Conditions: Atherosclerotic Cardiovascular Disease
Keywords: Hyperlipidemia Secondary Cardiovascular Prevention Atherosclerotic Cardiovascular Disease (ASCVD) Hypercholesterolemia Lipid lowering therapies Inclisiran
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 450
Healthy volunteers: no

Brief summary:
The purpose of this study was to assess the effectiveness of an "inclisiran first" implementation strategy (addition of inclisiran to maximally tolerated statin therapy immediately upon failure to achieve acceptable LDL-C with maximally tolerated statin therapy alone) compared to usual care in an atherosclerotic cardiovascular disease (ASCVD) population.

Detailed description:
The study design was a randomized, two-arm, parallel-group, open-label, multicenter, clinical trial comparing an "inclisiran first" implementation strategy to usual care (1:1 randomization) with established ASCVD and elevated LDL-C (or non-HDL-C) despite treatment with maximally tolerated statin therapy.

Eligible patients had established ASCVD and elevated LDL-C levels ≥ 70 mg/dL (or non-HDL-C ≥ 100 mg/dL) despite treatment with maximally tolerated statin therapy.

In the "inclisiran first" implementation strategy group post-randomization, addition of other non-statin LDL-C lowering therapies (e.g., ezetimibe or bempedoic acid, excluding PCSK9 inhibiting monoclonal antibodies) were allowed to reach acceptable LDL-C levels. In the "inclisiran first" implementation strategy group, inclisiran was administered initially at randomization, 90 days later, and six months, thereafter.

Arms:
arm 1: Inclisiran sodium 300 mg 1.5 ml (equivalent to 284 mg of inclisiran) + usual care arm 2: Treating physicians were recommended to treat patients in accordance with the 2018 ACC/AHA guidelines

Interventions: intervention 1: Inclisiran
Intervention descriptions: intervention 1: Inclisiran sodium 300 mg/1.5 ml (equivalent to 284 mg inclisiran liquid) in prefilled syringe (PFS).

Protocol document:
Prot_000.pdf: 
Novartis Research and Development 
KJX839 
Clinical Trial Protocol CKJX839A1US02 / NCT04929249 
A randomized, multicenter, open-label trial comparing the 
effectiveness of an "inclisiran first" implementation strategy 
to usual care on LDL cholesterol (LDL-C) in patients with 
atherosclerotic cardiovascular disease and elevated LDL-C 
(≥70 mg/dL) despite receiving maximally tolerated statin 
therapy (VICTORION-INITIATE) 
Document type: 
Clinical Trial Protocol 
EUDRACT number: 
Not applicable 
Version number: 
02 (Amended Protocol) 
Clinical Trial Phase: 
IIIb 
Release date: 
20-Oct-2022 (content final)
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020 


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Table of contents 
Table of contents .................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ....................................................................................................................... 6 
Glossary of terms ............................................................................................................... 10 
Amendment 02 .......................................................................................................................... 13 
Amendment 01 .......................................................................................................................... 13 
Protocol summary .............................................................................................................. 15 
1 
Introduction ........................................................................................................................ 22 
1.1 
Background ............................................................................................................ 22 
1.1.1 
Atherosclerotic cardiovascular disease (ASCVD) ................................ 22 
1.1.2 
Mechanism of RNA interference ........................................................... 23 
1.1.3 
Inclisiran ................................................................................................ 23 
1.1.4 
Nonclinical studies ................................................................................ 24 
1.1.5 
Clinical studies ...................................................................................... 24 
1.2 
Purpose ................................................................................................................... 24 
2 
Objectives, endpoints and estimands ................................................................................. 26 
2.1 
Primary estimands .................................................................................................. 27 
2.2 
Secondary estimands .............................................................................................. 28 
3 
Study design ....................................................................................................................... 29 
4 
Rationale ............................................................................................................................ 31 
4.1 
Rationale for study design ...................................................................................... 31 
4.1.1 
Rationale for choice of background therapy ......................................... 33 
4.2 
Rationale for dose/regimen and duration of treatment ........................................... 33 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ....................................................................................................................... 34 
4.4 
Purpose and timing of interim analyses/design adaptations ................................... 34 
4.5 
Risks and benefits .................................................................................................. 34 
4.6 
Rationale for Public Health Emergency mitigation procedures ............................. 35 
5 
Study Population ................................................................................................................ 35 
5.1 
Inclusion criteria .................................................................................................... 35 
5.2 
Exclusion criteria ................................................................................................... 36 
6 
Treatment ........................................................................................................................... 38 
6.1 
Study treatment ...................................................................................................... 38 


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6.1.1 
Investigational and control drugs .......................................................... 38 
6.1.2 
Additional study treatments ................................................................... 38 
6.1.3 
Treatment arms/group............................................................................ 38 
6.1.4 
Treatment duration ................................................................................ 38 
6.2 
Other treatment(s) .................................................................................................. 38 
6.2.1 
Concomitant therapy ............................................................................. 38 
6.2.2 
Prohibited medication ............................................................................ 39 
6.3 
Participant numbering, treatment assignment, randomization ............................... 39 
6.3.1 
Participant numbering............................................................................ 39 
6.3.2 
Treatment assignment, randomization ................................................... 40 
6.4 
Treatment blinding ................................................................................................. 40 
6.5 
Dose escalation and dose modification .................................................................. 40 
6.5.1 
Dose modifications ................................................................................ 40 
6.5.2 
Follow-up for toxicities ......................................................................... 41 
6.6 
Additional treatment guidance ............................................................................... 43 
6.6.1 
Treatment compliance ........................................................................... 43 
6.7 
Preparation and dispensation .................................................................................. 43 
6.7.1 
Handling of study treatment and additional treatment .......................... 43 
6.7.2 
Instruction for prescribing and taking study treatment .......................... 44 
7 
Informed consent procedures ............................................................................................. 44 
8 
Visit schedule and assessments .......................................................................................... 45 
8.1 
Screening ................................................................................................................ 49 
8.1.1 
Information to be collected on screening failures .................................. 49 
8.2 
Participant demographics/other baseline characteristics ........................................ 49 
8.3 
Efficacy .................................................................................................................. 49 
8.3.1 
Primary efficacy assessments ................................................................ 50 
8.3.2 
Other efficacy assessments .................................................................... 51 
8.3.3 
Appropriateness of efficacy assessments ............................................... 51 
8.4 
Safety ..................................................................................................................... 51 
8.4.1 
Laboratory evaluations .......................................................................... 52 
8.4.2 
Electrocardiogram (ECG) ...................................................................... 54 
8.4.3 
Pregnancy and assessments of fertility .................................................. 54 
8.4.4 
Other safety evaluations ........................................................................ 54 
8.4.5 
Appropriateness of safety measurements .............................................. 55 
8.5 
Additional assessments .......................................................................................... 55 


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 55 
 
 55 
 
 56 
9 
Study discontinuation and completion ............................................................................... 56 
9.1 
Discontinuation and completion ............................................................................ 56 
9.1.1 
Study treatment discontinuation and study discontinuation .................. 56 
9.1.2 
Withdrawal of informed consent ........................................................... 57 
9.1.3 
Lost to follow-up ................................................................................... 58 
9.1.4 
Early study termination by the sponsor ................................................. 58 
9.2 
Study completion and post-study treatment ........................................................... 58 
10 Safety monitoring and reporting ........................................................................................ 59 
10.1 
Definition of adverse events and reporting requirements ...................................... 59 
10.1.1 
Adverse events....................................................................................... 59 
10.1.2 
Serious adverse events ........................................................................... 60 
10.1.3 
SAE reporting ........................................................................................ 61 
10.1.4 
Pregnancy reporting ............................................................................... 62 
10.1.5 
Reporting of study treatment errors including misuse/abuse................. 62 
10.2 
Additional Safety Monitoring ................................................................................ 63 
10.2.1 
Liver safety monitoring ......................................................................... 63 
10.2.2 
Renal safety monitoring......................................................................... 64 
10.2.3 
Steering Committee ............................................................................... 64 
11 Data Collection and Database management....................................................................... 64 
11.1 
Data collection ....................................................................................................... 64 
11.2 
Database management and quality control ............................................................ 65 
11.3 
Site monitoring ....................................................................................................... 66 
12 Data analysis and statistical methods ................................................................................. 67 
12.1 
Analysis sets ........................................................................................................... 67 
12.2 
Participant demographics and other baseline characteristics ................................. 68 
12.3 
Treatments .............................................................................................................. 68 
12.4 
Analysis supporting primary objectives ................................................................. 68 
12.4.1 
Definition of primary endpoints ............................................................ 68 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 68 
12.4.3 
Handling of intercurrent events of primary estimand ............................ 70 
12.4.4 
Handling of missing values not related to intercurrent event ................ 70 
12.4.5 
Sensitivity analyses ............................................................................... 70 


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12.4.6 
Supplementary analysis ......................................................................... 70 
12.4.7 
Supportive analyses ............................................................................... 71 
12.5 
Analysis supporting secondary objectives .............................................................. 71 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) ..................................... 71 
12.5.2 
Safety endpoints .................................................................................... 72 
12.5.3 
Pharmacokinetics ................................................................................... 73 
12.5.4 
DNA ...................................................................................................... 73 
12.5.5 
Biomarkers ............................................................................................ 73 
12.5.6 
PK/PD relationships .............................................................................. 73 
 
