRT). The system will be supplied by a 
vendor, who will also manage the database. The data will be sent electronically to Novartis (or 
a designated CRO) at specific timelines. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked. Any changes to the database after that time can only 
be made after written agreement by Novartis study team management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis/UBC 
representative will review the protocol and data capture requirements (i.e., direct EHR data 
capture or eCRFs) with the investigators and their staff. During the study, Novartis employs 
several methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ 
data. The field monitor will conduct on-site or virtual monitoring visits to check the 
completeness of participant records, the accuracy of data capture / data entry, the adherence to 
the protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Video 
conferencing, electronic Trial Master File (eTMF) and remote source document review 
technologies will be utilized as needed to ensure that essential monitoring functions are 
supported when virtual monitoring visits are conducted. 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/UBC/CRA organization. Additionally, a central analytics organization may analyze 
data & identify risks & trends for site operational parameters, and provide reports to 
Novartis clinical teams to assist with trial oversight. 
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 


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participant's file.  The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 
12 
Data analysis and statistical methods 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
The analysis will be performed at the end of the trial, after the data for all participants are 
available. 
Unless otherwise specified, all statistical tests will be conducted against a two-sided alternative 
hypothesis, employing a significance level of 0.05. 
Efficacy, safety, and other data will be summarized. For continuous variables, summary 
statistics (mean, standard deviation, median, 25th and 75th percentiles, interquartile range, 
minimum, and maximum) at each time point and for change from baseline to each time point 
will be reported by treatment group. For discrete variables, frequency counts and percentages 
at each time point will be reported by treatment group. 
12.1 
Analysis sets 
The Full Analysis Set (FAS) comprises all randomized participants. According to the intent-to-
treat principle, participants will be analyzed according to the treatment group they have been 
assigned to during the randomization procedure. 
The Per-Protocol Set is a subset of the Full Analysis Set in which participants are not treated 
with any inclisiran if they are randomized to the usual care treatment group or do not have any 
major protocol deviations (including deviations from inclusion/exclusion criteria) in either 
treatment group.    
The Restricted Set 1 is a subset of the Full Analysis Set which includes only participants without 
changes in background lipid-lowering therapy. 
The Restricted Set 2 is a subset of the Full Analysis Set which includes only participants who 
received three doses of inclisiran in the inclisiran + usual care group (i.e., excludes patients in 
the inclisiran + usual care group who missed one or more doses) and all participants in the usual 
care group (including participants who may have used commercially available inclisiran). 
The Safety Set includes all participants who received study treatment. Participants will be 
analyzed according to the study treatment received, where treatment received is defined as the 
randomized/assigned treatment if the participant took at least one dose of that treatment or the 
first treatment received if the randomized/assigned treatment was never received.  


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12.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group for the Full Analysis Set. 
Relevant medical histories and current medical conditions at baseline (i.e., prior to first dose of 
study treatment) will be summarized by system organ class and preferred term, by treatment 
group for the Safety Set.  
12.3 
Treatments 
Concomitant medications and significant non-drug therapies prior to and after the start of 
treatment will be listed and summarized according to the Anatomical Therapeutic Chemical 
(ATC) classification system, by treatment group, for the Safety Set. 
12.4 
Analysis supporting primary objectives 
12.4.1 
Definition of primary endpoints 
The primary efficacy variables are the following: 
1. Percent change from baseline in LDL-C  
2. Achieving LDL-C < 70 mg/dL (yes, no) 
The primary analysis time point for both primary efficacy variables is at Day 330. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
The primary analysis of primary efficacy variable 1 to address the primary objective will be 
based on the following estimand: 
• Population: Defined through appropriate inclusion/exclusion criteria to reflect the 
targeted population 
• Variable: Percent change from baseline in LDL-C [The primary analysis time point is 
at Day 330.] 
• Treatment: Inclisiran + usual care or usual care 
• Remaining intercurrent events: 1. Potential use of inclisiran by participants in the usual 
care group. This intercurrent event will be ignored in the analysis, as the design of the 
trial allows for participants in the usual care group to potentially use inclisiran. 2. 
Discontinuation of study treatment.  This intercurrent event will be ignored in the 
analysis. 
• Summary measure: Least-squares mean difference between inclisiran + usual care 
group and usual care group 
The null hypothesis is that the mean percent change from baseline in LDL-C at Day 330 for 
inclisiran + usual care and usual care treatment groups are equal. The alternative hypothesis is 
that the mean percent change from baseline in LDL-C at Day 330 for inclisiran + usual care 
treatment group is not equal to that of the usual care treatment group. 


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Primary efficacy variable 1 will be analyzed using mixed-effects model repeated measures 
(MMRM) with treatment, visit, baseline, treatment-by-visit interaction, and baseline-by-visit 
interaction as explanatory variables. An unstructured working correlation matrix will be 
assumed for this model (Diggle et al 2002).  Least-squares mean of each treatment group, least-
squares mean treatment difference, two-sided 97.5% confidence interval for the treatment 
difference, and p-value based on the fitted MMRM will be reported for each applicable visit 
(day). If the p-value based on a two-sided test for treatment at Day 330 is < 0.025 and the 
corresponding least squares mean treatment difference ([inclisiran + usual care] - usual care) is 
less than 0, statistical significance in favor of inclisiran + usual care is shown.  All efforts will 
be made to follow up participants until the end of the study.  Participants will be expected to 
follow the visit schedule and assessments even after discontinuation of study treatment.  Data 
after participants discontinued study treatment will be used in the analysis (“retrieved dropout”). 
The primary analysis of primary efficacy variable 2 to address the primary objective will be 
based on the following estimand: 
• Population: Defined through appropriate inclusion/exclusion criteria to reflect the 
targeted population 
• Variable: Achieving LDL-C < 70 mg/dL (yes, no)  [The primary analysis time point is 
at Day 330.] 
• Treatment: Inclisiran + usual care or usual care 
• Remaining intercurrent events: 1. Potential use of inclisiran by participants in the usual 
care group. This intercurrent event will be ignored in the analysis, as the design of the 
trial allows for participants in the usual care group to potentially use inclisiran. 2. 
Discontinuation of study treatment.  This intercurrent event will be ignored in the 
analysis. 
• Summary measure: Odds ratio of inclisiran + usual care to usual care for achieving 
LDL-C < 70 mg/dL 
Let πj denote the probability of achieving LDL-C < 70 mg/dL at Day 330 for treatment group 
j, j = 0, 1, where 0 corresponds to usual care and 1 corresponds to inclisiran + usual care. 
Accordingly, πj/(1 – πj) is the odds for treatment group j, j = 0, 1. 
The following null hypothesis (H0) will be tested against the alternative hypotheses (HA), 
corresponding to the comparison inclisiran + usual care versus usual care: 
H0: [π1/(1 – π1)]/[π0/(1 – π0)] ≤ 1 versus HA: [π1/(1 – π1)]/[π0/(1 – π0)] > 1 
Primary efficacy variable 2 will be analyzed at each post-baseline visit using a logistic 
regression model with treatment and baseline LDL-C as explanatory variables 
(Stokes et al 2012). The odds ratio, two-sided 97.5% confidence interval for the odds ratio, and 
p-value based on the fitted model will be reported. If the p-value based on a two-sided test for 
inclisiran + usual care versus usual care at Day 330 is < 0.025 and the corresponding odds ratio 
is greater than 1, statistical significance in favor of inclisiran + usual care is shown. 
The primary analysis of both primary efficacy variables will be based on the Full Analysis Set. 


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12.4.3 
Handling of intercurrent events of primary estimand 
The remaining intercurrent event of the primary estimand for the two primary efficacy variables 
are the following: 1. Potential use of inclisiran by participants in the usual care group. This 
intercurrent event will be ignored in the analysis, as the design of the trial allows for participants 
in the usual care group to potentially use inclisiran. 2. Discontinuation of study treatment.  This 
intercurrent event will be ignored in the analysis. 
12.4.4 
Handling of missing values not related to intercurrent event 
For the primary analysis of primary efficacy variable 1, the MMRM implicitly imputes missing 
data under a missing at random assumption. 
For the primary analysis of primary efficacy variable 2, participants with missing LDL-C data 
will be assumed to have LDL-C ≥ 70 mg/dL (i.e., “non-responder”). 
12.4.5 
Sensitivity analyses 
The sensitivity analysis of primary efficacy variable 1 to address the primary objective will be 
based on the following estimand: 
• Population: Defined through appropriate inclusion/exclusion criteria to reflect the 
targeted population 
• Variable: Percent change from baseline in LDL-C [The primary analysis time point is 
at Day 330.] 
• Treatment: Inclisiran + usual care or usual care 
• Remaining intercurrent events: 1. Potential use of inclisiran by participants in the usual 
care group. This intercurrent event will be ignored in the analysis, as the design of the 
trial allows for participants in the usual care group to potentially use inclisiran. 2. 
Discontinuation of study treatment.  This intercurrent event will be ignored in the 
analysis. 
• Summary measure: Probability of observing the same or a more favorable response 
with inclisiran + usual care relative to usual care 
For the above estimand, primary efficacy variable 1 will be analyzed at each time point for the 
Full Analysis Set using the Wilcoxon rank-sum test. The probability of observing the same or 
a more favorable response with inclisiran relative to usual care will be estimated using 
nonparametric methods, and the associated two-sided 97.5% confidence interval will also be 
reported (Chen and Kianifard 2000). 
The sensitivity analysis of primary efficacy variable 2 to address the primary objective will be 
based on the following estimand: 
• Population: Defined through appropriate inclusion/exclusion criteria to reflect the 
targeted population 
• Variable: Achieving LDL-C < 70 mg/dL (yes, no) [The primary analysis time point is 
at Day 330.]   
• Treatment: Inclisiran + usual care or usual care 


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• Remaining intercurrent events: 1. Potential use of inclisiran by participants in the usual 
care group. This intercurrent event will be ignored in the analysis, as the design of the 
trial allows for participants in the usual care group to potentially use inclisiran. 2. 
Discontinuation of study treatment.  This intercurrent event will be ignored in the 
analysis. 
• Summary measure: Treatment difference ([inclisiran + usual care] – usual care) in the 
proportion of participants who achieve LDL-C < 70 mg/dL 
For the above estimand, primary efficacy variable 2 will be analyzed at each post-baseline visit 
for the Full Analysis Set using the two-sample z-test (normal approximation to the binomial 
distribution) to compare inclisiran + usual care versus usual care. If the treatment comparison 
p-value at Day 330 is < 0.025 and the proportion of participants who achieve LDL-C < 70 
mg/dL is higher in inclisiran + usual care treatment group, statistical significance in favor of 
inclisiran + usual care is shown. A two-sided 97.5% confidence interval for the difference 
between inclisiran + usual care and usual care in the proportion of participants who achieve 
LDL-C < 70 mg/dL will be calculated, using the normal approximation to the binomial 
distribution. 
12.4.6 
Supplementary analysis 
A supplementary analysis of primary efficacy variable 1 will be based on the following 
estimand: 
• Population: Defined through appropriate inclusion/exclusion criteria to reflect the 
targeted population 
• Variable: Percent change from baseline in LDL-C [The primary analysis time point is 
at Day 330.]  
• Treatment: Inclisiran + usual care or usual care  
• Remaining intercurrent events: 1. Potential use of inclisiran by participants in the  usual 
care group. 2. Discontinuation of study treatment.  Data after the occurrence of either 
one of the above two intercurrent events will be excluded from the analysis (using 
MMRM).  
• Summary measure: Least-squares mean difference between inclisiran + usual care group 
and usual care group 
Subgroup analyses of the two primary efficacy variables will be performed by background lipid-
lowering therapy at baseline. Other subgroups to be considered will be defined in the Statistical 
Analysis Plan. 
12.4.7 
Supportive analyses 
The primary analysis of the two primary efficacy variables will be repeated for the Per-Protocol 
Set, Restricted Set 1, and Restricted Set 2. 


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12.5 
Analysis supporting secondary objectives 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) 
The secondary efficacy variables are the following: 
1. Absolute change from baseline in LDL-C 
2. Average percent change from baseline in LDL-C levels to each post-baseline visit 
3. Average absolute change from baseline in LDL-C levels to each post-baseline visit 
4. Achieving LDL-C < 100 mg/dL (yes, no) (among the subset of participants with LDL-
C ≥ 100 mg/dL at baseline) 
5. Achieving ≥ 50% reduction from baseline in LDL-C (yes, no) 
6. Achieving LDL-C < 55 mg/dL (yes, no) 
7. Percent change from baseline in apoB 
8. Absolute change from baseline in apoB 
9. Percent change from baseline in VLDL 
10. Absolute change from baseline in VLDL 
11. Percent change from baseline in non-HDL-C 
12. Absolute change from baseline in non-HDL-C 
13. Percent change from baseline in total cholesterol 
14. Absolute change from baseline in total cholesterol 
15. Percent change from baseline in Lp(a) 
16. Absolute change from baseline in Lp(a) 
17. Percent change from baseline in HDL-C 
18. Absolute change from baseline in HDL-C 
19. Percent change from baseline in triglycerides 
20. Absolute change from baseline in triglycerides 
21. Intensity of lipid-lowering therapy (decrease in dose, no change in dose, increase in 
dose) 
22. Proportion of days covered (total number of days on either statin, ezetimibe, or PCSK9 
inhibiting monoclonal antibody therapies divided by total number of study days) 
23. Discontinuation of statin therapy (i.e., no statin use ≥ 30 days before the end-of-study 
visit) (yes, no) 
Analyses of secondary efficacy variables 1 and 7 - 20 will be similar to the primary analysis of 
primary efficacy variable 1 (using MMRM, but with a two-sided 95% confidence interval for 
the treatment difference). 


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Secondary efficacy variables 2, 3, and 22 will be analyzed using a linear model with treatment 
and baseline LDL-C as explanatory variables. Least-squares mean of each treatment group, 
least-squares mean treatment difference, 95% confidence interval for the treatment difference, 
and p-value based on the fitted model will be reported. 
Secondary efficacy variables 4 - 6 and 23 will be analyzed at each post-baseline visit using a 
logistic regression model with treatment and baseline LDL-C as explanatory variables 
(Stokes et al 2012). The odds ratio, 95% confidence interval for the odds ratio, and p-value 
based on the fitted model will be reported. Missing data will be imputed using “non-responder” 
(i.e., “negative” outcome) imputation. 
Secondary efficacy variable 21 will be analyzed at each post-baseline visit using a proportional 
odds model with treatment and baseline LDL-C as explanatory variables (Stokes et al 2012). 
The odds ratios, 95% confidence intervals for the odds ratios, and p-values based on the fitted 
model will be reported. Missing data will not be imputed. 
Analyses of secondary efficacy variables will be based on the Full Analysis Set. 
12.5.2 
Safety endpoints 
For all safety analyses, the Safety Set will be used. All listings and tables will be presented by 
treatment group. 
Adverse events 
All information obtained on adverse events will be displayed by treatment group and 
participant. 
The number (and percentage) of participants with treatment-emergent adverse events (events 
started after the first dose of study medication or events present prior to start of double-blind 
treatment but increased in severity based on preferred term) will be summarized in the following 
ways: 
• by treatment group, primary system organ class and preferred term. 
• by treatment group, primary system organ class, preferred term and maximum 
severity. 
• by treatment group, Standardized MedDRA Query (SMQ) and preferred term. 
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation. 
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class. 
Vital signs 
All vital signs data will be listed by treatment group, participant, and visit/time and if ranges 
are available, abnormalities will be flagged. Summary statistics will be provided by treatment 
and visit/time. 
Clinical laboratory evaluations 






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For primary efficacy variable 2, i.e., achieving LDL-C < 70 mg/dL (yes, no), a z-test, an 
allocation ratio of 1:1, and a two-sided significance level of 0.025 were used in the calculation 
of sample size. Table 12-2 considers total sample sizes for several expected proportions of 
participants who achieve LDL-C < 70 mg/dL at Day 330 in the usual care and inclisiran + usual 
care treatment groups, and powers of 0.85 and 0.90 (nQuery Version 8.4.1.0). From Table 12-
2, the expected proportions of 0.55 and 0.75 in the usual care and inclisiran + usual care 
treatment groups, respectively, and a power of 0.85 were chosen to provide a total sample size 
of 242 participants. 
Table 12-2 
Sample size calculations for achieving LDL-C < 70 mg/dL 
Proportion in usual 
care group 
Proportion in inclisiran 
+ usual care group 
Power = 0.85 
Power = 0.90 
0.50 
0.65 
464 
536 
0.50 
0.70 
256 
294 
0.55 
0.70 
446 
514 
0.55 
0.75 
242 
278 
Based on the sample size calculations in Table 12-1 and Table 12-2, a total sample size of 306 
together with a loss to follow-up rate of 20% at Day 330 require approximately 384 participants 
(192 participants per treatment group) to be randomized. This will also allow examination of 
subgroups with reasonable sample sizes. 
12.8.2 
Secondary endpoint(s) 
Not applicable. 
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 


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requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (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 
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. 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented. 


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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 
Anderson JL, Knowlton KU, May HT, et al (2018) Temporal changes in statin prescription 
and intensity at discharge and impact on outcomes in patients with newly diagnosed 
atherosclerotic cardiovascular disease-Real-world experience within a large integrated health 
care system: The IMPRES study. J Clin Lipidol 12(4):1008-1018.e1. 
Ashwell G, Morell AG (1974) The role of surface carbohydrates in the hepatic recognition 
and transport of circulating glycoproteins. Adv Enzymol Relat Areas Mol Biol 41(0):99-128. 
Atkinson MJ, Kumar R, Cappelleri JC, et al (2005) Hierarchical construct validity of the 
treatment satisfaction questionnaire for medication (TSQM version II) among outpatient 
pharmacy consumers. Value Health 8( Suppl 1):S9-S24. 
Baigent C, Blackwell L, et al (2010) Efficacy and safety of more intensive lowering of LDL 
cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 
376(9753):1670-81. 
Bangalore S, Breazna A, DeMicco DA, et al (2015) Visit-to-visit low-density lipoprotein 
cholesterol variability and risk of cardiovascular outcomes: insights from the TNT trial. J Am 
Coll Cardiol 65(15):1539-48. 
Cannon CP, Blazing MA, Giugliano RP, et al (2015) Ezetimibe Added to Statin Therapy after 
Acute Coronary Syndromes. N Engl J Med 372(25):2387-97. 
Cannon CP, Braunwald E, McCabe CH, et al (2004) Intensive versus moderate lipid lowering 
with statins after acute coronary syndromes. N Engl J Med 350(15):1495-504. 
Cannon CP, Khan I, Klimchak AC, et al (2017) Simulation of Lipid-Lowering Therapy 
Intensification in a Population With Atherosclerotic Cardiovascular Disease. JAMA Cardiol 
2(9):959-966. 
Chan AHY, Horne R, Hankins M, et al (2020) The Medication Adherence Report Scale: A 
measurement tool for eliciting patients' reports of nonadherence. Br J Clin Pharmacol 
86(7):1281-1288. 
Chen M, Kianifard F (2000) A nonparametric procedure associated with a clinically 
meaningful efficacy measure. Biostatistics 1(3):293-8. 
Coelho T, Adams D, Conceição I, et al (2020) A phase II, open-label, extension study of long-
term patisiran treatment in patients with hereditary transthyretin-mediated (hATTR) 
amyloidosis. Orphanet J Rare Dis 15(1):179. 
Collins R, Reith C, Emberson J, et al (2016) Interpretation of the evidence for the efficacy and 
safety of statin therapy. Lancet 388(10059):2532-2561. 
Diggle PJ, Heagerty P, Liang KY, et al (2002) Analysis of longitudinal data, 2nd ed; Oxford: 
Oxford University Press. 
Elbashir SM, Harborth J, Lendeckel W, et al (2001) Duplexes of 21-nucleotide RNAs mediate 
RNA interference in cultured mammalian cells. Nature 411(6836):494-8. 


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Geisbert TW, Hensley LE, Kagan E, et al (2006) Post-exposure protection of guinea pigs 
against a lethal ebola virus challenge is conferred by RNA interference. J Infect Dis 
193(12):1650-7. 
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. 
Circulation 139(25):e1082-e1143. 
Horne R, Weinman J (2002) Self-regulation and self-management in asthma: exploring the 
role of illness perceptions and treatment beliefs in explaining non-adherence to preventer 
medication. Psychol Health 17(1):17-32. 
Khunti K, Danese MD, Kutikova L, et al (2018) Association of a Combined Measure of 
Adherence and Treatment Intensity With Cardiovascular Outcomes in Patients With 
Atherosclerosis or Other Cardiovascular Risk Factors Treated With Statins and/or Ezetimibe. 
JAMA Netw Open 1(8):e185554. 
Koskinas KC, Windecker S, Pedrazzini G, et al (2019) Evolocumab for Early Reduction of 
LDL Cholesterol Levels in Patients With Acute Coronary Syndromes (EVOPACS). J Am 
Coll Cardiol 74(20):2452-2462. 
Lambert-Kerzner A, Havranek EP, Plomondon ME, et al (2015) Perspectives of patients on 
factors relating to adherence to post-acute coronary syndrome medical regimens. Patient 
Prefer Adherence 9:1053-9. 
Mills EJ, O'Regan C, Eyawo O, et al (2011) Intensive statin therapy compared with moderate 
dosing for prevention of cardiovascular events: a meta-analysis of >40 000 patients. Eur Heart 
J 11:1409-15. 
Morrissey DV, Blanchard K, Shaw L, et al (2005) Activity of stabilized short interfering RNA 
in a mouse model of hepatitis B virus replication. Hepatology 41(6):1349-56. 
Nishikido T, Ray KK (2018) Inclisiran for the treatment of dyslipidemia. Expert Opin 
Investig Drugs 27(3):287-294. 
Ray KK, Landmesser U, Leiter LA, et al (2017) Inclisiran in Patients at High Cardiovascular 
Risk with Elevated LDL Cholesterol. N Engl J Med 376(15):1430-1440. 
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):1507-1519. 
Rosenblit PD (2019) Lowering Targeted Atherogenic Lipoprotein Cholesterol Goals for 
Patients at "Extreme" ASCVD Risk. Curr Diab Rep 19(12):146. 
Sabatine MS, Giugliano RP, Keech AC, et al (2017) Evolocumab and Clinical Outcomes in 
Patients with Cardiovascular Disease. N Engl J Med 376(18):1713-1722. 
Sampson HA, Munoz-Furlong A, Bock SA, et al (2005) Symposium on the definition and 
management of anaphylaxis: summary report. J Allergy Clin Immunol 115(3):584-91. 


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Sampson HA, Munoz-Furlong A, Campbell RL, et al (2006) Second symposium on the 
definition and management of anaphylaxis: summary report--Second National Institute of 
Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy 
Clin Immunol 117:391-7. 
Schwartz GG, Steg PG, Szarek M, et al (2018) Alirocumab and Cardiovascular Outcomes 
after Acute Coronary Syndrome. N Engl J Med 379(22):2097-2107. 
Soutschek J, Akinc A, Bramlage B, et al (2004) Therapeutic silencing of an endogenous gene 
by systemic administration of modified siRNAs. Nature 432(7014):173-8. 
Stokes ME, Davis CS, Koch GG (2012) Categorical data analysis using the SAS system. 3rd 
ed; Cary, NC: SAS Institute, Inc. 
Tabernero J, Shapiro GI, LoRusso PM, et al (2013) First-in-humans trial of an RNA 
interference therapeutic targeting VEGF and KSP in cancer patients with liver involvement. 
Cancer Discov 3(4):406-17. 
Wilson PWF, Polonsky TS, Miedema MD, et al (2019) Systematic Review for the 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. 
Circulation 139(25):e1144-e1161. 
Zimmermann TS, Lee AC, Akinc A, et al (2006) RNAi-mediated gene silencing in non-
human primates. Nature 441(7089):111-4. 


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


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


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ALT or AST 
TBL 
Liver Symptoms 
Action 
If normal at baseline: 
ALT or AST > 5 x ULN 
for more than two 
weeks 
Normal 
For patients with 
Gilbert’s syndrome: No 
change in baseline 
TBL 
None 
• 
Interrupt study 
drug 
• 
Measure ALT, 
AST, ALP, GGT, 
TBL, direct and 
indirect 
bilirubin, PT/INR, 
albumin, CK, and 
GLDH in 48-72 
hours. 
• 
Follow-up for 
symptoms. 
• 
Initiate close 
monitoring and 
workup for 
competing 
etiologies. 
• 
Study drug can be 
restarted only if 
another etiology is 
identiﬁed and liver 
enzymes return to 
baseline. 
If elevated at 
baseline: 
ALT or AST > 3 x 
baseline 
or > 300 U/L 
(whichever occurs 
ﬁrst) for more than two 
weeks 
If normal at baseline: 
ALT or AST > 8 x ULN 
Normal 
None 
ALT or AST increase with bilirubin increase: 
If normal at baseline: 
ALT or AST > 3 x ULN 
TBL > 2 x ULN (or INR 
> 1.5) 
For patients with 
Gilbert’s syndrome: 
Doubling of direct 
bilirubin 
None 
If elevated at 
baseline: 
ALT or AST > 2 x 
baseline 
or > 300 U/L 
(whichever occurs 
ﬁrst) 
If normal at baseline: 
ALT or AST > 3 x ULN 
Normal or elevated 
Severe fatigue, 
nausea, vomiting, right 
upper quadrant pain 
If elevated at 
baseline: 
ALT or AST > 2 x 
baseline 
or > 300 U/L 
(whichever occurs 
ﬁrst) 
Table 16-5 
Follow up requirements for liver laboratory triggers  
Criteria 
Actions required 
Follow-up monitoring 
Total Bilirubin (isolated) 
  
  
>1.5 – 3.0 ULN 
• 
Maintain treatment 
• 
Repeat LFTs within 48-72 
hours 
Monitor LFTs weekly until 
resolutiona to ≤ Grade 1 or to 
baseline 
> 3 - 10 × ULN (in the absence 
of known Gilbert syndrome) 
• 
Interrupt treatment 
• 
Repeat LFT within 48-72 
hours 
Monitor LFTs weekly until 
resolutiona to ≤ Grade 1 or to 
baseline (ALT, AST, total 
bilirubin, Albumin, PT/INR, ALP 
and GGT) 


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Criteria 
Actions required 
Follow-up monitoring 
• 
Hospitalize if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors (e.g., 
conmeds, med hx, lab) in 
the appropriate CRF 
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin) 
> 10 x ULN 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize the participant 
• 
Establish causality 
• 
Record the AE and 
contributing factors(e.g., 
conmeds, med hx, lab) in 
the appropriate CRF 
ALT, AST, total bilirubin, 
Albumin, PT/INR, ALP and 
GGT until resolutionc 
(frequency at investigator 
discretion) 
Any AE potentially indicative of 
a liver toxicity* 
• 
Consider study treatment 
interruption or 
discontinuation 
• 
Hospitalization if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors(e.g., 
conmeds, med hx, lab) in 
the appropriate CRF 
Investigator discretion 
aResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level 
after a maximum of 6 months, (4) liver transplantation, and (5) death. 
Based on investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: Serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease. 