 73 
 
 73 
12.7 
Interim analyses ..................................................................................................... 74 
12.8 
Sample size calculation .......................................................................................... 74 
12.8.1 
Primary endpoint(s) ............................................................................... 74 
12.8.2 
Secondary endpoint(s) ........................................................................... 75 
13 Ethical considerations and administrative procedures ....................................................... 75 
13.1 
Regulatory and ethical compliance ........................................................................ 75 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 75 
13.3 
Publication of study protocol and results ............................................................... 76 
13.4 
Quality Control and Quality Assurance ................................................................. 76 
14 Protocol adherence ............................................................................................................. 76 
14.1 
Protocol amendments ............................................................................................. 77 
15 References .......................................................................................................................... 78 
16 Appendices ......................................................................................................................... 82 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs .......................... 82 
16.2 
Appendix 2: Liver event and laboratory trigger definitions & follow-up 
requirements ........................................................................................................... 83 
16.3 
Appendix 3: Specific Renal Alert Criteria and Actions and Event Follow-up ...... 86 
16.4 
Appendix 4: Sampson Criteria for Diagnosing Anaphylaxis ................................. 88 
 
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List of tables 
Table 2-1 
Objectives and related endpoints ........................................................... 26 
Table 6-1 
Investigational and control drug ............................................................ 38 
Table 6-2 
Prohibited medication ............................................................................ 39 
Table 6-3 
Guidance on specific clinical and diagnostic assessments which 
can be performed to rule out possible alternative causes of 
observed LFT abnormalities .................................................................. 42 
Table 6-4 
Dose and treatment schedule ................................................................. 44 
Table 8-1 
Assessment Schedule ............................................................................. 47 
Table 8-2 
Safety Assessment ................................................................................. 52 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse .......................................................................................... 63 
Table 12-1 
Sample size calculations for percent change from baseline in LDL- 
C ............................................................................................................ 74 
Table 12-2 
Sample size calculations for statin therapy discontinuation .................. 75 
Table 16-1 
Clinically notable vital signs ................................................................. 82 
Table 16-2 
Clinically notable laboratory abnormalities for selected tests ............... 82 
Table 16-3 
Liver event and laboratory trigger definitions ....................................... 83 
Table 16-4 
Follow up requirements for liver laboratory triggers with liver 
symptoms ............................................................................................... 83 
Table 16-5 
Follow up requirements for liver laboratory triggers ............................ 84 
Table 16-6 
Specific Renal Alert Criteria and Actions ............................................. 86 
Table 16-7 
Renal event follow-up ........................................................................... 87 
 
 
List of figures 
Figure 3-1 
Study Design ......................................................................................... 30 


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List of abbreviations 
ACC 
American College of Cardiology 
ACE 
Angiotensin Converting Enzyme 
AE 
Adverse Event 
AHA 
American Heart Association 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ApoB 
Apolipoprotein B 
ARB 
Angiotensin II Receptor Blockers 
ASCVD 
Atherosclerotic Cardiovascular Disease 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
 
 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CABG 
Coronary Artery Bypass Grafting 
CHD 
Coronary Heart Disease 
CMO&PS 
Chief Medical Office and Patient Safety 
 
 
COVID-19 
Coronavirus Disease 2019 
CPK 
Creatinine Phosphokinase 
CRA 
Clinical Research Associate 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CT 
Computerized Tomography 
CTA 
Computed Tomography Angiography 
CV 
Cardiovascular 
CVD 
Cardiovascular Disease 
DIN 
Drug Inducted Nephrotoxicity 
dL 
Decilitre 
DNA 
Deoxyribonucleic Acid 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
eGFR 
Estimated Glomerular Filtration Rate 
EHR 
Electronic Health Record 
EMA 
European Medicines Agency 
eTMF 
Electronic Trial Master File 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
g 
Gram 


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GalNAc 
N-Acetylgalactosamine 
GCP 
Good Clinical Practice 
GDMT 
Guideline-Directed Medical Therapy 
GGT 
Gamma-Glutamyl Transferase 
GLDH 
Glutamate Dehydrogenase 
GPP 
Good Pharmaceopidemiology Practices 
 
 
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 
HRSA 
Health Resources and Services Administration 
NYHA 
New York Heart Association 
IUD 
Intrauterine Device 
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 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISR 
Injection Site Reaction 
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 
 
 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MDCT 
Multidetector Computed Tomography 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram(s) 


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MI 
Myocardial Infarction 
mL 
Milliliter(s) 
MMRM 
Mixed-Effects Model Repeated Measures 
MRI 
Magnetic Resonance Imaging 
mRNA 
Messenger Ribonucleic Acid 
 
 
non-HDL-C 
Non-High-Density Lipoprotein Cholesterol 
NYHA 
New York Heart Association 
PAD 
Peripheral Arterial Disease 
PCI 
Percutaneous Coronary Intervention 
PCSK9 
Proprotein Convertase Subtilisin/Kexin Type 9 
PFS 
Pre-filled Syringe 
PI 
Principal Investigator 
 
 
PT 
Prothrombin Time 
QMS 
Quality Management System 
RISC 
RNA-Induced Silencing Complex 
RNA 
Ribonucleic Acid 
RNA-PCR 
Reversed Transcription and Subsequent Polymerase Chain Reaction 
RBC 
Red Blood Cell(s) 
RNAi 
Ribonucleic Acid Interference 
s.c. 
Subcutaneous 
SC 
Steering Committee 
SAE 
Serious Adverse Event 
sCR 
Serum Creatinine 
siRNAs 
Small Interfering Ribonucleic Acids 
SMQ 
Standardized MedDRA Query 
SOP 
Standard Operating Procedures 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBL 
Total Bilirubin 
 
 
 
 
μL 
Microliter 
U/L 
Units per Litre 
ULN 
Upper Limit of Normal 
US 
United States 
VLDL-C 
Very-Low-Density Lipoprotein Cholesterol 
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 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 
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. 
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. 


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Investigational 
drug/ treatment 
The drug whose properties are being tested in the study 
Maximally tolerated 
statin therapy 
Maximally tolerated statin therapy in accordance with the 2018 ACC/AHA 
guidelines 
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 newly-diagnosed disease 
Participant 
A trial participant (can be a healthy volunteer or a patient) 
Participant number 
A unique number assigned to each participant upon signing the informed 
consent. This number is the definitive, unique identifier for the participant and 
should be used to identify the participant throughout the study for all data 
collected, sample labels, etc. 
Period 
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the study phases and will 
be used in clinical trial database setup and eventually in analysis 
Personal data 
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data includes 
participant identifier information, study information and biological samples. 
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 
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 


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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 video-conference, 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 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 02 
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 #15 has been modified. Similarly, the study 
design has been modified to reflect the same. Protocol Summary and Section 5 reflects “50” US sites. 
 
Changes to the protocol 
o 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.” 
o Protocol Summary and Section 5: Reflects a change of “40” sites to “50” US sites. 
o Section 5.2 Exclusion #15: Added “Treatment with monoclonal antibodies directed 
towards PCSK9 or inclisiran within 90 days of screening.” 
 
Amendment 01 
Amendment rationale 
The purpose of the clinical study amendment is to update the protocol in order to be aligned 
with other inclisiran Phase III studies with respect to the documentation of statin intolerance, 
cardiovascular medical history, assessment of injection site reactions and definition of 
hyperglycemia-related events. 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 
• Section 3 added language ‘if and when inclisiran becomes commercially available’ and 
changed to ‘approximately’ 40 sites 
• Figure 3-1 removed ‘Baseline’ from Visit 1 
• Section 6.5.1 revised dose modification text 
• Section 6.5.2 removed ‘not applicable’ 
• Section 6.5.2.1 added 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 
o 
 