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16.3 
Appendix 3: Specific Renal Alert Criteria and Actions and Event 
Follow-up 
  
Table 16-6 
Specific renal alert criteria and actions 
Renal event 
Actions 
Confirmed serum creatinine (sCr) increase 25 – 
49% 
Consider causes and possible interventions 
Follow up within 2-5 days 
Serum creatinine increase ≥ 50% + + OR if <18 
years old, eGFR ≤ 35 mL/min/1.73 m2 + 
Consider causes and possible interventions 
Repeat assessment within 24-48h if possible 
Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected 
Consider participant hospitalization and 
specialized treatment 
New onset dipstick proteinuria ≥ 3+ 
OR 
Protein-creatinine ratio (PCR) ≥ 1g/g Cr (or 
mg/mmol equivalent as converted by the 
measuring laboratory) 
Consider causes and possible interventions 
Assess serum albumin & serum total protein 
Repeat assessment to confirm 
Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected 
New onset hematuria ≥ 3+ on urine dipstick 
Repeat assessment to confirm 
Distinguish hemoglobinuria from hematuria 
Urine sediment microscopy 
Assess sCr 
Exclude infection, trauma, bleeding from the 
distal urinary tract/bladder, menstruation 
Consider bleeding disorder 
+ Corresponds to KDIGO (Kidney Disease: Improving Global Outcomes) criteria for Acute Kidney 
Injury 
Additional specialized assessments are available to assess renal function or renal pathology. 
(Note: In exceptional cases, when a nephrologist considers a renal biopsy, it is recommended 
to make slide specimen available for evaluation by the RSG to potentially identify project-wide 
patterns of nephrotoxicity.) 
Whenever a renal event is identified, a detailed patient history and examination are indicated to 
identify and potentially eliminate risk factors that may have initiated or contributed to the event: 
• Blood pressure assessment (after 5-minute rest, with an appropriate cuff size) 
• Signs and symptoms like fever, headache, shortness of breath, back or abdominal pain, 
dysuria or hematuria, dependent or periorbital edema 
• Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output 
• Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic 
failure, contrast media or other known nephrotoxin administration, or other diseases or 
causes, e.g., dehydration due to delirium, tumor lysis   


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Table 16-7 
Renal event follow-up 
Follow-up of renal events 
Assess, document and record in appropriate eCRF(s): 
Urine dipstick and sediment microscopy evidence of drug-induced nephrotoxicity (DIN): crystals, red 
blood cells (dysmorphic/glomerular vs. non-dysmorphic/non-glomerular), white blood cells, tubular 
epithelial cells 
Blood pressure and body weight 
Serum creatinine, BUN, electrolytes (sodium, potassium, phosphate, calcium), bicarbonate and uric 
acid 
Urine output 
Review and record possible contributing factors to the renal event (co-medications, other co-morbid 
conditions) and additional diagnostic procedures (MRI etc.) in the appropriate eCRF(s) 
Monitor participant regularly (frequency at investigator’s discretion) until – 
- Event resolution: (sCr within 10% of baseline or PCR < 1 g/g Cr, or albumin-to-creatinine ratio 
(ACR) <300 mg/g Cr) 
or 
- Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio 
stabilization at a new level with ±50% variability over last 6 months. 
- Analysis of urine markers in samples collected over the course of the DIN event 
ACR (Albumin-to-creatinine ratio), DIN (Drug-Induced Nephrotoxicity), PCR (Protein-creatinine ratio), 
MRI (Magnetic Resonance Imaging), sCR (serum creatinine) 
  
 
 


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16.4 
Appendix 4: Sampson Criteria for Diagnosing Anaphylaxis 
Anaphylaxis is highly likely when any one of the following three criteria is fulfilled: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-tongue-uvula) 
AND AT LEAST ONE OF THE FOLLOWING: 
a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow [PEF], hypoxemia) 
b. Reduced blood pressure or associated symptoms of end-organ dysfunction (e.g., hypotonia 
[collapse], syncope, incontinence) 
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours): 
a. Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen lips-
tongue-uvula) 
b. Respiratory compromise (e.g., dyspnea, wheeze, bronchospasm, stridor, reduced PEF, 
hypoxemia 
c. Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, incontinence) 
d. Persistent gastrointestinal symptoms (e.g., painful abdominal cramps, vomiting) 
3. Reduced blood pressure after exposure to a known allergen for that patient (minutes to several 
hours): 
a. Adults: systolic blood pressure <90 mmHg or >30% decrease from that person’s baseline 
Source: Sampson et al 2005 and Sampson et al 2006 
 
 
 







SAP_001.pdf: 
Clinical Development 
KJX839 
CKJX839A1US01 / NCT04873934
A randomized, controlled, multicenter, open-label trial comparing a 
hospital post-discharge care pathway involving aggressive LDL-C 
management that includes inclisiran with usual care versus usual 
care alone in patients with a recent acute coronary syndrome 
(VICTORION-INCEPTION) 
Statistical Analysis Plan (SAP) 
Document type: 
SAP Documentation 
Document status: 
Final Amendment 01 
Release date: 
29-Aug-2024
Number of pages: 
45 
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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Document History – Changes compared to previous final version of SAP 
 
Date, 
Version 
Time 
point 
Reason for 
update 
Outcome for update 
Section and 
title impacted 
(Current) 
16-Jun-
2021,  
Final v1.0 
Prior to 
DB lock 
Creation of final 
version 
N/A - First version 
NA 
 
 
 
 
 
29-Aug-
2024, Final 
Amendment 
01 
Prior to 
DB lock 
Necessary 
correction or 
clarification; 
harmonization 
across inclisiran 
studies 
Clarification on use of calculated 
LDL-C for statistical analysis and 
use of SI and/or US conventional 
units for selected lab parameters. 
Section 2. 1 
 
 
 
Definition of screening value 
Section 2.1.1 
 
 
 
Subgroups for subgroup analyses 
of primary efficacy variables added 
and updated. 
Section 2.2.1 
 
 
 
List of demographic variables 
updated. 
Section 2.3.2 
 
 
 
Definition of changes in lipid-
lowering therapies prior to baseline 
was added. 
Section 2.4.2 
 
 
 
Methodology in case of non-
convergence of statistical models 
was added. 
Section 2.5.2 
 
 
 
Sensitivity analyses were added to 
address participants with low 
baseline LDL-C. 
Section 2.5.5 
 
 
 
Common adverse event tables 
using 3% within either treatment 
group as the threshold was added. 
Section 2.7.1 
 
 
 
Addition of adverse events of 
special interest terms. 
Section 2.7.1.1 
 
 
 
Reference and definition of eGFR 
derivation were added. Summary 
tables for new onset or worsening 
of diabetes were added. Update of 
baseline diabetes status to baseline 
glycemic status. 
Section 2.7.3 
 
 
 
Summary tables for participants 
satisfying Hy’s Law will be repeated 
excluding the normal baseline 
value requirement. 
Section 2.7.3 
 
 
 
 
 




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Table of contents 
Table of contents ................................................................................................................. 4 
List of tables ........................................................................................................................ 6 
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) .............................................................................. 12 
1.2.2 
Secondary estimand(s) .......................................................................... 14 
2 
Statistical methods ............................................................................................................. 14 
2.1 
Data analysis general information ......................................................................... 14 
2.1.1 
General definitions ................................................................................ 15 
2.2 
Analysis sets .......................................................................................................... 17 
2.2.1 
Subgroup of interest .............................................................................. 18 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 19 
2.3.1 
Patient disposition ................................................................................. 19 
2.3.2 
Demographics and other baseline characteristics ................................. 19 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ........................................................................................................... 20 
2.4.1 
Study treatment / compliance ................................................................ 20 
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 .......................... 22 
2.5.3 
Handling of intercurrent events ............................................................. 23 
2.5.4 
Handling of missing values not related to intercurrent event ............... 23 
2.5.5 
Sensitivity analyses ............................................................................... 23 
2.5.6 
Supplementary analyses ........................................................................ 24 
2.5.7 
Subgroup analyses ................................................................................. 25 
2.6 
Analysis supporting secondary objectives ............................................................. 25 
2.6.1 
Secondary endpoint(s) ........................................................................... 25 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 27 
2.6.3 
Handling of missing values ................................................................... 28 
2.6.4 
Sensitivity analyses ............................................................................... 28 
2.6.5 
Supplementary analyses ........................................................................ 28 


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2.6.6 
Subgroup analyses ................................................................................. 28 
2.7 
Safety analyses ...................................................................................................... 28 
2.7.1 
Adverse events (AEs) ............................................................................ 29 
2.7.2 
Deaths .................................................................................................... 30 
2.7.3 
Laboratory data ..................................................................................... 30 
2.7.4 
Other safety data ................................................................................... 33 
2.8 
Pharmacokinetic endpoints .................................................................................... 34 
2.9 
PD and PK/PD analyses ........................................................................................ 34 
2.10 
Patient-reported outcomes ..................................................................................... 34 
2.11 
Biomarkers ............................................................................................................. 34 
2.12 
Other Exploratory analyses ................................................................................... 34 
2.13 
Interim analysis ...................................................................................................... 38 
3 
Sample size calculation ..................................................................................................... 38 
4 
Change to protocol specified analyses .............................................................................. 39 
5 
Appendix ........................................................................................................................... 40 
5.1 
Imputation rules ..................................................................................................... 40 
5.1.1 
Study drug ............................................................................................. 40 
5.1.2 
Adverse event and concomitant medication date imputation ............... 40 
5.2 
AEs coding/grading ............................................................................................... 41 
5.3 
Laboratory parameters derivations ........................................................................ 41 
5.3.1 
Handling data with special symbols ...................................................... 41 
5.3.2 
Criteria for potentially clinically significant and clinically 
significant abnormal laboratory tests .................................................... 42 
5.4 
Statistical models ................................................................................................... 43 
5.4.1 
Analysis supporting primary objective(s) ............................................. 43 
5.4.2 
Analysis supporting secondary objective(s) ......................................... 43 
5.5 
Rule of exclusion criteria of analysis sets ............................................................. 44 
6 
Reference ........................................................................................................................... 45 
 


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List of tables 
Table 2-1 
Planned and Actual Treatment Definitions ........................................... 16 
Table 2-2 
Analysis Windows for Each Scheduled Visit ....................................... 17 
Table 2-3 
Lipid-lowering Therapies ...................................................................... 21 
Table 2-4 
Definition of Baseline Glycemic Status ................................................ 32 
 
 34 
Table 2-6 
MACE Definitions (using TEAEs only) ............................................... 35 
 
 37 
Table 3-1 
Sample Size Calculations for Percent Change from Baseline in 
LDL-C ................................................................................................... 38 
Table 3-2 
Sample Size Calculations for Achieving LDL-C < 70 mg/dL .............. 39 
Table 5-1 
Laboratory Test Criteria ........................................................................ 42 
Table 5-2 
Criteria Leading to Exclusion ............................................................... 44 
 
List of figures 
Figure 1-1 
Study Design ......................................................................................... 10 
 


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List of abbreviations 
ACC 
American College of Cardiology 
ACS 
Acute coronary syndrome 
AE 
Adverse Event 
AHA 
American Heart Association 
apoB 
Apolipoprotein B 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
CK 
Creatine Kinase 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CS 
Clinically significant 
CV 
Cardiovascular 
dL 
Deciliter 
EHR 
Electronic Health Record 
ECG 
Electrocardiogram 
eGFR 
Estimated Glomerular Filtration Rate 
EOS 
End of Study 
FAS 
Full Analysis Set 
HbA1c 
Hemoglobin A1c 
HDL-C 
High density lipoprotein cholesterol 
H0 
Null hypothesis 
HA 
Alternative hypothesis 
hsCRP 
High sensitivity C-Reactive protein 
LDL-C 
Low density lipoprotein cholesterol 
LLN 
Lower Limit Normal 
LLT 
Lipid lowering therapies 
Lp(a) 
Lipoprotein(a) 
MACE 
Major adverse cardiovascular events  
 
 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
mg 
Milligram(s) 
MI 
Myocardial Infarction 
MMRM 
Mixed-effects Model for Repeated Measures 
PCS 
Potentially clinically significant 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PFS 
Prefilled syringe 
PT 
Preferred Term 


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SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis System 
s.c. 
subcutaneous 
SOC 
System Organ Class 
TBL 
Total bilirubin 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
 
 
ULN 
Upper Limit Normal 
VLDL 
Very low density lipoprotein cholesterol 
WHO 
World Health Organization 
 
 
 


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1 
Introduction 
This document describes the planned statistical methods for all safety and efficacy analyses 
which will be performed in the Phase 3b clinical trial CKJX839A1US01.  
The aim of the trial and the described statistical analysis methodologies is to study the effect of 
implementation of a systematic low density lipoprotein cholesterol (LDL-C) management 
pathway including treatment with inclisiran in participants who have experienced a recent acute 
coronary syndrome (ACS) and have an increased LDL-C (≥70 mg/dL) despite being treated 
with a statin drug. 
Analysis plans in this document refer to the related statistical analysis sections in the Clinical 
Study Report (CSR). Data will be analyzed by Summit Analytical, LLC using Statistical 
Analysis Software (SAS®, version 9.4), according to Section 12 (Data analysis and statistical 
methods) of the study protocol which is available in Appendix 16.1.1 of the CSR.   
Please refer to the following document: Clinical Protocol CKJX839A1US01 v04 (amended 
protocol dated 20-Oct-2022) and CRF v16.0 (dated 18-Dec-2023). 
1.1 
Study design 
This is a randomized, parallel-group, open-label, multicenter study comparing an LDL-C 
management strategy including inclisiran plus usual care with usual care. A total of 
approximately 384 participants will be randomized 1:1 to aggressive LDL-C management with 
inclisiran plus usual care (intervention arm) and usual care (control arm). Identification of 
participants will take place during hospitalization or in the weeks following discharge with 
screening soon thereafter. Screening of participants must take place within 5 weeks after 
discharge. The randomization schedule will not be stratified by any factors. 
Potential participants who are discharged after an ACS on statin therapy (which is considered 
routine care) or have documented statin intolerance will be screened and receive an LDL-C test 
within 5 weeks post-discharge (to allow for the realization of the full effect of statin therapy). 
After the LDL-C test, participants with an LDL-C ≥70 mg/dL are eligible for the trial as long 
as they meet all other inclusion criteria. Participants will be randomized to inclisiran + usual 
care or usual care. All participants will be maintained on statin therapy during inclisiran 
treatment, but concomitant lipid-lowering therapy and LDL-C assessments will be at the 
discretion of the treating (primary) physician, mimicking real-world clinical decision-making 
and enabling the evaluation of inclisiran compared to usual care in patients with a recent ACS. 
Usual care may therefore include addition of ezetimibe, proprotein convertase subtilisin/kexin 
type 9 (PCSK9)-inhibiting monoclonal antibodies and/or commercially available inclisiran 
(Note: participants treated with inclisiran should not be treated with PCSK9-inhibiting 
monoclonal antibodies). After randomization, the treating physician will not have access to 
LDL-C values obtained as part of the study but will be able to perform LDL-C assessments at 
their discretion, to mimic usual care. The rationale of not providing the treating physician the 
LDL-C values obtained as part of the study is that those results might influence decisions made 
by him/her and could therefore undermine “usual care”. Commercially available inclisiran may 
be used for appropriate patients in the usual care arm at the sole discretion of the treating 
physician, without any influence from the PI. LDL-C measurement and assessment of lipid 


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lowering medications at each visit will be performed to assess adherence to background statin 
therapy. 
The collection of data from trial sites through eCRFs may also be complemented with Electronic 
Health Record (EHR) data and claims data (e.g., lipid measurements and concomitant 
medications), if available. While study visits will be preferentially performed in-person at the 
study sites, phone or virtual home-visits are an acceptable alternative if in-person visits are not 
permitted or impractical (e.g., due to a public health emergency). Site or home health nursing 
service may be used to assist with blood draws and/or study medication administration if 
required at these visits. 
Figure 1-1 
Study Design 
 
Additional important considerations of the study design include: 
• Recruitment: Potentially eligible participants, recently hospitalized for an ACS (in-
patient/out-patient), will be identified by the primary investigator and be invited to contact 
the research site for screening and inclusion. Eligible participants will need to consent to 
having health records made available as part of the collection of medical and pharmacy 
claims in order to 
. 
• Open label: The study will be performed as an open-label study to mimic decision 
making in usual care, following from the primary objective of the study. For example, if 
the study would have been performed as a double-blind placebo-controlled study, it would 
not be possible to study the effect of inclisiran treatment on statin discontinuation as 
participants and investigators would not be aware of treatment allocation. 
• Duration of study period: The study is designed as a one-year trial with a total of three 
inclisiran doses. The Phase III trials of inclisiran had a follow-up duration of 18 months. A 
follow-up duration of one year enables: 1) observation of the steady-state LDL-C lowering 
effect of inclisiran, 2) observation of a meaningful difference in statin discontinuations, 


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should such a difference exist, and 3) observation of potential differences in variables that 
likely require longer-term treatment of inclisiran to become apparent, such as patient 
reported outcomes.  
1.2 
Study objectives, endpoints and estimands  
 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To assess the effect on LDL-C of implementation of 
an LDL-C management care pathway that includes 
initiation of inclisiran in participants with a recent 
hospitalization (in-patient/out-patient) for an ACS 
with LDL-C ≥70 mg/dL despite receiving statin 
therapy compared to usual care without inclisiran 
at Day 330 
• 
Percent change from baseline in LDL-C 
• 
Achieving LDL-C < 70 mg/dL (yes, no) 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To assess (1) the absolute change from baseline in 
LDL-C level by visit, and (2) average of percent and 
absolute changes from baseline in LDL-C levels to 
each post-baseline visit, in the inclisiran + usual 
care group compared to usual care group at Day 330  
• 
Absolute change from baseline in LDL-C 
• 
Average percent change from baseline in LDL-
C levels to each post-baseline visit 
• 
Average absolute change from baseline in 
LDL-C levels to each post-baseline visit 
• 
To assess the proportion of participants reaching pre-
specified LDL-C targets in the inclisiran + usual care 
group compared to usual care group at Day 330 
• 
Achieving ≥ 50% reduction from baseline in 
LDL-C (yes, no) 
• 
Achieving LDL-C < 100 mg/dL (yes, no) 
(among the subset of participants with LDL-C 
≥ 100 mg/dL at baseline) 
• 
Achieving LDL-C < 55 mg/dL (yes, no) 
• 
To assess plasma lipoproteins and triglycerides in the 
inclisiran + usual care group compared to usual care 
group at Day 330 
• 
Percent change and absolute change from 
baseline in apoB 
• 
Percent change and absolute change from 
baseline in VLDL 
• 
Percent change and absolute change from 
baseline in non-HDL-C 
• 
Percent change and absolute change from 
baseline in total cholesterol 
• 
Percent change and absolute change from 
baseline in Lp(a) 
• 
Percent change and absolute change from 
baseline in HDL-C 
• 
Percent change and absolute change from 
baseline in triglycerides 
• 
To assess changes in and adherence to background 
lipid-lowering therapy in the inclisiran + usual 
care group compared to usual care group at Day 330 
• 
Intensity of lipid lowering therapy (decrease in 
dose, no change in dose, increase in dose) 
• 
Proportion of days covered (total number of 
days on either statin, ezetimibe, or PCSK9 
inhibiting monoclonal antibody therapies 
divided by total number of study days) 


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Objective(s) 
Endpoint(s) 
• 
Discontinuation of statin therapy (i.e., no statin 
use ≥ 30 days before the end-of-study visit) 
(yes, no) 
• 
To assess overall safety and tolerability of inclisiran 
• 
Adverse events 
Exploratory objective(s) 
Endpoint(s) for exploratory objective(s) 
• 
To assess major adverse cardiovascular events 
(MACE) (investigator determination) in the inclisiran 
+ usual care group compared to usual care group at 
Day 330 
• 
Cardiovascular death (yes, no) 
• 
Non-fatal MI (yes, no) 
• 
Resuscitated cardiac arrest (yes, no) 
• 
Non-fatal ischemic stroke (yes, no) 
• 
Composite MACE (cardiovascular death, non-
fatal MI, resuscitated cardiac arrest, or non-
fatal ischemic stroke) (yes, no) 
Note that endpoints identified as “absolute” change from baseline correspond to values that are 
calculated as a change from baseline (post-baseline value minus baseline value). 
1.2.1 
Primary estimand(s) 
The estimand is the precise description of the treatment effect and reflects strategies to address 
events occurring during the trial conduct which could impact the interpretation of the trial 
results (e.g., premature discontinuation of treatment).   


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The primary clinical question of interest in this study is to evaluate the effect on LDL-C of 
implementation of an LDL-C management care pathway with inclisiran versus usual care in 
participants who are discharged after an ACS on statin therapy or have documented statin 
intolerance and do not have their LDL-C at the target level. The justification for the primary 
estimand is that it will evaluate the LDL-C lowering effect of inclisiran on both the percent 
change in LDL-C and the achievement of the target LDL-C (<70 mg/dL) compared to a usual 
care of implementation pathway in participants following a recent ACS, including potential 
changes in concomitant therapy. Further details can be found in Section 12 of the protocol.  
Primary estimand 1: The primary analysis of primary efficacy variable 1 (percent change from 
baseline in LDL-C) to address the primary objective will be based on the following estimand: 
• Population: Defined through appropriate inclusion/exclusion criteria to reflect the 
targeted population 
• Variable: Percent change from baseline in LDL-C [The primary analysis time point is 
at Day 330.] 
• Treatment: Inclisiran + usual care or usual care 
• Remaining intercurrent events: 1. Potential use of inclisiran by participants in the 
usual care group. This intercurrent event will be ignored in the analysis, as the design 
of the trial allows for participants in the usual care group to potentially use inclisiran. 
2. Discontinuation of study treatment. This intercurrent event will be ignored in the 
analysis. 3. Use of prohibited medication (monoclonal antibodies directed against 
PCSK9) in the inclisirian + usual care group. This intercurrent event will be ignored 
in the analysis. 
• Summary measure: Least-squares mean difference between inclisiran + usual care 
group and usual care group 
Primary estimand 2: The primary analysis of primary efficacy variable 2 (achieving LDL-C < 
70 mg/dL) to address the primary objective will be based on the following estimand: 
• Population: Defined through appropriate inclusion/exclusion criteria to reflect the 
targeted population 
• Variable: Achieving LDL-C < 70 mg/dL (yes, no) [The primary analysis time point is 
at Day 330.] 
• Treatment: Inclisiran + usual care or usual care 
• Remaining intercurrent events: 1. Potential use of inclisiran by participants in the usual 
care group. This intercurrent event will be ignored in the analysis, as the design of the 
trial allows for participants in the usual care group to potentially use inclisiran. 2. 
Discontinuation of study treatment. This intercurrent event will be ignored in the 
analysis. 3. Use of prohibited medication (monoclonal antibodies directed against 
PCSK9) in the inclisirian + usual care group. This intercurrent event will be ignored in 
the analysis. 
• Summary measure: Odds ratio of inclisiran + usual care to usual care for achieving 
LDL-C < 70 mg/dL 


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1.2.2 
Secondary estimand(s) 
Not applicable. 
2 
Statistical methods 
This section contains information that will be used to draft CSR Section 9.7 on statistical 
analysis. 
2.1 
Data analysis general information 
It is planned that the data from all centers that participate in this protocol will be combined, so 
that an adequate number of participants will be available for analysis.  
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
The analysis will be performed at the end of the trial, after the clinical database is locked. 
Unless otherwise specified, all statistical tests will be conducted against a two-sided alternative 
hypothesis, employing a significance level of 0.05. 
Efficacy, safety, and other data will be summarized. For continuous variables, summary 
statistics (mean, standard deviation, median, 25th and 75th percentiles, minimum, and maximum) 
at each time point and for change from baseline to each time point will be reported by treatment 
group. For discrete variables, frequency counts and percentages at each time point will be 
reported by treatment group. 
LDL-C values, lipid parameters, and laboratory units 
Any statistical analysis involving LDL-C will be based on calculated LDL-C values as provided 
by the central laboratory. For the remainder of this SAP and the corresponding output shells, 
the abbreviated term “LDL-C” refers to calculated LDL-C. 
Tabular summaries, listings, and figures of lipid parameters, creatinine, and fasting glucose will 
be provided in US conventional units. Select analyses of these parameters will be provided in 
SI units as well. All other laboratory parameters will be reported in SI units. Both US 
conventional and SI units will be included in SDTM and ADaM datasets as applicable per 
laboratory parameter. The lipid parameters include the following, with US and SI units as 
applicable in this study: 
1. LDL Cholesterol (mg/dL, mmol/L) 
2. Total Cholesterol (mg/dL, mmol/L) 
3. HDL Cholesterol (mg/dL, mmol/L) 
4. Non-HDL Cholesterol (mg/dL, mmol/L) 
5. VLDL Cholesterol (mg/dL, mmol/L) 
6. Triglycerides (mg/dL, mmol/L) 
7. Apolipoprotein B (mg/dL) 


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8. Lipoprotein(a) (nmol/L) 
Due to differences in measurement techniques as well as molecular differences between 
individuals, a standardized conversion factor is not available to convert Lipoprotein(a) values 
from standard to US conventional units. Therefore, Lipoprotein(a) results will only be reported 
in nmol/L. 
2.1.1 
General definitions  
Study treatment 
The following are the investigational treatments: 
• Inclisiran (KJX839), 284 mg, 1.5 ml liquid in a single-use prefilled syringe (PFS) for 
s.c. administration plus usual care 
• Usual care alone 
The following treatment labels will be used for all tables, listings and figures: 
• Inclisiran + Usual Care 
• Usual Care 
Study treatment start and end date 
Study treatment start date is defined as the first date when a non-zero dose of study drug is 
administered for the inclisiran + usual care group. If a participant, who is randomized to the 
inclisiran + usual care group, does not take any study drug then treatment start date will be the 
randomization date.   
For the usual care alone group the study treatment start date will be the randomization date.  
“Day 1” will be used to identify study treatment start date for both treatments. 
Study treatment end date is defined as the treatment phase completion date recorded on the 
“Treatment Disposition” CRF for inclisiran + usual care participants.  For the usual care alone 
group, the study treatment end date is the last recorded contact/participation date in the database. 
Study start and end date 
Study start date is defined as the first date when a non-zero dose of study drug is administered 
for the inclisiran + usual care group. If a participant, who is randomized to the inclisiran + usual 
care group, does not take any study drug then study start date will be the randomization date.   
For the usual care alone group the study start date will be the randomization date.  
Study end date is defined as the date of last recorded contact/participation date in the database. 
Duration of exposure to inclisiran 
For the inclisiran + usual care group, duration of exposure to inclisiran (in days) is defined as 
the number of days from Day 1 to the study treatment end date. Duration of exposure will not 
be defined for the usual care alone group. 
 