o removed pregnant partner information 






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• 
To assess plasma lipids, lipoproteins and triglycerides in participants 
receiving an "inclisiran first" implementation strategy compared to usual 
care at Day 330 
• 
To assess changes in and adherence to background lipid-lowering therapy in 
participants receiving an "inclisiran first" implementation strategy compared 
to usual care at Day 330 
• 
To assess visit-to-visit LDL-C variability from Day 90 until Day 330 
• 
To assess overall safety and tolerability of inclisiran 
Study design 
The study design will be a randomized, two-arm, parallel-group, open-label, 
multicenter, clinical trial comparing an "inclisiran first" implementation strategy to 
usual care in approximately 444 participants (1:1 randomization) with established 
ASCVD and elevated LDL-C (or non-HDL-C) despite treatment with maximally 
tolerated statin therapy. 
Study 
population 
The study will include male and female participants ≥18 years of age with a 
history of ASCVD (coronary heart disease, ischemic cerebrovascular disease or 
peripheral arterial disease) who have elevated LDL-C (≥70 mg/dL) or non-HDL-C 
(≥100 mg/dL) despite being treated with maximally tolerated statin therapy. A 
total of approximately 444 participants will be randomized to the “inclisiran first” 
implementation strategy or usual care in a 1:1 ratio at approximately 50 US sites. 
Key Inclusion 
criteria 
Participants eligible for inclusion in this study must meet all of the following 
criteria: 
1. Signed informed consent must be obtained prior to participation in the 
study 
2. Males and females ≥18 years of age 
3. History of ASCVD, documented by hospital records, claims data and/or prior 
laboratory/imaging assessments 
a. 
Coronary heart disease 
(CHD): 
• 
Prior myocardial 
infarction 
• 
Prior coronary revascularization (PCI or CABG) 
• 
Angiographic or CT-imaging (e.g., MDCT/CTA) 
evidence of coronary atherosclerosis (>70% stenosis 
in at least one major epicardial coronary artery) 
b. Cerebrovascular disease: 
• 
Prior ischemic stroke confirmed by a brain imaging study, 
CT orMRI; thought not to be caused by atrial fibrillation, 
valvular heartdisease or mural thrombus 
• 
Carotid artery stenosis >70% on prior angiography or 
ultrasound 
• 
History of prior percutaneous or surgical carotid 
arteryrevascularization 
c. Peripheral arterial disease (PAD): 
• 
Prior documentation of a resting ankle-brachial index ≤0.85 
• 
History of prior percutaneous or surgical revascularization 
of aniliac, femoral, or popliteal artery or aortic aneurysm 
• 
Prior non-traumatic amputation of a lower extremity 
due toperipheral artery disease 
4. Serum LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL 
5. Fasting triglyceride <5.65 mmol/L (<500 mg/dL) at screening 


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6. Calculated glomerular filtration rate >30 mL/min by estimated glomerular 
filtration rate (eGFR) using standardized local clinical methodology 
7. Participants should be on maximally tolerated statin therapy, as determined by 
the investigator, with no immediate plans to modify lipid lowering therapies. Statin 
intolerant patients are eligible if they had documented side effects on at least 2 
different statins, including one at the lowest standard dose 
8. 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 
Key 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 III or IV heart failure or last known 
left ventricular ejection fraction <30% 
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. Major adverse cardiovascular event within 6 months prior to randomization 
6. Uncontrolled severe hypertension: systolic blood pressure >180 mmHg or 
diastolic blood pressure >110 mmHg prior to randomization despite 
antihypertensive therapy 
7. Severe concomitant non-cardiovascular disease that carries the risk of reducing 
life expectancy to less than 2 years 
8. History of malignancy that required surgery (excluding local and wide-local 
excision), radiation therapy and/or systemic therapy during the two years prior to 
randomization 
9. 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: 
a. 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 
b. 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 
c. Male sterilization (at least 6 m prior to screening). For female 
participants in the study, the vasectomized male partner should be the 
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d. Barrier methods of contraception: Condom or Occlusive cap (diaphragm 
or cervical/vault caps) 
e. Use of oral (estrogen and progesterone), injected or implanted hormonal 
methods of contraception or other forms of hormonal contraception that 
have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception or placement of an 
intrauterine device (IUD) or intrauterine system (IUS) 
In case of use of oral contraception, women should have been stable on the same 
pill for a minimum of 3 months before taking 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. 
10. Known history of alcohol and/or drug abuse within the last 5 years 
(occasional casual users of illicit drugs in the opinion of the investigators are not 
excluded) 
11. Treatment with other investigational products or devices within 30 days or five 
half-lives of the screening visit, whichever is longer. 
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 – including 
potential participants who indicate that their participation is contingent on 
receiving inclisiran) 
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. Previous or current treatment (within 90 days of screening) with monoclonal 
antibodies directed towards PCSK9, or with inclisiran or ezetimibe. 
16. Active liver disease defined as any known current infectious, neoplastic, or 
metabolic pathology of the liver or alanine aminotransferase (ALT) elevation >3x 


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ULN, aspartate aminotransferase (AST) elevation >3x ULN, or total bilirubin 
elevation >2x ULN (except patients with Gilbert’s syndrome) at screening 
confirmed by a repeat measurement at least one week apart 
Study 
treatment 
Inclisiran (KJX839), 284 mg, 1.5 ml Liquid in a single-use prefilled syringe (PFS) 
for s.c. administration 
Usual care per treating physician 
Treatment of 
interest 
An "inclisiran first" implementation strategy (addition of inclisiran to maximally 
tolerated statin therapy immediately upon failure to reach acceptable LDL-C 
levels with maximally tolerated statin therapy alone) compared to usual care (per 
treating physician). 
Efficacy 
assessments 
The primary efficacy assessments will be LDL-C and discontinuation of statin 
therapy. Other efficacy assessments will include measurement of Apo B, Lp(a), 
non-HDL-C, VLDL-C, total cholesterol, triglycerides, and HDL-C. 
Key safety 
assessments 
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. 
Data analysis 
The primary efficacy variables are the following: 
1. Percent change from baseline in LDL-C 
2. Discontinuation of statin therapy (i.e., no statin use ≥ 30 days before the end- 
of-study visit) (yes, no) 
The primary analysis time point for both primary efficacy variables is at Day 330. 
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. 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 effect 
at Day 330 is < 0.025 and the corresponding least squares mean treatment 
difference ("inclisiran first" implementation strategy – usual care) is less than 0, 
statistical significance in favor of "inclisiran first" implementation strategy is shown. 
For primary efficacy variable 2, a one-sided 98.75% confidence interval for 
treatment difference ("inclisiran first" implementation strategy – usual care) in the 
proportion of participants who discontinued statin therapy at Day 330 will be 
computed using the normal approximation to the binomial distribution. Non- 
inferiority of the "inclisiran first" implementation strategy to usual care will be 
declared if the upper limit of the confidence interval does not exceed the non- 
inferiority margin of 15%. 
The secondary efficacy variables are the following: 
1. Absolute change from baseline in LDL-C 


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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 ≥ 50% reduction from baseline in LDL-C (yes, no) 
5. Achieving LDL-C < 100 mg/dL (yes, no) (among the subset of participants with 
LDL-C ≥ 100 mg/dL at baseline) 
6. Achieving LDL-C < 70 mg/dL (yes, no) 
7. Achieving LDL-C < 55 mg/dL (yes, no) 
8. Percent change from baseline in apoB 
9. Absolute change from baseline in apoB 
10. Percent change from baseline in non-HDL-C 
11. Absolute change from baseline in non-HDL-C 
12. Percent change from baseline in VLDL-C 
13. Absolute change from baseline in VLDL-C 
14. Percent change from baseline in total cholesterol 
15. Absolute change from baseline in total cholesterol 
16. Percent change from baseline in Lp(a) 
17. Absolute change from baseline in Lp(a) 
18. Percent change from baseline in HDL-C 
19. Absolute change from baseline in HDL-C 
20. Percent change from baseline in triglycerides 
21. Absolute change from baseline in triglycerides 
22. Intensity of lipid-lowering therapy (decrease in dose, no change in dose, 
increase in dose) 
23. Proportion of days covered (total number of days on either statin, ezetimibe, 
bempedoic acid or PCSK9 inhibiting monoclonal antibody therapies prescribed 
divided by total number of study days) 
Analyses of secondary efficacy variables 1 and 8 - 21 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 variable 2, 3, and 23 will be analyzed using a linear model with 
treatment, baseline LDL-C, and 
 as 
explanatory variables. 
Secondary efficacy variables 4 - 7 will be analyzed at each time point using a 
logistic regression model with treatment, baseline LDL-C, 
 
 as explanatory variables. 
Secondary efficacy variable 22 will be analyzed at each time point using a 
proportional odds model with treatment, baseline LDL-C, and 
 
 as explanatory variables. 


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Visit-to-visit LDL-C variability from Day 90 until Day 330 will be reported, using 
various measures of variability (standard deviation, coefficient of variation). 
Key words 
Hyperlipidemia, 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 (s.c.) 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 
established atherosclerotic cardiovascular disease (ASCVD) who are treated with maximally 
tolerated statin therapy compared to placebo in randomized, double-blind, placebo-controlled 
trials (Ray et al 2020). 
This protocol describes a trial to evaluate the effectiveness of an "inclisiran-first" 
implementation strategy (i.e., initiation of inclisiran immediately after failing to reach 
acceptable LDL-C levels with maximally tolerated statin therapy alone, before addition of 
ezetimibe) compared to usual care without inclisiran in a population with ASCVD 
 
. This study will be conducted in compliance with 
Good Clinical Practices (GCP) and Good Pharmaceopidemiology Practices (GPP), including 
the Declaration of Helsinki and all applicable regulatory requirements. 
 