 


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Planned and actual treatment definitions 
The following definitions will be used for planned and actual treatment. 
Table 2-1 
Planned and Actual Treatment Definitions 
Randomized 
Treatment Group 
Inclisiran Use Scenario During Study 
(Inclisiran Use Recorded as Study 
Treatment or Concomitant 
Medication) 
Planned  
Treatment 
Actual  
Treatment 
Inclisiran + Usual 
Care 
Received at least one dose of inclisiran 
Inclisiran + 
Usual Care 
Inclisiran + 
Usual Care 
Inclisiran + Usual 
Care 
Never received inclisiran  
Inclisiran + 
Usual Care 
Usual Care 
Usual Care 
Received at least one dose of inclisiran  
Usual Care 
Inclisiran + 
Usual Care 
Usual Care 
Never received inclisiran  
Usual Care 
Usual Care 
Study day 
Study day will be calculated as (event date – study treatment start date + 1 day) for events that 
occurred on or after study treatment start date (e.g., visit, lab samples, AEs). For events prior to 
study treatment start date (e.g., time of diagnosis), study day will be negative and calculated as 
(event date – study treatment start date). Note that study treatment start date is study Day 1 and 
the day before study drug start date is study Day -1 (i.e., no study Day 0). 
Screening, baseline and post-baseline definitions 
A screening value refers to the last available measurement from the set of nominal 
Screening/Visit 1 records irrespective of collection date being before or after start of study 
treatment, and any unscheduled visit data collected before (<) study Day 1.  
In general, a baseline value refers to the last measurement available prior to administration of 
the first dose of study treatment (before or on study Day 1). A post-baseline value refers to a 
measurement taken after the first dose of study treatment (after study Day 1). 
Lost to follow up 
Participants whose study completion status is unclear because they fail to appear for study visits 
without stating an intention to withdraw. 
On-treatment period 
The period where the participants are exposed to the study treatment or usual care. For this 
study the treatment phase consists of 330 days. 
Study Completer 
Completers are defined as a participant who has a Subject Status of ‘completed’ on the Study 
Completion/Exit CRF page. 
Analysis Visit Windows 
The following analysis windows will be used for efficacy and safety analyses. 


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Table 2-2 
Analysis Windows for Each Scheduled Visit 
Analysis Visit 
Target Study Day* 
Analysis Window 
From 
To 
Baseline 
1 
 
Before randomization/First 
Study Treatment 
Day 90 
91 
1 
180 
Day 270 
271 
181 
300 
Day 330 
331 
301 
375 
* Study Day 1 is being used to identify study treatment start date. When calculating study day, 
the target study day will correspond to the planned study day of the nominal visit.  The analysis 
visit values (Baseline, Day 90, Day 270, and Day 330) will be used for all presentations. 
Data collected at scheduled or unscheduled visits will be used in the analysis if they fall into 
an analysis window for an analysis visit. If more than one visit (scheduled or unscheduled) is 
made within the window specified above for any analysis visit, the non-missing assessment 
closest to the target study day will be used in the analysis for that visit. In the case of tied 
visits, non-missing data from the later visit will be used. In the case of identical collection 
dates and times, the average of the two visits will be used. However, all data will be included 
in the participant data listings.  
Last Visit Summaries 
The protocol uses the term End of Study (EOS) for Day 330.  If a participant discontinues from 
the study early, they will have an early termination visit that is before Day 330. Using the 
windowing provided in Table 2-2, the early termination visit will be assigned to the nearest 
analysis visit. Tables that summarize data by visit will include data by analysis visit (Baseline, 
Day 90, Day 270, and Day 330) along with a Day 330/Last Visit which will combine data from 
Day 330 for those participants who have data collected within the Day 330 analysis window 
with the data from the last post-baseline visit for those participants who do not have data 
collected in the Day 330 analysis window. 
2.2 
Analysis sets  
The Full Analysis Set (FAS) comprises all randomized participants. According to the intent-
to-treat principle, participants will be analyzed according to the treatment group they have been 
assigned to during the randomization procedure. 
The Per-Protocol Set is a subset of the FAS in which participants are not treated with any 
inclisiran if they are randomized to the usual care treatment group or do not have any major 
protocol deviations (including deviations from inclusion/exclusion criteria) in either treatment 
group.    
The Restricted Set 1 is a subset of the FAS which includes only participants without changes 
in background lipid-lowering therapy. A change includes starting a new lipid-lowering therapy 
or stopping an existing lipid-lowering therapy after the study treatment start date. 


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The Restricted Set 2 is a subset of the FAS which includes only participants who received three 
doses of inclisiran in the inclisiran + usual care group (i.e., excludes participants in the inclisiran 
+ usual care group who missed one or more doses) and all participants in the usual care group 
(including participants who may have used commercially available inclisiran). 
The Safety Set includes all participants who received study treatment. Participants will be 
analyzed according to the study treatment received. Refer to Table 2-1 for assignment of actual 
treatment for the different scenarios. Participants in the usual care treatment group who have 
data collected at the baseline visit will be included in the Safety Set. 
2.2.1 
Subgroup of interest 
Subgroup analyses of the two primary efficacy variables and the secondary endpoint of absolute 
change from baseline in LDL-C will be performed for the following subgroups (note that results 
for a subgroup category will only be presented if the total across both treatment groups within 
the category is at least 10 participants): 
• Background lipid-lowering therapy at baseline: Yes, No 
• Medical history of statin intolerance: Yes, No (from medical history statin intolerance 
CRF page) 
• Baseline statin intensity: High, Moderate or Low, None 
• Age: <65 years, >= 65 years 
• Sex: Male, Female 
• Race subgroup 1: White, Non-White/Multiple (unknown will be excluded from 
subgroup analyses) 
• Race subgroup 2: White, Black or African American, Non-White/Non-Black or 
African American/Multiple (unknown will be excluded from subgroup analyses) 
• Ethnicity: Hispanic or Latino, Not Hispanic or Latino (unknown or not reported will 
be excluded from subgroup analyses) 
• BMI: >=30 vs < 30, and >=25 vs < 25 kg/m2 
• Renal impairment by eGFR categories at baseline: <15, ≥15 to <30, ≥30 to <60, ≥60 
to <90, or ≥90 mL/min/1.73m2  
• Baseline LDL-C: <=100 and > 100 mg/dL; by median; and then by quartiles 
• Index myocardial infarction: ST segment elevation myocardial infarction (STEMI), 
Non-ST-segment elevation myocardial infarction (NSTEMI), No myocardial 
infarction (from ACS medical history) 
• Atrial fibrillation associated with index myocardial infarction: Yes, No (from ACS 
medical history) 
• Revascularization procedure during index ACS event: Yes, No (from ACS medical 
history) 
• History of diabetes: Yes, No (from ACS medical history) 
• Baseline glycemic status: Diabetes, Pre-diabetes, Normoglycemia 
For definition of baseline glycemic status, refer to Section 2.7.3, Table 2-4. 


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2.3 
Patient disposition, demographics and other baseline 
characteristics 
Summary statistics will be presented for continuous demographic and baseline characteristics 
and the number and percentage of participants in each category will be presented for 
categorical variables for each treatment group. The summaries will be reported for the FAS, if 
not otherwise stated. 
2.3.1 
Patient disposition 
Participant disposition will be summarized as follows: 
• The number of participants who signed the informed consent form, are screen 
failures, are randomized, are treated (Safety Set), completed the study or who 
discontinued early along with reasons for early study discontinuation, the number of 
screened subjects, completed screening phase and were randomized, completed 
screening phase but were not randomized, did not complete screening phase, and 
primary reason for not completing screening phase will be summarized for all 
screened participants. 
• The number of participants in each analysis population will be summarized by 
treatment group for all randomized participants. 
• The number of participants who complete the treatment phase or who discontinued 
treatment early along with reasons for early treatment discontinuation will be 
summarized for the inclisiran + usual care group for the FAS. 
• The duration of exposure to inclisiran (in days) will be summarized for the inclisiran 
+ usual care group for the FAS. 
• The number of participants who complete the study or who discontinued the study 
early along with reasons for early study discontinuation will be summarized by 
treatment group for the FAS. 
• The duration on study (number of days from study start date to study end date [last 
recorded contact/participation date in the database]) will be summarized by treatment 
for the FAS. 
The number and percentage of participants with important protocol deviations will be 
summarized by treatment group for the FAS. 
2.3.2 
Demographics and other baseline characteristics 
Participant demographics including age, age category (<65 years vs ≥65 years; 18 to <50, 50 
to <65, 65 to <75, ≥75 years), race, ethnicity, sex, and child bearing potential status; and 
baseline characteristics such as source of participant referral, smoking status by substance, 
body height, weight, BMI, LDL-C, and non-HDL-C will be summarized by treatment group 
using the FAS.  
Medical history (ACS medical history, other medical history, and medical history of statin 
intolerance) will be summarized by treatment group using the FAS. Other medical history will 


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be summarized by system organ class and preferred term. Tabulation of ACS medical history 
will include summaries by treatment group for the following durations: 
• Duration from index hospitalization discharge to informed consent: number of days 
from date of hospitalization discharge for the index ACS event to date of informed 
consent 
• Duration from index hospitalization discharge to study treatment start: number of 
days from date of hospitalization discharge for the index ACS event to study 
treatment start date (Day 1) 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
Study drug administration will be summarized overall and by dosing visits for the Safety Set. 
Summaries will also include missed doses and number of participants randomized to usual care 
who received at least one dose of inclisiran on study. 
2.4.2 
Prior, concomitant and post therapies 
Concomitant medications and significant non-drug therapies prior to and after study treatment 
start date will be listed and summarized according to the Anatomical Therapeutic Chemical 
(ATC) classification system and preferred drug name, by treatment group, for the Safety Set. 
Additional summaries will be provided for lipid-lowering therapies. ATC Level 3 will be used 
for summaries of medications. If a medication is not coded at the ATC Level 3, the ATC Level 
2 will be utilized. See list of lipid-lowering therapies below. Medications will be coded using 
the World Health Organization (WHO) drug dictionary, and will be coded/re-coded with up-
version during the course of study. The final coding version used in this study will be 
WHODrug Global B3 March 1, 2024. Medications recorded as part of medical history will be 
presented separately and will not be considered in any analysis of prior or concomitant therapy. 
Partially missing medication dates will be imputed following Appendix 5.1.2. Prior medications 
include all medications stopped prior to study treatment start date. Concomitant medications 
include any medications taken on or after study treatment start date. In case the medication date 
values do not allow unequivocally allocating a medication to prior or concomitant medication, 
the medication will be considered as concomitant medication in the statistical analysis. This 
rule does not apply to medications recorded on the “ACS Medical History” or the “Medical 
History of Statin Intolerance” CRFs as no medication dates were captured on these forms by 
design.  
The statin intensity (none, low, moderate, high) will be defined by clinical review of the data 
according to American College of Cardiology/American Heart Association (ACC/AHA) 
classification of high intensity and based on the specific statin drug name, dose (unit), and 
frequency recorded in the data.  
Lipid-lowering therapies (LLT) taken at baseline, changes in lipid-lowering therapies prior to 
baseline, concomitant lipid-lowering therapies by visit, a shift table from baseline statin 


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intensity level to post-baseline lipid-lowering therapy addition group, and a shift table for statin 
intensity from baseline to Day 330/Last Visit will also be provided. To this end, the LLTs and 
statin intensity for Day 330/Last Visit will be assessed on the Day 330 visit date for participants 
with recorded Day 330 visit date, or on the study end date (date of last participation) otherwise. 
For the shift table for statin intensity from baseline to Day 330/Last Visit, the “None” category 
includes participants who did not take statin post baseline or who stopped the statin during the 
study. 
Changes in LLTs prior to baseline will focus on statin and bempedoic acid taken within 30 days 
prior to study treatment start date, i.e. any time from day -30 to day -1. Number and percentage 
of participants will be presented for the following statin categories: initiation of statin therapy 
(no statin record present at day -30), discontinuation of statin therapy (no statin record present 
at day -1), increase in statin intensity, decrease in statin intensity, and change of statin within 
the same intensity group. Treatment gaps and/or overlapping treatment periods in case of two 
or more statins within the 30-day period will be ignored for analysis. If at least one statin record 
is present indicating that the statin was taken consistenly on all days within the 30-day period, 
the participant will not be considered as having had any change in statin therapy. 
For the analysis of lipid-lowering therapies at baseline a modified lipid-lowering therapy 
definition is also employed.  For this analysis a modified lipid lowering therapy includes any 
statin, ezetimibe, PCSK9 inhibiting monoclonal antibodies, or bempedoic acid therapies. 
The following medications will be included in the lipid-lowering therapy tables. 
Table 2-3 
Lipid-lowering Therapies 
Medication 
Medications included 
Lipid Lowering Therapy 
ATCCODE2=C10 
Statin 
ATCCODE2=C10 and CMDECOD contains ‘statin’, or 
ATCCODE4=C10AA, C10BA, or C10BX 
Ezetimibe 
ATCCODE2=C10 and CMDECOD contains ‘ezetimibe’ 
PCSK9 inhibiting 
monoclonal antibodies 
ATCCODE2=C10 and CMDECOD contains ‘evolocumab’ or ‘alirocumab’ 
Bempedoic acid 
ATCCODE2=C10 and CMDECOD contains ‘bempedoic acid’ 
Modified lipid lowering 
therapy 
ATCCODE2=C10 and CMDECOD contains ‘statin’, ‘ezetimibe’, 
‘evolocumab’, ‘alirocumab’, or ‘bempedoic acid’ 
2.5 
Analysis supporting primary objective(s) 
The primary objective is to assess the effect on LDL-C of implementation of an LDL-C 
management care pathway that includes initiation of inclisiran in participants with a recent 
hospitalization (in-patient/out-patient) for an ACS with LDL-C ≥70 mg/dL despite receiving 
statin therapy compared to usual care without inclisiran at Day 330. 
2.5.1 
Primary endpoint(s) 
The primary efficacy variables are the following: 
1. Percent change from baseline in LDL-C  


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2. Achieving LDL-C < 70 mg/dL (yes, no) 
The primary analysis time point for both primary efficacy variables is at Day 330. 
2.5.2 
Statistical hypothesis, model, and method of analysis  
Primary efficacy variable 1 
The null hypothesis is that the mean percent change from baseline in LDL-C at Day 330 for 
inclisiran + usual care and usual care treatment groups are equal. The alternative hypothesis is 
that the mean percent change from baseline in LDL-C at Day 330 for inclisiran + usual care 
treatment group is not equal to that of the usual care treatment group. 
Primary efficacy variable 1 will be analyzed using mixed-effects model repeated measures 
(MMRM) with treatment, visit (Day 90, Day 270, Day 330), baseline, treatment-by-visit 
interaction, and baseline-by-visit interaction as explanatory variables. An unstructured 
covariance matrix will be assumed for this model. Least-squares mean of each treatment group, 
least-squares mean treatment difference, two-sided 97.5% confidence intervals for the 
treatments, two-sided 97.5% confidence interval for the treatment difference, and p-value based 
on the fitted MMRM will be reported for each applicable visit (day). If the p-value based on a 
two-sided test for treatment at Day 330 is < 0.025 and the corresponding least squares mean 
treatment difference ([inclisiran + usual care] - usual care) is less than 0, statistical significance 
in favor of inclisiran + usual care is shown. All efforts will be made to follow up participants 
until the end of the study. Participants will be expected to follow the visit schedule and 
assessments even after discontinuation of study treatment. Data after participants discontinued 
study treatment will be used in the analysis (“retrieved dropout”). In case of non-convergence 
of a model while using an unstructured covariance matrix, compound symmetry will be tried 
instead. 
The primary analysis of primary efficacy variable 1 will be based on the FAS. The primary 
analysis of this variable will be repeated for the Per-Protocol Set, Restricted Set 1, and 
Restricted Set 2. 
Primary efficacy variable 2 
Let πj denote the probability of achieving LDL-C < 70 mg/dL at Day 330 for treatment group j, 
j = 0, 1, where 0 corresponds to usual care and 1 corresponds to inclisiran + usual care. 
Accordingly, πj/(1 – πj) is the odds for treatment group j, j = 0, 1. 
The following null hypothesis (H0) will be tested against the alternative hypotheses (HA), 
corresponding to the comparison inclisiran + usual care versus usual care: 
H0: [π1/(1 – π1)]/[π0/(1 – π0)] ≤ 1 versus HA: [π1/(1 – π1)]/[π0/(1 – π0)] > 1 
Primary efficacy variable 2 will be analyzed at each post-baseline visit using a logistic 
regression model with treatment and baseline LDL-C as explanatory variables (Stokes et al. 
2012). The odds ratio, two-sided 97.5% confidence interval for the odds ratio, and p-value based 
on the fitted model will be reported. If the p-value based on a two-sided test for inclisiran + 
usual care versus usual care at Day 330 is < 0.025 and the corresponding odds ratio is greater 
than 1, statistical significance in favor of inclisiran + usual care is shown. In case of non-


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convergence of a logistic regression model, the model will be updated to use Firth's  penalized 
likelihood method (Firth 1993). If the model using Firth's method still shows convergence 
issues then the baseline LDL-C covariate may be removed from the model. Two-sided 97.5% 
confidence intervals for the proportion of participants who achieve LDL-C < 70 mg/dL in each 
treatment group will be calculated, using the normal approximation to the binomial distribution. 
The primary analysis of primary efficacy variable 2 will be based on the FAS. The primary 
analysis of this variable will be repeated for the Per-Protocol Set, Restricted Set 1, and 
Restricted Set 2. 
2.5.3 
Handling of intercurrent events  
The remaining intercurrent event of the primary estimand for the two primary efficacy variables 
are the following:  
1. Potential use of inclisiran by participants in the usual care group. This intercurrent event 
will be ignored in the analysis, as the design of the trial allows for participants in the 
usual care group to potentially use inclisiran.  
2. Discontinuation of study treatment (in inclisiran + usual care participants). This 
intercurrent event will be ignored in the analysis. 
3. Use of prohibited medication (monoclonal antibodies directed against PCSK9, as 
defined in Table 2-3) in the inclisirian + usual care group. This intercurrent event will 
be ignored in the analysis. 
2.5.4 
Handling of missing values not related to intercurrent event 
For the primary analysis of primary efficacy variable 1, the MMRM implicitly imputes missing 
data under a missing at random assumption. 
For the primary analysis of primary efficacy variable 2, participants with missing LDL-C data 
will be assumed to have LDL-C ≥ 70 mg/dL (i.e., “non-responder”). 
2.5.5 
Sensitivity analyses  
The sensitivity analysis of primary efficacy variable 1 to address the primary objective will be 
based on the following estimand: 
• Population: Defined through appropriate inclusion/exclusion criteria to reflect the 
targeted population 
• Variable: Percent change from baseline in LDL-C [The primary analysis time point is 
at Day 330.] 
• Treatment: Inclisiran + usual care or usual care 
• Remaining intercurrent events: 1. Potential use of inclisiran by participants in the 
usual care group. This intercurrent event will be ignored in the analysis, as the design 
of the trial allows for participants in the usual care group to potentially use inclisiran. 
2. Discontinuation of study treatment. This intercurrent event will be ignored in the 
analysis. 3. Use of prohibited medication (monoclonal antibodies directed against 


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PCSK9, as defined in Table 2-3) in the inclisirian + usual care group. This 
intercurrent event will be ignored in the analysis. 
• Summary measure: Probability of observing the same or a more favorable response 
with inclisiran + usual care relative to usual care 
For the above estimand, primary efficacy variable 1 will be analyzed at each time point for the 
FAS using the Wilcoxon rank-sum test.  
The probability of observing the same or a more favorable response (θ0) with inclisiran + usual 
care relative to usual care will be estimated using nonparametric methods, and the associated 
two-sided 97.5% confidence interval will also be reported (Chen and Kianifard 2000). 
The sensitivity analysis of primary efficacy variable 2 to address the primary objective will be 
based on the following estimand: 
• Population: Defined through appropriate inclusion/exclusion criteria to reflect the 
targeted population 
• Variable: Achieving LDL-C < 70 mg/dL (yes, no) [The primary analysis time point is 
at Day 330.] 
• Treatment: Inclisiran + usual care or usual care 
• Remaining intercurrent events: 1. Potential use of inclisiran by participants in the 
usual care group. This intercurrent event will be ignored in the analysis, as the design 
of the trial allows for participants in the usual care group to potentially use inclisiran. 
2. Discontinuation of study treatment. This intercurrent event will be ignored in the 
analysis. 3. Use of prohibited medication (monoclonal antibodies directed against 
PCSK9, as defined in Table 2-3) in the inclisirian + usual care group. This 
intercurrent event will be ignored in the analysis. 
• Summary measure: Treatment difference ([inclisiran + usual care] – usual care) in the 
proportion of participants who achieve LDL-C < 70 mg/dL 
For the above estimand, primary efficacy variable 2 will be analyzed at each post-baseline visit 
for the FAS using the two-sample z-test (normal approximation to the binomial distribution) to 
compare inclisiran + usual care versus usual care. Two-sided 97.5% confidence intervals will 
be calculated, using the normal approximation to the binomial distribution. 
For both primary efficacy variables 1 and 2, additional sensitivity analyses will be conducted 
by repeating the corresponding primary analyses on participants in the Full Analysis Set but 
excluding participants with baseline LDL-C < 70 mg/dL. 
2.5.6 
Supplementary analyses 
A supplementary analysis of primary efficacy variable 1 will be based on the following 
estimand: 
• Population: Defined through appropriate inclusion/exclusion criteria to reflect the 
targeted population 
• Variable: Percent change from baseline in LDL-C [The primary analysis time point is 
at Day 330.]  


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• Treatment: Inclisiran + usual care or usual care  
• Remaining intercurrent events: 1. Potential use of inclisiran by participants in the 
usual care group. 2. Discontinuation of study treatment. 3. Use of prohibited 
medication (monoclonal antibodies directed against PCSK9, as defined in Table 2-3) 
in the inclisirian + usual care group. Data after the occurrence of either one of the 
above three intercurrent events will be excluded from the analysis (using MMRM).  
• Summary measure: Least-squares mean difference between inclisiran + usual care 
group and usual care group 
A supplementary analysis of primary efficacy variable 2 will be conducted by repeating the 
primary analysis based on observed LDL-C values per visit. Missing data will not be imputed. 
Therefore, the denominator for deriving the proportion of participants achieving LDL-C <70 
mg/dL will be the number of participants with non-missing LDL-C per visit and treatment group. 
2.5.7 
Subgroup analyses 
The primary analysis for primary efficacy variables 1 and 2 will be  repeated for subgroups of 
participants according to the subgroup categories defined in Section 2.2.1. To this end, the same 
approach as defined in Section 2.5.2 for the primary analysis will be applied separately to the 
sets of participants within each subgroup category. Note that results for a subgroup category 
will only be presented if the total across both treatment groups within the category is at least 10 
participants.  
2.6 
Analysis supporting secondary objectives  
The secondary efficacy objectives include the following: 
• To assess (1) the absolute change from baseline in LDL-C level by visit, and (2) 
average of percent and absolute changes from baseline in LDL-C levels to each post-
baseline visit, in the inclisiran + usual care group compared to usual care group at 
Day 330 
• To assess the proportion of participants reaching pre-specified LDL-C targets in the 
inclisiran + usual care group compared to usual care group at Day 330 
• To assess plasma lipoproteins and triglycerides in the inclisiran + usual care group 
compared to usual care group at Day 330 
• To assess changes in and adherence to background lipid-lowering therapy in the 
inclisiran + usual care group compared to usual care group at Day 330 
2.6.1 
Secondary endpoint(s) 
The secondary efficacy variables are the following: 
1. Absolute change from baseline in LDL-C 
2. Average percent change from baseline in LDL-C levels to each post-baseline visit 
3. Average absolute change from baseline in LDL-C levels to each post-baseline visit 


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4. Achieving LDL-C < 100 mg/dL (yes, no) (among the subset of participants with LDL-
C ≥ 100 mg/dL at baseline) 
5. Achieving ≥ 50% reduction from baseline in LDL-C (yes, no) 
6. Achieving LDL-C < 55 mg/dL (yes, no) 
7. Percent change from baseline in apoB 
8. Absolute change from baseline in apoB 
9. Percent change from baseline in VLDL 
10. Absolute change from baseline in VLDL 
11. Percent change from baseline in non-HDL-C 
12. Absolute change from baseline in non-HDL-C 
13. Percent change from baseline in total cholesterol 
14. Absolute change from baseline in total cholesterol 
15. Percent change from baseline in Lp(a) 
16. Absolute change from baseline in Lp(a) 
17. Percent change from baseline in HDL-C 
18. Absolute change from baseline in HDL-C 
19. Percent change from baseline in triglycerides 
20. Absolute change from baseline in triglycerides 
21. Intensity of lipid-lowering therapy (decrease in dose, no change in dose, increase in dose) 
Intensity of therapy is only available for statins, not for other lipid-lowering therapies 
used in this study. Therefore, for each participant and analysis visit, the highest statin 
intensity on each nominal visit date will be compared to baseline statin intensity. The 
decrease, no change, and increase in statin intensity at each visit will be assigned as 
follows: 
Statin Intensity 
Post-baseline Visit 
Baseline 
 
High 
Moderate 
Low 
None 
High 
No change 
Decrease 
Decrease 
Decrease 
Moderate 
Increase 
No change 
Decrease 
Decrease 
Low 
Increase 
Increase 
No change 
Decrease 
None 
Increase 
Increase 
Increase 
No change 
22. Proportion of days covered (total number of days on either statin, ezetimibe, or PCSK9 
inhibiting monoclonal antibody therapies divided by total number of study days) 
If a participant did not take any of the three medications, then the total number of days 
will be assumed to be zero. Total number of study days is the total study duration (not 
treatment duration). 