1.1.1 
Atherosclerotic cardiovascular disease (ASCVD) 
Despite advances in treatment, cardiovascular disease (CVD) is the leading cause of death 
worldwide, resulting in approximately 18 million deaths annually (Roth et al 2017). Eighty 
percent of all CVD deaths are due to coronary heart disease (CHD) or strokes. Elevated LDL- 
C is a major risk factor for the development of CVD (Grundy et al 2019). Lowering LDL-C has 
been shown to reduce the risk of CHD and strokes and the clinical risk reduction is linearly 
proportional to the absolute LDL-C reduction without an apparent threshold below which 
further lowering yields no further benefit (Giugliano et al 2017; Baigent et al 2010). Moreover, 
large trials combined with evidence from studies of people with genetically-determined lower 
LDL-C have confirmed the safety of exposure to low levels of LDL-C over long periods of time 
(Cohen et al 2006; Giugliano et al 2017). 
Approximately 30 million people in the United States are treated with lipid lowering therapies, 
predominantly statins, to lower LDL-C and the associated risk of ASCVD (Wong et al 2016). 
The 2018 American College of Cardiology (ACC) / American Heart Association (AHA) 
cholesterol guidelines recommend a step-wise algorithm for LDL-C lowering in patients with 
established ASCVD (Grundy et al 2019). Briefly, all ASCVD patients should be treated with 
high intensity statin therapy. If LDL-C remains 70 mg/dL or higher, ezetimibe can be 
considered. If LDL-C remains 70 mg/dL or higher despite treatment with statins and ezetimibe, 
addition of a PCSK9 inhibiting monoclonal antibody can be considered in very high risk 
patients (Grundy et al 2019). The position of PCSK9 inhibiting monoclonal antibodies after 
ezetimibe is partially due to the high price of those therapies as well as the inconvenience of 
frequent parenteral administration (Grundy et al 2019). Nonetheless, ezetimibe lowers LDL-C 
by only approximately 20% and therefore many patients may still have elevated LDL-C despite 
statin-ezetimibe combination therapy, while many more patients would be able to reach 
acceptable LDL-C levels if more potent LDL-C lowering therapies would be initiated before 
ezetimibe. This would also reduce the problem of polypharmacy. 


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Additional contributing factors responsible for the fact that only a minority of patients with 
ASCVD have LDL-C levels <70 mg/dL include suboptimal guideline implementation, inability 
to tolerate statins at sufficiently high doses, poor adherence to therapies, and system barriers 
such as high cost of therapy (Wong et al 2016; Lowenstern et al 2018; Fitchett et al 2015;Mann 
et al 2010; Poluzzi et al 2008; Cannon et al 2020). 
These and other factors are responsible for the fact that the trend in the United States (US) of 
lower CV morbidity and mortality observed between 1980 and 2010 has stalled. In fact recent 
data show an increase in CV mortality (Virani et al 2020). 
 
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 a N-acetylgalactosamine (GalNAc) 
carbohydrate ligand (Ashwell and Morell 1974). Conjugation of a triantennary GalNAc ligand 
to an 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 (Khvorova 2017). 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. Inclisiran is now approved by the trade name as LEQVIO by FDA 
for commercial use. 


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1.1.4 
Nonclinical 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 (Ray et al 2020). 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. This is highlighted by tissue distribution studies in rats showing that compared to liver, 
inclisiran exposure in other tissues was 36- to 1076-fold lower than liver. 
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 which is highly conserved across diverse ethnic and geographical populations (Ray 
et al 2020). The specificity of the active antisense strand of inclisiran was determined by 
performing a comprehensive search against the human transcriptome using an exhaustive 
“brute-force” algorithm implemented in the python script ‘BruteForce.py’. The search revealed 
20 possible off-target transcripts, two of which are not normally expressed in liver cells. The 
other 18 transcripts were subsequently assayed in an in vitro study to experimentally assess 
their response to inclisiran. The 18 gene transcripts were transfected into liver cells along with 
inclisiran and expression analysis indicated a ≥45-fold difference between the “on target” 
suppression of PCSK9 and the suppression of any of the “off-target” transcripts. 
Inclisiran was well tolerated in all animal studies. 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 the 
double-blind, placebo-controlled, multicenter Phase III ORION trials, involving 3,655 
participants (about half of whom received inclisiran, n=1,833), after the initial administration 
of inclisiran, LDL-C levels were quickly reduced with more than 75% of patients 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. 
 
1.2 
Purpose 
Phase III trials with inclisiran have provided high-quality evidence supporting the efficacy, 
safety and tolerability of inclisiran compared to placebo on top of maximally tolerated statin 
therapy with or without ezetimibe. The clinical value of systematic implementation of an 
"inclisiran first" strategy (addition of inclisiran to maximally tolerated statin therapy 




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2 
Objectives, endpoints and estimands 
Table 2-1 
Objectives and related endpoints 
 
Objective(s) 
Endpoint(s) 
 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To assess the effect on LDL-C of an "inclisiran- 
first" implementation strategy compared to 
usual care at Day 330 in participants with 
ASCVD and an LDL-C ≥70 mg/dL despite 
maximally tolerated statin therapy 
• 
To assess the non-inferiority of an "inclisiran 
first" implementation strategy compared 
to usual care on discontinuation of background 
statin therapy at Day 330 
• 
Percent change from baseline in LDL-C 
 
 
 
• 
Discontinuation of statin therapy (i.e., no 
statin use ≥ 30 days before the end-of- 
study visit) (yes, no) 
 
 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To assess the absolute change in LDL-C of an 
"inclisiran first" implementation strategy 
compared to usual care at Day 330, as well as 
average of percent and absolute changes in 
LDL-C levels to each post-baseline visit 
 
• 
To assess the proportion of participants 
reaching pre-specified LDL-C targets among 
those receiving an "inclisiran first" 
implementation strategy compared to usual 
care at Day 330 
 
 
 
• 
To assess plasma lipids, lipoproteins and 
triglycerides in participants receiving an 
"inclisiran first" implementation 
strategy compared to usual care at Day 330 
 
 
 
 
 
 
 
 
 
 
 
• 
To assess changes in and adherence to 
background lipid-lowering therapy in 
participants receiving an "inclisiran first" 
• 
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 to each post-baseline visit 
• 
Achieving ≥ 50% reduction from baseline 
in LDL-C (yes, no) 
• 
Achieving LDL-C < 100 mg/dL (among 
the subset of participants with LDL- 
C >100 mg/dL at baseline) (yes, no) 
• 
Achieving LDL-C < 70 mg/dL (yes, no) 
• 
Achieving LDL-C < 55 mg/dL (yes, no) 
• 
Percent change and absolute change 
from baseline in apoB 
• 
Percent change and absolute change 
from baseline in non-HDL-C 
• 
Percent change and absolute change 
from baseline in VLDL-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 
• 
Intensity of lipid lowering therapy 
(decrease in dose, no change in dose, 
increase in dose) 


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Objective(s) 
Endpoint(s) 
implementation strategy compared to usual 
care at Day 330 
 
 
 
• 
To assess visit-to-visit LDL-C variability from 
Day 90 until Day 330 
• 
To assess overall safety and tolerability of 
inclisiran 
• 
Proportion of days covered (total number 
of days on either statin, ezetimibe, 
bempedoic acid or PCSK9 inhibiting 
monoclonal antibody therapies divided by 
total number of study days) 
• 
LDL-C measures of variability (standard 
deviation, coefficient of variation) 
• 
Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
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 is: 
What is the effectiveness of an "inclisiran first" implementation strategy compared to usual care 
in patients who have not reached their LDL-target despite treatment with a maximally tolerated 
statin? Inclisiran will be added to maximally tolerated statin therapy and will be compared to 
usual care. Eligible participants will have established ASCVD and elevated LDL-C despite 
being treated with maximally tolerated statin therapy and should not be on ezetimibe or PCSK9 
inhibiting monoclonal antibodies. Although at baseline there should be no plans to modify 


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background lipid-lowering therapy, the participants’ treating physicians are recommended to 
treat patients in accordance with the 2018 ACC/AHA cholesterol guideline (Grundy et al 2019). 
The justification for the primary estimands is that these will capture both the effects of the 
inclisiran and the effect of changes in, adherence to, and discontinuation of additional 
medications, mirroring the conditions in clinical practice. 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: 
• 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 first" implementation strategy 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 first" 
implementation strategy and usual care 
Primary estimand 2: The primary analysis of primary efficacy variable 2 (discontinuation of 
statin therapy) to address the primary objective will be based on the following estimand: 
• Population: Defined through appropriate inclusion/exclusion criteria to reflect the 
targeted population and if a participant was not statin intolerant at the beginning of the 
trial 
• Variable: Discontinuation of statin therapy (yes, no) [The primary analysis time point 
is at Day 330.] 
• Treatment: "Inclisiran first" implementation strategy 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: Treatment difference ("inclisiran first" implementation strategy – 
usual care) in the proportion of participants who discontinue statin therapy 




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The sponsor will not provide access to therapies other than inclisiran (only for patients 
randomized to the “inclisiran first” implementation strategy group). In both groups, laboratory 
assessments (including LDL-C) will be performed at screening, Day 0, Day 90, Day 180, Day 
270 and Day 330. The results of the laboratory assessments performed as part of the trial will 
be available tothe participants' physicians in both study groups. Hence, to minimize reporting 
bias, participants in the "inclisiran first" implementation group and participants in the usual care 
group will havean equivalent number of study visits, and an equivalent number of blood draws 
(including LDL-C tests). 
The study will identify approximately 50 sites for participation. Each site will have a principal 
investigator (PI) who is responsible for study visits, while all aspects of the participants' routine 
care will remain the responsibility of the participants' own treating physician in both groups. 
While it is expected that most patients will have a treating physician who is distinct from the 
PI, a PI who wishes to include his or her own patients in the trial would have to be (temporarily) 
transition routine care to a separate physician. This will reduce the effect that trial participation 
might have on treatment decisions if the PI and treating physician were the same individual 
(e.g., more aggressive treatment due to more frequent touchpoints). 
Since inclisiran is commercially available in the US as of late-2021, utilization of it in the usual 
care group at the sole discretion of the treating physician will not be encouraged, but will also 
not be prohibited to avoid withholding of appropriate care. If treatment with a PCSK9-inhibiting 
monoclonal antibody was initiated and a patient would have to be transitioned to inclisiran, the 
PCSK9- inhibiting monoclonal antibody should be discontinued. 
The collection of data from trial sites through eCRFs will be complemented with EHR data and 
claims data (e.g., lipid measurements and concomitant medications). 
Participants randomized to “inclisiran first” implementation strategy group will receive 
inclisiran at Day 0, Day 90 and Day 270, consistent with the dosing regimen studied in the 
Phase III trials. 
While study visits will be preferentially performed in-person at the study sites, phone or virtual 
visits are an acceptable alternative if in-person visits are not permitted or impractical 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. 
The remote procedures will be offered at certain sites as determined by Novartis based on 
national and local regulations. 
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 
Participants with established ASCVD are at increased risk of (recurrent) ischemic events. 
Lowering LDL-C reduces the risk of CV events in patients with ASCVD, with a magnitude of 
clinical benefit that is proportional to the reduction in LDL-C levels (Giugliano et al 2017). In 
view of the high risk of (recurrent) events in patients with established ASCVD and the fact that 
the majority of patients with established ASCVD have elevated LDL-C despite the availability 
of highly effective treatment options, addition of better or less frequently administered non- 
statin therapies could be beneficial. 
This trial will compare an "inclisiran first" implementation strategy to usual care. The Phase III 
trials, which were designed to test the efficacy and safety of inclisiran, compared inclisiran to 
placebo. Neither changes in background lipid-lowering therapy, nor LDL-C tests, were allowed 
in those trials. Given the availability of non-statin LDL-C lowering therapies other than 
inclisiran and the fact that LDL-C tests are performed in routine care to assess adherence and 
to guide therapeutic management, a comparison with usual care which may include other non- 
statin therapies is more clinically relevant for clinicians and healthcare decision makers. 
Clinical treatment guidelines recommend addition of non-statin LDL-C lowering therapies in 
patients with ASCVD and LDL-C ≥70 mg/dL despite maximally tolerated statin therapy 
(Grundy et al 2019). Non-statin therapies that are currently included in the 2018 ACC/AHA 
cholesterol guidelines include ezetimibe and PCSK9-inhibiting monoclonal antibodies. In large 
part due to the high costs and inconvenience of administration of PCSK9 inhibiting monoclonal 
antibodies, the guidelines recommend initial use of ezetimibe and addition of PCSK9 inhibiting 
monoclonal antibodies only in very high risk patients who fail to reach acceptable LDL-C levels 






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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 maximally-tolerated statin therapy 
with or without other LDL-C lowering therapies. 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 – participants will 
not be withheld appropriate care. The study may also provide information that may benefit 
ASCVD 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 that included the population eligible 
for this study. 
• Inclisiran was considered to be generally well-tolerated in Phase III trials 
(Ray et al 2017). Injection site reactions were more frequent in inclisiran-treated 
participants than in participants receiving placebo, but were localized, predominantly 
mild or occasionally moderate, transient, and resolved without sequelae. 
• The potential for immunogenicity of inclisiran was shown to be low 
(Landmesser et al 2020). 
• Reduction of LDL-C has been associated with reduced CV risk both by epidemiology 
and in controlled clinical trials (Grundy et al 2019). 
An expanded risk-benefit summary is provided in the Inclisiran Investigator’s Brochure (IB). 
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. 


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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 
The study will include male and female participants ≥18 years of age with a history of ASCVD 
(coronary heart disease, ischemic cerebrovascular disease or peripheral arterial disease) who 
have elevated LDL-C (≥70 mg/dL) or non-HDL-C (≥100 mg/dL) despite being treated with 
maximally tolerated statin therapy. A total of approximately 444 participants will be 
randomized to the “inclisiran first” implementation strategy or usual care in a 1:1 ratio at 
approximately 50 US sites. 
 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study 
2. Males and females ≥18 years of age 
3. History of ASCVD, documented by hospital records, claims data and/or prior 
laboratory/imaging assessments 
a. Coronary heart disease (CHD): 
 Prior myocardial infarction 
 Prior coronary revascularization (PCI or CABG) 
 Angiographic or CT-imaging (e.g., MDCT/CTA) evidence of coronary 
atherosclerosis (>70% stenosis in at least one major epicardial coronary artery) 
b. Cerebrovascular disease: 
 Prior ischemic stroke confirmed by a brain imaging study – CT or MRI; thought 
not to be caused by atrial fibrillation, valvular heart disease or mural thrombus 
 Carotid artery stenosis >70% on prior angiography or ultrasound 
 History of prior percutaneous or surgical carotid artery revascularization 
c. Peripheral arterial disease (PAD): 
 Prior documentation of a resting ankle-brachial index ≤0.85 
 History of prior percutaneous or surgical revascularization of an iliac, femoral, or 
popliteal artery or aortic aneurysm 
 Prior non-traumatic amputation of a lower extremity due to peripheral artery 
disease 
4. Serum LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL 
5. Fasting triglyceride <5.65 mmol/L (<500 mg/dL) at screening 


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6. Calculated glomerular filtration rate >30 mL/min by estimated glomerular filtration rate 
(eGFR) using standardized local clinical methodology 
7. Participants should be on maximally tolerated statin therapy, as determined by the 
investigator, with no immediate plans to modify lipid lowering therapies. Statin intolerant 
patients are eligible if they had documented side effects on at least 2 different statins, 
including one at the lowest standard dose 
8. 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 
 
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 
eitherinterfere 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 
clinicalstudy results 
3. New York Heart Association (NYHA) class III or IV heart failure or last known left 
ventricular ejection fraction <30% 
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. Major adverse cardiovascular event within 6 months prior to randomization 
6. Uncontrolled severe hypertension: systolic blood pressure >180 mmHg or diastolic 
bloodpressure >110 mmHg prior to randomization despite antihypertensive therapy 
7. Severe concomitant noncardiovascular disease that carries the risk of reducing life 
expectancy to less than 2 years 
8. History of malignancy that required surgery (excluding local and wide-local 
excision),radiation therapy and/or systemic therapy during the two years prior to 
randomization 
9. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using basic methods of contraception during 
dosing ofinvestigational drug. Basic contraception methods include: 
a. 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 
b. 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 
c. Male sterilization (at least 6 m prior to screening). For female participants in the 
study, the vasectomized male partner should be the sole partner for that participant 


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d. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps). 
e. 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) 
f. In case of use of oral contraception, women should have been stable on the same pill 
for aminimum 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 leastsix 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. 
 
10. Known history of alcohol and/or drug abuse within the last 5 years (occasional casual 
users of illicit drugs in the opinion of the investigators are not excluded) 
11.  Treatment with other investigational products or devices within 30 days or five half- 
lives of the screening visit, whichever is longer. 
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 – including potential participants who indicate 
that their participation is contingent on receiving inclisiran) 
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. Previous or current treatment (within 90 days of screening) with monoclonal 
antibodies directed towards PCSK9, or with inclisiran or ezetimibe. 


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16. Active liver disease defined as any known current infectious, neoplastic, or metabolic 
pathology of the liver or alanine aminotransferase (ALT) elevation >3x ULN, 
aspartate aminotransferase (AST) elevation >3x ULN, or total bilirubin elevation >2x 
ULN (except patients with Gilbert’s syndrome) at screening confirmed by a repeat 
measurement at leastone week apart. 
 
 
6 
Treatment 
6.1 
Study treatment 
Inclisiran (KJX839), 284 mg, 1.5 ml liquid in a single-use PFS for s.c. administration. 
Usual care per treating physician 
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 the following 2 treatment groups 
("inclisiran first" implementation strategy vs usual care) in a ratio of 1:1 using a randomization 
process to enroll approximately 444 participants (222 participants per treatment group). 
 
6.1.4 
Treatment duration 
The planned duration of treatment is 330 days from date of randomization. Participants may be 
discontinued from treatment at any time due to adverse events, disease progression and/or 
treatment is discontinued 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 (i.e. aspirin, thienopyridines), 
anticoagulants, beta-blockers, ACE-inhibitors or ARBs, other antihypertensives, antidiabetics, 
and lipid lowering therapies) administered before the participant is enrolled in the study but still 


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receiving must be recorded in the appropriate electronic 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 electronic Case Report Forms, or where applicable, sourced from the EHR 
and mapped into the clinical study database. 
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 below table are not allowed to be used simultaneously with 
inclisiran in the active arm but may be prescribed independently via the treating physician’s 
discretion 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 
All participants derived from the EHR database will receive an invitation from their treating 
physician to be involved in a clinical trial and to have an in-person screening visit at the 
investigator site. Each potential participant who agrees to participation will be 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 


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the informed consent form, the participant is assigned to the next sequential Participant No. 
available. 
A new ICF will need to be signed if the investigator chooses to re-screen the participant after a 
participant has screen failed, and the participant will be assigned a new Participant No. 
 