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23. Discontinuation of statin therapy (i.e., no statin use ≥ 30 days before the end-of-study 
visit) (yes, no) 
If a participant is considered a study completer and has a non-missing visit date for the 
nominal Day 330 visit recorded, a statin assessment date (to assess if the participant was 
taking statins at this point in time) will be calculated by subtracting 30 days from the 
Day 330 visit date (e.g., study Day 300 if the participant completes on study Day 330). 
The statin assessment date will be compared to the maximum statin end date of all statin 
medications taken by the participant. If the last statin is recorded as ongoing at study 
end date, the maximum statin end date will be set to the study end date. 
If the participant was on a statin on or after this statin assessment day (maximum statin 
end date ≥ statin assessment date), the participant will be considered as discontinued 
statin = ‘no’. 
If the participant was not on a statin on and after this statin assessment day (maximum 
statin end date < statin assessment date), or they were a completer who did not have a 
Day 330 visit, the participant will be considered as discontinued statin = ‘yes’. 
All early termination participants will be considered to not be on a statin for this 
endpoint (the participant will be considered as discontinued statin = ‘yes’). 
Participants who were not taking any statin while on study will be considered to not be 
on a statin for this endpoint (the participant will be considered as discontinued statin = 
‘yes’). 
The analysis will be based on the FAS excluding participants who had medical history 
of statin intolerance. 
2.6.2 
Statistical hypothesis, model, and method of analysis 
Analyses of secondary efficacy variables 1 and 7 - 20 will be similar to the primary analysis of 
primary efficacy variable 1 (using MMRM, but with a two-sided 95% confidence interval for 
the treatment difference). 
Secondary efficacy variables 2, 3, and 22 will be analyzed using an analysis of covariance 
(ANCOVA) linear model with treatment and baseline LDL-C as explanatory variables. Least-
squares mean of each treatment group, 95% confidence interval for the treatment group least-
squares means, least-squares mean treatment difference, 95% confidence interval for the 
treatment difference, and p-value based on the fitted model will be reported. Variables 2 and 3 
are calculated by averaging the observed post-baseline values (change or percent change) for 
each participant across analysis visits Day 90, Day 270, and Day 330. The outcome value for 
variable 22 is a proportion that is calculated for each participant with total number of study days 
equal to duration on study as defined in Section 2.3.1. 
Secondary efficacy variables 4 - 6 and 23 will be analyzed at each applicable post-baseline visit 
using a logistic regression model with treatment and baseline LDL-C as explanatory variables 
(Stokes et al. 2012). The odds ratio, 95% confidence interval for the odds ratio, and p-value 
based on the fitted model will be reported. Confidence intervals for the percentages per 
treatment group will be presented and will be derived from the normal approximation to the 


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binomial distribution. Missing data will be imputed using “non-responder” (i.e., “negative” 
outcome) imputation. 
Secondary efficacy variable 21 will be analyzed at each post-baseline visit using a proportional 
odds model with treatment and baseline LDL-C as explanatory variables (Stokes et al. 2012). 
The odds ratios, 95% confidence intervals for the odds ratios, and p-values based on the fitted 
model will be reported. Confidence intervals for the percentages per treatment group will be 
presented and will be derived from the normal approximation to the binomial distribution. 
Missing data will not be imputed. 
Analyses of secondary efficacy variables will be based on the FAS. 
2.6.3 
Handling of missing values 
For the analysis of secondary efficacy variables 1 and 7-20, the MMRM implicitly imputes 
missing data under a missing at random assumption. 
For the analysis of secondary efficacy variables 4 – 6 and 23, participants with missing data 
will be imputed using “non-responder” (i.e., “negative” outcome) imputation. 
For the analysis of secondary efficacy variables 2, 3, 21 and 22, missing data will not be imputed. 
2.6.4 
Sensitivity analyses 
Not applicable. 
2.6.5 
Supplementary analyses 
Secondary efficacy variables 2 and 3 will be analyzed using MMRM similar to the analysis of 
primary efficacy variable 1 and secondary efficacy variable 1, respectively. A linear 
combination of the estimated means will be used to estimate the time-adjusted percent change 
and absolute change from baseline in LDL-C, where “time-adjusted” refers to the estimated 
average from Day 90 through Day 330. Least-squares mean of each treatment group, least-
squares mean treatment difference, 95% confidence interval for the treatment difference, and 
p-value based on the fitted model will be reported. 
Secondary efficacy variables 4 – 6 will be analyzed similar to the supplementary analysis of 
primary efficacy variable 2 based on observed data only. 
2.6.6 
Subgroup analyses 
The analysis for secondary efficacy variable 1 (absolute change from baseline in LDL-C) will 
be repeated for subgroups of participants according to the subgroup categories defined in 
Section 2.2.1. To this end, the same approach as defined in Section 2.6.2 for the analysis of 
secondary efficacy variable 1 will be applied separately to the sets of participants within each 
subgroup category. Note that results for a subgroup category will only be presented if the total 
across both treatment groups within the category is at least 10 participants.  
2.7 
Safety analyses 
All safety analyses will be performed on the Safety Set. 


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2.7.1 
Adverse events (AEs) 
The Medical Dictionary for Regulatory Activities (MedDRA) dictionary will be used for coding 
AEs, and up-versioning will be applied during the course of study. The final MedDRA version 
used in this study will be v27.0. Partially missing AE dates will be imputed following Appendix 
5.1.2. An AE (classified as preferred term) occurring during the treatment period will be 
counted as a treatment-emergent AE (TEAE) either if it is not present at Day 1 before treatment 
or if it is present before treatment but increased in severity during the treatment period. 
Therefore, all recorded AEs with onset on or after the study treatment start date will be counted 
as TEAE. In case the AE date values do not allow unequivocally allocating an AE record to 
TEAE or non-TEAE, the AE will be considered as TEAE in the statistical analysis.The 
following summary tables will be presented:  
• Overall Summary of TEAEs 
• TEAEs by System Organ Class (SOC) and Preferred Term (PT) 
• TEAEs by PT 
• Common (≥3% within either treatment group) by PT 
• TEAEs by SOC, PT, and Severity 
 
• TEAEs by SOC, PT, and Relationship to Study Treatment 
• Related TEAEs by SOC, PT, and Severity 
• Treatment Emergent Serious AEs (TESAEs) by SOC and PT 
• TESAEs by PT 
• TESAEs by SOC, PT, and Severity 
• TESAEs by SOC, PT, and Relationship to Study Treatment 
• Related TESAEs by SOC, PT, and Severity 
• TEAEs Leading to Withdrawal of Study Treatment by SOC and PT 
• TEAEs with a Fatal Outcome by SOC and PT  
If more than one event occurred with the same PT for the same participant, the participant will 
be counted only once for that PT using the most severe or related occurrence for the summary 
by severity, or relationship to study drug, respectively.  
Missing severity and relationship will not be imputed and will be identified as ‘missing’ in the 
tables.   
For common (3% within either treatment group) TEAEs, serious TEAEs and TEAEs leading to 
withdrawal of study treatment, risk ratios along with 95% confidence intervals will be presented 
to compare treatment groups with respect to risk. 
For tables presented by SOC and PT, system organ classes are sorted alphabetically and within 
each system organ class, the preferred terms are sorted in descending order of total frequency. 
For tables presented by PT, preferred terms are sorted in descending order of total frequency. 
Listings will be presented for participants with SAEs and AEs leading to discontinuation of 
study treatment. 


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2.7.1.1 
Adverse events of special interest / grouping of AEs 
TESAEs and TEAEs of special interest will be tabulated. 
SAEs of special interest include: 
1. Hepatotoxicity  
2. Renal events 
AEs of special interest include: 
1. TEAE at the injection site  
• TEAE identified as being an AE at the injection site on the AE CRF page 
• Injection site reaction (HLT)  
2. Hepatotoxicity  
• Drug related hepatic disorders - comprehensive search (SMQ, broad and narrow)  
3. Renal events  
• Acute renal failure (SMQ, broad and narrow) 
4. New-onset/worsening of diabetes  
• Hyperglycemia/new-onset diabetes mellitus (SMQ, narrow)  
• Diabetic Complications (HLGT)  
• Diabetes Mellitus (HLT)  
• Carbohydrate tolerance analyses (HLT), excluding PT “Blood glucose decreased”  
5. Hypersensitivity  
• Hypersensitivity (SMQ, broad and narrow) excluding  
• PTs ‘infusion site %’ (e.g., ‘'infusion site dermatitis', 'infusion site eczema’, 
'infusion site hypersensitivity', 'infusion site rash', 'infusion site urticaria', 
'infusion site vasculitis) and  
• PTs ‘injection site %’ (e.g., 'injection site dermatitis', 'injection site eczema’, 
'injection site hypersensitivity', 'injection site rash', 'injection site urticaria' and 
'injection site vasculitis')  
TEAEs at the injection sites will be presented for all participants and then by baseline glycemic 
status, specifically for participants with diabetes at baseline and for participants without 
diabetes at baseline (i.e., participants with pre-diabetes or normoglycemia). The definition of 
baseline glycemic status is provided in Table 2-4. 
2.7.2 
Deaths 
Listings will be presented for participants with SAEs/AEs leading to a death. 
2.7.3 
Laboratory data 
Laboratory values will be summarized by treatment group, including the observed value, 
changes and percent changes from baseline at each analysis visit (including Day 330/Last Visit). 


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Estimated glomerular filtration rate (eGFR) in mL/min/1.73m2 will be derived using the 
Modification of Diet in Renal Disease approach according to the following formula based on 
serum creatinine values in mg/dL (Levey et al. 2006): 
eGFR = 175 × Serum Cr-1.154 × Age-0.203 × 1.212 (if participant is black) × 0.742 (if female). 
Fasting glucose parameter, when used in any analysis, will require the lab sample to be taken 
while fasting. Glucose values recorded under non-fasting conditions will not be used. For all 
safety analyses, baseline fasting glucose uses the average of the last two assessments 
measured under fasting conditions at or prior to baseline. If only one fasting glucose value is 
available at or prior to baseline, the analysis will be based on the available data. 
A shift analysis using the normal range (except for eGFR and HbA1c) will be done which counts 
the number of participants with a low, normal or high value at baseline and a low, normal or 
high value post baseline.  
The following ranges will be used for eGFR and hemoglobin A1c (HbA1c): 
• For eGFR, the categories will be Severe = <30 mL/min/1.73m2; Moderate = ≥ 30 to 
<60 mL/min/1.73m2; Mild = ≥ 60 to <90 mL/min/1.73m2; and Normal = ≥90 
mL/min/1.73m2. 
• For HbA1c, the categories will be ≤5.6%, ≥5.7% to ≤6.4%, and ≥6.5%. 
The baseline and worst post-baseline value will be utilized for the shift tables.  Note that the 
shift table dealing with the fasting glucose parameter will require the lab sample to be taken 
while fasting. Samples taken while the participant was not fasting will not be analyzed. For 
CSR purposes, HbA1c will be reported under clinical chemistry, not hematology. 
New onset or worsening of diabetes during the study will be identified by evaluating different 
components: 1) adverse events, 2) laboratory measures of either fasting glucose of glycated 
hemoglobin (HbA1c) and 3) initiation of antidiabetic medication. New onset or worsening of 
diabetes is defined if ANY of the following conditions are met post-baseline: 
• Laboratory results indicating diabetes, which can be any of the following:   
• The participant has HbA1c ≥6.5% on two consecutive tests.  
• The participant has fasting glucose ≥126 mg/dL on two consecutive fasted tests.  
• The participant has HbA1c ≥6.5% and fasting glucose ≥126 mg/dL on the same 
occasion.  
• The participant has HbA1c ≥6.5% on one occasion and has fasting glucose ≥126 
mg/dL on the succeeding occasion.  
• The participant has fasting glucose ≥126 mg/dL on one occasion and has HbA1c 
≥6.5% on the succeeding occasion. 
• Diabetic TEAEs identified by the search terms:  
• Hyperglycaemia/new onset diabetes mellitus (SMQ, narrow) 
• Diabetic complications (HLGT) 
• Diabetes mellitus (incl subtypes) (HLT) 


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• Carbohydrate tolerance analyses (incl diabetes) (HLT), excluding PT “Blood 
glucose decreased” 
• Initiation of anti-diabetic medication (ATC level 2 code: A10) at any time post-
baseline. 
The number and percentage of participants presenting with new onset of diabetes post-baseline 
according to the criteria above will be summarized among participants without diabetes at 
baseline (i.e., participants with pre-diabetes or normoglycemia). To this end, baseline glycemic 
status will be determined as per the criteria in Table 2-4. Baseline glycemic status will also be 
used in the subgroup analysis of the primary and key secondary efficacy endpoints, as well as 
in the analysis of TEAEs at the injection site (Section 2.7.1.1). Participants for whom the 
baseline glycemic status cannot be determined according to the rules below will be excluded 
from the analysis. 
Table 2-4 
Definition of Baseline Glycemic Status 
Category 
Definition 
Diabetes 
Participants with diabetes at baseline are those with ANY of the following: 
• Medical history of diabetes recorded on ACS medical history CRF 
(diabetes recorded as “Yes”).  
• Anti-diabetic medication (ATC level 2 code: A10) at baseline 
• HbA1c ≥6.5% AND fasting glucose ≥126 mg/dL at baseline. 
Pre-diabetes 
Participants with pre-diabetes at baseline are those with ALL of the following: 
• No medical history of diabetes recorded on ACS medical history CRF 
(diabetes not recorded as “Yes”). 
• No anti-diabetic medication (ATC level 2 code: A10) at baseline. 
• HbA1c ≥5.7% OR fasting glucose ≥100 mg/dL at baseline, but not both 
HbA1c ≥6.5% AND fasting glucose ≥126 mg/dL at baseline. 
Note: Either baseline HbA1c or baseline fasting glucose have to be non-
missing to evaluate this category. 
Normoglycemia 
Participants with normal glucose control status at baseline are those with ALL 
of the following: 
• No medical history of diabetes recorded on ACS medical history CRF 
(diabetes not recorded as “Yes”). 
• No anti-diabetic medication (ATC level 2 code: A10) at baseline. 
• HbA1c < 5.7% AND fasting glucose < 100 mg/dL at baseline. 
Note: Both baseline HbA1c and baseline fasting glucose have to be non-
missing to evaluate this category. 
 