6.3.2 
Treatment assignment, randomization 
At visit 2, all eligible participants will be randomized via Interactive Response Technology 
(IRT) to one of the two treatment groups in 1:1 ratio ("inclisiran first" implementation strategy 
or 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 numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased. 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). 
Randomization will be stratified by 
. The stratification 
ensures balanced allocation of participants to treatment groups within the 
strata. 
The randomization scheme for participants will be reviewed and approved by a member of 
the Novartis Biometrics group. 
 
6.4 
Treatment blinding 
Not applicable. 
 
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 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: 




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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 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 canbe 
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. 


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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. 
 
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. 
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 (inclisiran) 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 study medication label. No study medications will 
be provided for usual care group. 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis CO Quality Assurance. 


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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. 
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 in PFS, 1.5M 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 s.c. 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. 


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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 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the participant 
informed consent and should be discussed with the participant during the study as needed. Any 
new information regarding the safety profile of the investigational drug that is identified 
between IB updates will be communicated as appropriate, for example, via an investigator 
notification or an aggregate safety finding. New information might require an update to the 
informed consent and then must be discussed with the participant. 
The following informed consents are included in this study: 
• Main study consent, which also included: 
- A subsection that requires a separate signature for the ‘Optional Consent for 
Additional Research’ to allow future research on data/samples collected during this 
study 
- As applicable, the consent will include language for the use of de-identification and 
tokenization technology that will allow for the acquisition and linkage of the 
participant to their health care data that exists in pharmacy and medical administrative 
claims databases 
• As applicable, Pregnancy Outcomes Reporting Consent for female participants who took 
study treatment 
Women of childbearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements. 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
Participants might be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience. 
 
8 
Visit schedule and assessments 
The Assessment Schedule (Table 8-1) lists the assessments when they are performed. All data 
obtained from these assessments must be supported in the participant’s source documentation. 
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1) or as close to the designated day/time as possible (+/- 7 days). Missed or rescheduled 
visits should not lead to automatic discontinuation. Participants may be seen at 


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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. 
Participants who discontinue from study treatment should continue to attend the remaining 
study visits as indicated in the Assessment Schedule (Table 8-1). 
Participants who discontinue from study or withdraw their consent should be scheduled for a 
final evaluation visit if they agree, as soon as possible, at which time all of the assessments 
listed for the final visit will be performed. At this final visit, all investigational product should 
be reconciled, and the adverse event and concomitant medications not previously reported must 
be recorded on the eCRF. 
Participants will have to comply with the following restrictions during the study: 
• 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. 


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Table 8-1 
Assessment Schedule 
 
Epoch 
Screening 
Treatment1 
Visit Name 
Visit 1 
Baseline/Visit 2 
Visit 3 
Visit 4 
Visit 5 
EOS/Visit 6 
Days 
-30 to -1 
0 
90 
180 
270 
330 
Inclusion / Exclusion Criteria 
X 
X 
Informed Consent 
X 
Medical History 
X 
ASCVD Medical History 
X 
Statin Intolerance Medical History 
X 
Demography 
X 
Pregnancy and Assessments of Fertility2 
X 
X 
X 
X 
X 
X 
Height and Weight3 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
Physical Examination4 
S 
S 
S 
S 
S 
Electrocardiogram (ECG) 
X 
Full Clinical Chemistry 
X 
X 
Limited Clinical Chemistry 
X 
X 
X 
X 
Hepatitis Markers 
X 
Hematology 
X 
X 
X 
X 
Coagulation 
X 
X 
X 
Urinalysis 
X 
X 
Lipids and Lipoproteins5 
X 
X 
X 
X 
X 
X 
Randomization 
X 
IRT Transaction 
X 
X 
X 
X 
X 
X 
Inclisiran Dose Administration 
X 
X 
X 


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Epoch 
Screening 
Treatment1 
Visit Name 
Visit 1 
Baseline/Visit 2 
Visit 3 
Visit 4 
Visit 5 
EOS/Visit 6 
Days 
-30 to -1 
0 
90 
180 
270 
330 
Adverse Events 
X 
X 
X 
X 
X 
X 
Injection Site Reaction Assessment 
X 
X 
X 
X 
X 
Prior/Concomitant Medications7 
X 
X 
X 
X 
X 
X 
Surgical/Medical Procedures 
X 
X 
X 
X 
X 
X 
HealthiVibe Trial Feedback Questionnaire9 
X 
X 
X 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 Due to a Public Health Emergency, if participant is unable to attend in-person visit, phone or virtual visit is an acceptable alternative. At home visits by site staff or a 
nursing service may be used to assist with blood draws and/or study medication administration if required at this visit. 
2 All female participants of childbearing potential will have a serum pregnancy test (hCG) performed at Visit 1 (central lab). A urine pregnancy test will be conducted in 
the local laboratory for remaining visits. 
3 Height only to be performed at Visits 1 and 2 
4 Visits 3, 4 and 5 will be a limited/focused physical examination. 
5 LDL-C, apolipoprotein B, Lp(a), non-HDL-C, VLDL-C, total cholesterol, triglycerides, and HDL-C. 
 
 
 
7 30 days prior to randomization 
 
 
9 Questionnaire is optional for trial participants. 


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8.1 
Screening 
A participant who enters screening but is determined not to be eligible 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. 
Participants must provide new written informed consent before they are re-screened. 
 
8.1.1 
Information to be collected on screening failures 
Participants who sign an informed consent form and subsequently found to be ineligible prior 
to randomization will be considered a screen failure. The reason for screen failure should be 
recorded on the appropriate 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). The IRT must be notified within 2 days of the screen fail. 
Participants who are randomized and fail to start treatment, e.g. participants randomized in error, 
will be considered an early terminator. The reason for early termination should be recorded on 
the appropriate Case Report Form. 
 
8.2 
Participant demographics/other baseline characteristics 
Patient demographic and baseline characteristic data to be collected on all participants include: 
age, sex, race, ethnicity, type of insurance, household income and highest completed education. 
Relevant medical history/current medical condition data includes data collected up to the point 
in which informed consent is signed. 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. Discontinuation of statin therapy (i.e., no statin script ≥ 30 days before the end-of-study 
visit) (yes, no) 
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 ≥ 50% reduction from baseline in LDL-C (yes, no) 
5. Achieving LDL-C < 100 mg/dL (yes, no) (among the subset of participants with LDL-C ≥ 
100 mg/dL at baseline) 


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6. Achieving LDL-C < 70 mg/dL (yes/no) 
7. Achieving LDL-C < 55 mg/dL (yes, no) 
8. Percent change from baseline in apoB 
9. Absolute change from baseline in apoB 
10. Percent change from baseline in non-HDL-C 
11. Absolute change from baseline in non-HDL-C 
12. Percent change from baseline in VLDL-C 
13. Absolute change from baseline in VLDL-C 
14. Percent change from baseline in total cholesterol 
15. Absolute change from baseline in total cholesterol 
16. Percent change from baseline in Lp(a) 
17. Absolute change from baseline in Lp(a) 
18. Percent change from baseline in HDL-C 
19. Absolute change from baseline in HDL-C 
20. Percent change from baseline in triglycerides 
21. Absolute change from baseline in triglycerides 
22. Intensity of lipid-lowering therapy (decrease in dose, no change in dose, increase in dose) 
23. Proportion of days covered (total number of days on either statin, ezetimibe, bempedoic 
acid or PCSK9 inhibiting monoclonal antibody therapies prescribed divided by total 
number of study days) 
 
8.3.1 
Primary efficacy assessments 
The primary efficacy assessments will be LDL-C and discontinuation of statin therapy. Samples 
for LDL-C will be collected at screening (Visit 1) and on visit days 2, 3, 4, 5 and 6 (Table 8-1). 


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8.3.2 
Other efficacy assessments 
Other efficacy assessments will include measurement of Apolipoprotein B, Lp(a), non-HDL-C, 
VLDL-C, total cholesterol, triglycerides, and HDL-C. Samples for these additional efficacy 
biomarkers will be collected at Visits 1, 2, 3, 4, 5 and 6 (Table 8-1). 
 
8.3.3 
Appropriateness of efficacy assessments 
The assessment of lipids and lipoproteins is standard in both clinical practice and in trials 
evaluating the efficacy of lipid-modifying therapies (Grundy et al 2019). Utilization of other 
therapies (including, but not limited to, statin discontinuation, adherence to therapies and 
changes in therapy) are frequently used variables to evaluate the effectiveness of therapies in 
clinical studies. The patient-reported outcomes instruments used in this study are validated 
instruments that have been previously used in clinical trials. 
 
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. 