The number and percentage of participants with potentially clinically significant (PCS) 
laboratory values or clinically significant (CS) laboratory values (refer to Appendix 5.3.2 for 
the criteria) will be summarized. It is possible that some laboratory values for a parameter may 
be classified as PCS while others are CS.  In this case, the CS laboratory value for that parameter 
will be used in the summaries.  For AST, ALT and CK, the most severe result for each subject 
will be used. For creatinine, the CS criterion will additionally be broken down into the following 
three mutually exclusive categories: 












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2.13 
Interim analysis 
After all participants complete their baseline visit, the demographic and baseline characteristics 
may be summarized to help design new studies. No analysis will be performed using post-
baseline data. Thus, there is no need to adjust the level of significance for such interim analysis 
of baseline data. 
3 
Sample size calculation 
The sample size was calculated for the two primary efficacy variables with adjustment for 
multiple testing by using the Bonferroni procedure. 
For primary efficacy variable 1, i.e., percent change from baseline in LDL-C, the standard 
deviation is assumed to be 40, partly based on the results from ORION-10 and ORION-11 
clinical trials and considering that the standard deviation will likely be larger in this trial since 
changes in lipid-lowering therapy are allowed in both treatment groups. An expected mean 
treatment difference of 15 is assumed, which is smaller than the mean difference observed in 
the Phase III trials, to account for 1) potential lower utilization of background lipid-lowering 
therapy in the inclisiran + usual care treatment group compared to the usual care treatment 
group, and 2) the ability to add non-statin lipid lowering therapy in the usual care treatment 
group. A z-test, an allocation ratio of 1:1, and a two-sided significance level of 0.025 were also 
used in the calculation of sample size. 
Table 3-1 considers total sample sizes for expected mean treatment differences of 10, 15, and 
20, and powers of 0.85 and 0.90 (nQuery Version 8.4.1.0). From Table 3-1, an expected mean 
treatment difference of 15 (based on means of 40 and 55 at Day 330 in the usual care and 
inclisiran + usual care treatment groups, respectively) and a power of 0.85 were chosen to 
provide a total sample size of 306 participants. 
Table 3-1 
Sample Size Calculations for Percent Change from Baseline in LDL-C 
Mean treatment difference 
Power = 0.85 
Power = 0.90 
10 
688 
796 
15 
306 
354 
20 
172 
200 
For primary efficacy variable 2, i.e., achieving LDL-C < 70 mg/dL (yes, no), a z-test, an 
allocation ratio of 1:1, and a two-sided significance level of 0.025 were used in the calculation 
of sample size.  
Table 3-2 considers total sample sizes for several expected proportions of participants who 
achieve LDL-C < 70 mg/dL at Day 330 in the usual care and inclisiran + usual care treatment 
groups, and powers of 0.85 and 0.90 (nQuery Version 8.4.1.0). From Table 3-2, the expected 
proportions of 0.55 and 0.75 in the usual care and inclisiran + usual care treatment groups, 
respectively, and a power of 0.85 were chosen to provide a total sample size of 242 participants. 
 
 
 


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Table 3-2 
Sample Size Calculations for Achieving LDL-C < 70 mg/dL 
Proportion in usual 
care group 
Proportion in inclisiran + 
usual care group 
Power = 0.85 
Power = 0.90 
0.50 
0.65 
464 
536 
0.50 
0.70 
256 
294 
0.55 
0.70 
446 
514 
0.55 
0.75 
242 
278 
Based on the sample size calculations in the tables above, a total sample size of 306 together 
with a loss to follow-up rate of 20% at Day 330 require approximately 384 participants (192 
participants per treatment group) to be randomized. This will also allow examination of 
subgroups with reasonable sample sizes. 
4 
Change to protocol specified analyses 
Change from Protocol version 04 (amended protocol) include the following: 
1. Protocol Section 12.4.2 states that an unstructured working correlation matrix will be 
assumed for the MMRM.  An unstructured covariance matrix will be used instead. In 
case of convergence issues, compound symmetry will be tried instead. 
2. The protocol uses Day 0 as the first inclisiran dose day.  In order to aid in counting of 
dosing days the first dose day will be referred to as Day 1. 
3. Protocol Section 12 notes that the interquartile range will be provided. In order to 
streamline the tables this statistic was removed. 
4. Protocol Section 12.2 notes that relevant medical histories and current medical 
conditions at baseline would be summarized using the Safety Set, the FAS was used 
instead. 
5. Protocol Section 12.5.1 lists out secondary efficacy variables. The analysis of variable 
#21 (Intensity of lipid-lowering therapy (decrease in dose, no change in dose, increase 
in dose) was modified slightly.  Intensity of therapy is only available for statins, not 
for other lipid-lowering therapies used in this study. Therefore, for each participant 
and analysis visit, the highest statin intensity on each nominal visit date will be 
compared to baseline statin intensity. 
6. Protocol Section 12.5.2 notes that all vital signs and all laboratory data will be listed. 
In order to streamline the listings, only abnormal vital signs and laboratory data will 
be provided. 
7. Use of prohibited medication as defined in Protocol Section 6.2.2 (monoclonal 
antibodies directed against PCSK9) will be considered as an intercurrent event for 
participants in the inclisirian + usual care group and was therefore incorporated to all 
estimands as applicable. 




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Relationship 
Before start reference 
Partial date indicates start date prior to start reference 
After start reference 
Partial date indicates start date after start reference 
Uncertain 
Partial date insufficient to determine relationship of start date to 
start reference 
Imputation Calculation 
NC/Blank 
No date imputation 
(A) 
01MONYYYY 
(B) 
Start reference 
(C) 
15MONYYYY 
(D) 
01JULYYYY 
(E) 
01JANYYYY 
Complete date 
No date imputation 
 
End Date Imputation: 
• Imputed date = date part of original date, if complete date 
• Imputed date = min (study end date, DEC 31, date of death), if month is missing 
• Imputed date = min (study end date, last day of the month, date of death), if day is 
missing 
Imputed Date Flag: 
• If year of the imputed date is not equal to YYYY then date flag = Y 
• Else if month of the imputed date is not equal to MON then date flag = M 
• Else if day of the imputed date is not equal to day of original date then date flag = D 
• Else date flag = null 
5.2 
AEs coding/grading 
Not applicable. 
5.3 
Laboratory parameters derivations 
5.3.1 
Handling data with special symbols 
Any laboratory parameters with values identified as <x, ≤x, >x, or ≥x will be analyzed using 
the ‘x’ value (the analysis will ignore the <, ≤, >, or ≥ symbol). 


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5.3.2 
Criteria for potentially clinically significant and clinically significant 
abnormal laboratory tests 
Hemoglobin A1C criteria are explicitly stated in the table below. For all other parameters, a 
PCS/CS criterion is met when both of the following occur: 
• There is a post-baseline value that meets the threshold 
• The baseline value does not meet the threshold 
Some examples are: 
• For leukocytes, a subject satisfies “<= 2.8 x 10^9/L” criterion as long as the baseline 
value is > 2.8 x 10^9/L and any post-baseline value is <= 2.8 x 10^9/L; a subject 
satisfies “>=16 x 10^9/L” criterion as long as the baseline value is <16 x 10^9/L and 
any post-baseline value is >=16 x 10^9/L. 
• For CK, a subject satisfies “> 3 and ≤ 5 × ULN” criterion as long as the baseline 
value is ≤ 3 x ULN and any post-baseline value is > 3 and ≤ 5 × ULN. A subject 
satisfies “> 5 and ≤ 10 × ULN” criterion as long as the baseline value is ≤ 5 x ULN 
and any post-baseline value is > 5 and ≤ 10 × ULN. If a subject satisfies both “> 3 and 
≤ 5 × ULN” and “> 5 and ≤ 10 × ULN” criteria and does not satisfy the criteria of any 
more severe category, the subject will be presented under “> 5 and ≤ 10 × ULN” but 
not under “> 3 and ≤ 5 × ULN” because the most severe category will be used for 
CK. 
• For serum creatinine, the CS criterion is satisfied if at least one of the following is 
true: 
• The baseline value is ≤ 2 mg/dL and any post-baseline value is > 2 mg/dL. 
• Any post-baseline value is ≥ 50% increase from baseline, regardless of whether 
the baseline value is ≤ 2 mg/dL. 
• For creatinine, the CS criterion will additionally be broken down into the following 
three mutually exclusive categories: 
1. Subjects with baseline value ≤ 2 mg/dL and any post-baseline value > 2 mg/dL. 
2. Subjects with baseline value ≤ 2 mg/dL and any post-baseline ≥ 50% change 
from baseline but no post-baseline value > 2 mg/dL. 
3. Subjects with baseline value > 2 mg/dL and any post-baseline ≥ 50% change 
from baseline. 
 
Table 5-1 
Laboratory Test Criteria 
Variable 
Unit 
Lower Boundary 
Upper Boundary  
Hematology 
Hematocrit 
% 
≤0.8 × LLN 
N/A 
Hemoglobin 
g/dL 
≤10 g/dL 
N/A 
Platelet Count 
10^9/ L 
≤75* 
≥700* 
White Blood Cell Count 
10^9/L 
≤2.8 
≥16 


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Variable 
Unit 
Lower Boundary 
Upper Boundary  
Serum Chemistry 
Alanine Aminotransferase (ALT/SGPT) 
U/L 
N/A 
>1 and ≤3 × ULN 
Alanine Aminotransferase (ALT/SGPT) 
U/L 
N/A 
>3 and ≤5 × ULN* 
Alanine Aminotransferase (ALT/SGPT) 
U/L 
N/A 
>5 and ≤10 × ULN* 
Alanine Aminotransferase (ALT/SGPT) 
U/L 
N/A 
>10 and ≤20 × ULN* 
Alanine Aminotransferase (ALT/SGPT) 
U/L 
N/A 
>20 × ULN* 
Alkaline Phosphatase 
U/L 
N/A 
>2 × ULN* 
Aspartate Aminotransferase (AST/SGOT) 
U/L 
N/A 
>1 and ≤3 × ULN 
Aspartate Aminotransferase (AST/SGOT) 
U/L 
N/A 
>3 and ≤5 × ULN* 
Aspartate Aminotransferase (AST/SGOT) 
U/L 
N/A 
>5 and ≤10 × ULN* 
Aspartate Aminotransferase (AST/SGOT) 
U/L 
N/A 
>10 and ≤20 × ULN* 
Aspartate Aminotransferase (AST/SGOT) 
U/L 
N/A 
>20 × ULN* 
Creatine Kinase (CK) 
U/L 
N/A 
>1 and ≤3 × ULN 
Creatine Kinase (CK) 
U/L 
N/A 
>3 and ≤5 × ULN 
Creatine Kinase (CK) 
U/L 
N/A 
>5 × and ≤10 × ULN* 
Creatine Kinase (CK) 
U/L 
N/A 
>10 and ≤20 × ULN* 
Creatine Kinase (CK) 
U/L 
N/A 
>20 × ULN* 
Hemoglobin A1C 
% 
N/A 
≥6.5% and ≥0.5% 
change from baseline  
Serum Creatinine 
mg/dL 
N/A 
≥50% increase from 
baseline or >2 mg/dL* 
Total Bilirubin 
mg/dL 
N/A 
>2 × ULN* 
LLN: Lower limit of the standard reference (normal) range; ULN: Upper limit of the standard 
reference (normal) range; N/A is Not Applicable. 
For AST, ALT, and CK, the most severe result for each subject will be used. 
*Clinically significant laboratory boundaries. All others are potentially clinically significant. 
5.4 
Statistical models 
5.4.1 
Analysis supporting primary objective(s)  
Not applicable. 
5.4.2 
Analysis supporting secondary objective(s) 
Not applicable. 


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5.5 
Rule of exclusion criteria of analysis sets  
Table 5-2 
Criteria Leading to Exclusion 
Analysis Set 
Criteria that cause participants to be excluded 
FAS 
Not randomized 
Restricted Set 1 
Not randomized 
Changes in background lipid-lowering therapy 
Restricted Set 2 
Not randomized 
Less than three doses of inclisiran in the inclisiran + usual care group (miss 
one or more doses) 
Per Protocol Set 
Not randomized 
Treated with any inclisiran if randomized to usual care treatment group 
Major protocol deviations 
Safety 
Participants who have no data collected at baseline or any post-baseline visits.