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Table 8-2 
Safety Assessment 
 
 
Assessment 
Specification 
Physical examination 
A complete physical examination will be 
performed at Visits 1 and 6. It 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 examinations. If indicated based on 
medical history and/or symptoms, rectal, 
external genitalia, breast, and pelvic exams will 
be performed. Visits 3, 4 and 5 physical exams 
will be a limited/focused examination. 
Information for all physical examinations must 
be included in the source documentation at the 
study site. Clinically relevant findings that are 
present prior to signing informed consent must 
be recorded on the appropriate eCRF that 
captures medical history. Significant findings 
made after signing informed consent which meet 
the definition of an Adverse Event must be 
recorded as an adverse event. 
Vital signs 
Vital signs will be assessed at Visits 1, 2, 3, 4, 5 
and 6. This will include blood pressure and 
pulse measurements. BP will be measured 
using a standard sphygmomanometer with an 
appropriate sized cuff and the non- dominant 
arm in the sitting position after 5 minutes of rest. 
Every effort should be made to use the same 
arm for the participant for all vital signs 
assessments and where possible, the same 
person doing the assessment. 
Height and weight 
Height in centimeters if possible will be 
measured at Visits 1 and 2. Body weight to the 
nearest 0.1 kg without shoes, will be measured 
at Visits 1, 2, 3, 4, 5 and 6. 
 
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 (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. 
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse events as appropriate. 


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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. 
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. 
 
8.4.1.1 
Hematology 
Blood draws for hematology will include: 
Hemoglobin, hematocrit, erythrocytes, reticulocytes, mean cell hemoglobin (MCH), mean 
corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), platelet 
count, white blood cell count with differential. 
 
8.4.1.2 
Coagulation 
Blood draws for coagulation will include: 
Prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin 
(aPTT). 
 
8.4.1.3 
Chemistry 
Blood draws for chemistry will be performed per the Schedule of Assessments (Table 8-1). 
Analysis will vary based on visit day as follows: 
• Full serum chemistry: AST, ALT, alkaline phosphatase (ALP), gamma glutamyl 
transferase (GGT), total bilirubin (TBL), direct and indirect bilirubin, creatine 
phosphokinase (CPK), lactate dehydrogenase, bicarbonate, uric acid, creatinine, urea 
(BUN), estimated glomerular filtration rate (eGFR), hsCRP, sodium, potassium, 
magnesium, calcium, inorganic phosphate, chloride, albumin, total protein, hsCRP, 
glucose (fasting), 
 
• Limited serum chemistry: ONLY: AST, ALT, ALP, GGT, TBL, CPK, creatinine, eGFR, 
fasting glucose, hsCRP and 
. 


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8.4.1.4 
Urinalysis 
Urinalysis will be performed in accordance with the assessment schedule (Table 8-1) at the 
investigational site (a standardized dipstick test will be supplied by the Central Laboratory). 
Urinalysis will be performed from a sample of mid-stream urine. In case of abnormal results, 
microscopy and other assessments will be performed at the local laboratory and the abnormality 
recorded as an AE. 
The following parameters will be assessed: pH, specific gravity, presence of blood, protein, 
glucose, ketones, nitrates, leukocyte esterase, uro-bilinogen and bilirubin. Microscopic panel 
will be only performed in the event of abnormalities (Red Blood Cells, White Blood Cells, 
Casts, Crystals, Bacteria, Epithelial cells). 
 
8.4.1.5 
Hepatitis markers 
Hepatitis markers will be evaluated at screening only, and will include HBV-DNA, HBsAg, 
HBsAb, HBcAb and HCV RNA-PCR. Testing will be performed in a test sequence 
recommended by the Centers for Disease Control and Prevention. 
 
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. 
Clinically significant abnormalities must be recorded on the eCRF as either medical history 
and/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 in the local laboratory at visits 2, 3, 4, 5 and 6. If any of these tests 
are positive at Visits 1 and/or 2, the participant should not be enrolled in the trial. If a participant 
tests positive at Visits 3, 4 or 5, or should become pregnant during the trial, the participant may 
remain in the trial for follow-up visits, but cannot continue to receive inclisiran injections. 
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 
 
8.4.4.1 
Anaphylactic reactions 
Potential anaphylactic reactions should be assessed by Sampson criteria in Section 16.4 
(Appendix 4). 


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8.4.4.2 
Injection site reactions 
Injection site reactions (ISRs) should be monitored at each visit from the randomization visit 
onwards and through additional contacts with the participant between visits as needed. ISRs 
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. 
 
8.4.4.3 
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: 
 
 
 
 
• 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 (
) when: 
 
 
• New concomitant medication or increase in dose of current antidiabetic therapy is initiated 
to improve the control of plasma glucose level 
 
8.4.5 
Appropriateness of safety measurements 
The safety assessments selected are standard for the evaluation of patients with atherosclerotic 
cardiovascular disease and elevated LDL-C. 
 
8.5 
Additional assessments 
No additional tests will be performed on participants entered into this study. 
 
 
 
 


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8.5.3.3 
HealthiVibe Optional Trial Feedback Questionnaire 
This study includes an optional questionnaire, the “Trial Feedback Questionnaire” for 
participants to provide feedback on their clinical trial experience. Individual trial participant 
responses will not be reviewed by investigators. Responses may be used by the sponsor 
(Novartis) to understand where improvements can be made in the clinical trial process. This 
questionnaire does not ask questions about the trial participant's disease, symptoms, treatment 
effect, or adverse events, and, therefore is not considered as trial data. 
 
9 
Study discontinuation and completion 
9.1 
Discontinuation and completion 
9.1.1 
Study treatment discontinuation and study discontinuation 
Discontinuation of study treatment for a participant occurs when study treatment is stopped 
earlier than the protocol planned duration and can be initiated by either the participant or the 
investigator. 
The investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being. 


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Study treatment must be discontinued under the following circumstances: 
• Participant/guardian decision 
• Pregnancy 
• Use of prohibited treatment as per recommendations in the prohibited treatment section 
• Any situation in which study participation might result in a safety risk to the participant 
• Any severe suspected drug related AE at the investigator's discretion 
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 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 must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 


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Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study discontinuation. A final 
evaluation at the time of the participant’s study discontinuation should be made as detailed in 
the assessment table. 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation. 
 
9.1.3 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the participant, e.g. dates of 
telephone calls, registered letters, etc. A participant should not be considered as lost to follow- 
up until due diligence has been completed or until the end of the study. 
 
9.1.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time. 
Reasons for early termination: 
• Unexpected, significant, or unacceptable safety risk to participants enrolled in the study 
• Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
• Discontinuation of study drug development 
In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible and treated 
as a prematurely withdrawn participant. The investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the participant’s interests. The investigator or sponsor depending on local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial. 
 
9.2 
Study completion and post-study treatment 
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 no further study treatment will be made available to them). 


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For study participants who have successfully completed the study/treatment epoch, 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 (first patient last visit). For study participants who terminate prior to the end of the 
treatment epoch or who withdraw from treatment, continuing treatment should be managed by 
the investigator and/or referring 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. 


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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. 
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. 
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 participant 
with the underlying disease. Alert ranges for laboratory and other test abnormalities are included 
in 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 


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Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
o routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
o 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 
o social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
o 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. 


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All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, an associate from the Novartis 
Chief Medical Office and Patient Safety (CMO & PS) organization 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. 


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Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate eCRF irrespective of whether or not associated with an AE/SAE and reported 
to Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness. 
 
Table 10-1 
Guidance for capturing the study treatment errors includingmisuse/abuse 
 
 
Treatment error type 
Document in Dosing 
eCRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
 
 
 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with 
an SAE 
 
 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
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 and evaluation of liver events 
consistent with normal clinical practice and monitoring. 
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: 


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- serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history 
of concomitant drug use, exclusion of underlying liver disease 
All follow-up information and procedures performed must be recorded as appropriate in the 
eCRF. 
 
10.2.2 
Renal safety monitoring 
To ensure participant safety and enhance reliability in determining the nephrotoxicity potential 
of an investigational drug, a standardized process for identification and evaluationof renal 
events consistent with normal clinical practice and monitoring. Every renal laboratory trigger 
or renal event as defined in Table 16-6 in Section 16.3 (Appendix 3) should be followed up by 
the investigator or designated personnel at the trial site as summarized in Table 16-7 (Section 
16.3 (Appendix 3). 
 
10.2.3 
Steering Committee 
The Steering Committee (SC) for this study will comprise of 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 
11.1 
Data collection 
Integrated Data Acquisition Approach 
The study may utilize a de-identified integrated data acquisition approach entailing capture of 
data directly from available site EHR databases in addition to manual data entry by site 
personnel into an electronic CRF (eCRF) and integration of linked pharmacy claims data 
records. 
 
Direct EHR Data Capture 
If this approach is utilized by your site, the data collection would extract source data from a 
participant’s electronic medical record and map the data into the project database. When using 
an electronic source record as the original point of data capture, there would be no additional 
manual site data entry step for the selected data. These data can be mapped directly into the 
project database, reducing the need for sites to perform manual data entry in the eCRFfor 
required routine care study data elements that are captured as part of the participant’s 
EHR. If it is not possible to acquire data directly from the EHR, or if source data is not integrated 
to the clinical database, data capture and data management will revert to eCRF. 


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This study may incorporate electronic technology to map EHR data into the clinical 
database consistent with Use of Electronic Health Record Data in Clinical Investigations – 
Guidance for Industry July 2018 as well as FDA guidance regarding electronic source and 
regulations related to the maintenance of adequate participant case histories (21 CFR 312.62 
[b]). All electronic source documentation and data collected in this study will “meet the same 
fundamental elements of data quality (e.g. attributable, contemporaneous, original, and accurate) 
that are expected of “paper records” into a system that is fully validated and conforms to 21 
CFR Part 11 requirements. 
Virtual / remote source data review will take place in order to review the EHR data to confirm 
data accuracy and to ensure all study objectives are met when integrated into the clinical study 
database. 
 
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. 
 
Linked Pharmacy & Medical Claims Data 
Participants may be asked to consent to having health records made available as part of the 
collection of medical and pharmacy claims in order to assess concomitant medication and 
clinical outcomes. This data would be sourced from pharmacy & medical claims databases that 
have been de-identified and tokenized to match the participant in the study. This de-identified 
data would be mapped into the project database. Logic checks to confirm accurate linkage 
would be performed by the clinical monitoring and data management teams. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. All integrated data would be presented to the site in a 21 CFR 
Part 11 compliant system for review and clarification of accuracy and quality. 
The investigator/designee is responsible for assuring that all data (whether entered into the 
eCRF or harvested from the EHR) 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. 
 
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 


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requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system and the Data Review Portal. 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 all study treatment (s) dispensed to the participant and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines. 
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/
 
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/
/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 eCRFs must be traceable to these source documents in the 
participant's file. The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant). 


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The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 
 
12 
Data analysis and statistical methods 
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 first” implementation strategy group (i.e., 
excludes patients in the “inclisiran first” implementation strategy 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 at randomization. 


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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. Discontinuation of statin therapy (i.e., no statin use ≥ 30 days before the end-of-study 
visit) (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 first" implementation strategy 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 first" 
implementation strategy and usual care 
The null hypothesis is that the mean percent change from baseline in LDL-C at Day 330 for 
"inclisiran first" implementation strategy and usual care groups are equal. The alternative 
hypothesis is that the mean percent change from baseline in LDL-C at Day 330 for "inclisiran 
first" implementation strategy group is not equal to that of the usual care 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 
effect at Day 330 is < 0.025 and the corresponding least squares mean treatment difference 
("inclisiran first" implementation strategy – usual care) is less than 0, statistical significance in 
favor of "inclisiran first" implementation strategy is shown. All efforts will be made to follow 
up participants until the end of the study. Participants will be expected to followthe 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 and if a participant was not statin intolerant at the beginning of the 
trial 
• Variable: Discontinuation of statin therapy (yes, no) [The primary analysis time point 
is at Day 330.] 
• Treatment: "Inclisiran first" implementation strategy 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: Treatment difference ("inclisiran first" implementation strategy – 
usual care) in the proportion of participants who discontinue statin therapy 
The null hypothesis is that the difference ("inclisiran first" implementation strategy – usual care) 
in the proportion of participants who discontinue statin therapy at Day 330 is at least 0.15 (non- 
inferiority margin). The alternative hypothesis is that the difference ("inclisiran first" 
implementation strategy – usual care) in the proportion of participants who discontinue statin 
therapy at Day 330 is less than 0.15. 
For primary efficacy variable 2, a one-sided 98.75% confidence interval for treatment difference 
("inclisiran first" implementation strategy – usual care) in the proportion of participants who 
discontinued statin therapy at Day 330 will be computed using the normal approximation to the 
binomial distribution. Non-inferiority of the "inclisiran first" implementation strategy to usual 
care will be declared if the upper limit of the confidence interval does not exceed the non- 
inferiority margin of 0.15. 
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 events 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 for whom it cannot be 
ascertained that they are on statin therapy at the end of study will be assumed to have 
discontinued statin therapy. 
 
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 first" implementation strategy 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 first" implementation strategy 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 van Elteren test, adjusting for 
 
(Stokes et al 2012). The probability of observing the same or a more favorable response with 
"inclisiran first" implementation strategy relative to usual care will be estimated using 
nonparametric methods, and the associated 97.5% confidence interval will also be reported 
(Chen and Kianifard 2000). 
 
12.4.6 
Supplementary analysis 
A supplementary analysis of primary efficacy variable 1 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 first" implementation strategy 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 first" 
implementation strategy and usual care 
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. 
 
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 ≥ 50% reduction from baseline in LDL-C (yes, no) 
5. Achieving LDL-C < 100 mg/dL (yes, no) (among the subset of participants with LDL-C ≥ 
100 mg/dL at baseline) 
6. Achieving LDL-C < 70 mg/dL (yes, no) 
7. Achieving LDL-C < 55 mg/dL (yes, no) 
8. Percent change from baseline in apoB 
9. Absolute change from baseline in apoB 
10. Percent change from baseline in non-HDL-C 
11. Absolute change from baseline in non-HDL-C 
12. Percent change from baseline in VLDL-C 
13. Absolute change from baseline in VLDL-C 
14. Percent change from baseline in total cholesterol 
15. Absolute change from baseline in total cholesterol 
16. Percent change from baseline in Lp(a) 


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17. Absolute change from baseline in Lp(a) 
18. Percent change from baseline in HDL-C 
19. Absolute change from baseline in HDL-C 
20. Percent change from baseline in triglycerides 
21. Absolute change from baseline in triglycerides 
22. Intensity of lipid-lowering therapy (decrease in dose, no change in dose, increase in dose) 
23. Proportion of days covered (total number of days on either statin, ezetimibe, bempedoic 
acid or PCSK9 inhibiting monoclonal antibody therapies prescribed divided by total 
number of study days) 
Analyses of secondary efficacy variables 1 and 8 - 21 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 variable 2, 3, and 23 will be analyzed using a linear model with treatment, 
baseline LDL-C, and 
 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 - 7 will be analyzed at each post-baseline visit using a logistic 
regression model with treatment, baseline LDL-C, and 
 as 
explanatory variables (Stokes et al 2012). The odds ratio, 95% confidence intervals 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 22 will be analyzed at each post-baseline visit using a proportional 
odds model with treatment, baseline LDL-C, and 
 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. 
Visit-to-visit LDL-C variability from Day 90 until Day 330 will be reported, using various 
measures of variability (standard deviation, coefficient of variation) (Bangalore et al 2015). 
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 


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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 
All laboratory data will be listed by treatment group, participant, and visit/time, and if reference 
ranges are available, abnormalities will be flagged. Summary statistics will be provided by 
treatment and visit/time. 
 
12.5.3 
Pharmacokinetics 
Not applicable. 
 
12.5.4 
DNA 
Not applicable. 
 
12.5.5 
Biomarkers 
See Section 12.5.1. 
 
12.5.6 
PK/PD relationships 
Not applicable. 
 
 
 
 
 
 
 




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15 
306 
354 
20 
172 
200 
25 
112 
128 
For primary efficacy variable 2, i.e., discontinuation of statin therapy (yes, no), a 
 for a 
non-inferiority test of two proportions, an allocation ratio of 1:1, and a one-sided significance 
level of 0.0125 were used in the calculation of sample size. Table 12-2 considers total sample 
sizes for 0.20 and 0.25 as the true proportions of participants who discontinue statin therapy in 
each treatment group, and non-inferiority margins of 0.10 and 0.15 for the "inclisiran first" 
implementation group to be no worse than the usual care group (nQuery Version 8.4.1.0). From 
Table 12-2, a true proportion of 0.20 for participants who discontinue statin therapy in each 
treatment group by Day 330, a non-inferiority margin of 0.15, and a power of 0.90 were chosen 
to provide a total sample size of 354 participants. 
 
Table 12-2    Sample size calculations for statin therapy discontinuation 
 
Proportion in usual 
care group 
Non-inferiority margin 
Power = 0.85 
Power = 0.90 
0.20 
0.10 
688 
796 
0.20 
0.15 
306 
354 
0.25 
0.10 
806 
932 
0.25 
0.15 
360 
414 
Based on the sample size calculations in Table 12-1 and Table 12-2, a total sample size of 354 
together with a loss to follow-up rate of 10% at Day 330 and a statin intolerance rate at baseline 
of 10% (i.e., a total of 20% due to loss to follow-up and statin intolerance at baseline) require 
approximately 444 participants (222 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., 


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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 
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. 


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Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented. 
 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 




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Fitchett DH, Hegele RA, Verma S (2015) Cardiology patient page. Statin intolerance. 
Circulation 131:e389-391. 
Ford I, Norrie J (2016) Pragmatic Trials. N. Engl. J. Med. 375:454-463. 
Geisbert TW, Hensley LE, Kagan E, et al (2006) Postexposure protection of guinea pigs 
against a lethal ebola virus challenge is conferred by RNA interference. J. Infect. Dis. 
193(12):1650-7. 
Giugliano RP, Pedersen TR, Park JG, et al (2017) Clinical efficacy and safety of achieving 
very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a 
prespecified secondary analysis of the FOURIER trial. Lancet 390(10106):1962-1971. 
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. 
Khvorova A (2017) Oligonucleotide Therapeutics - A New Class of Cholesterol-Lowering 
Drugs. N. Engl. J. Med. 376(1):4-7. 
Koren MJ, Hunninghake DB, (2004) Clinical outcomes in managed-care patients with 
coronary heart disease treated aggressively in lipid-lowering disease management clinics: the 
alliance study. J. Am. Coll. Cardiol 44(9):1772-1779. 
Landmesser U, Haghikia A, Leiter LA, et al (2020) Effect of inclisiran, the siRNA against 
PCSK9, on platelets, immune cells and immunological biomarkers - a pre-specified analysis 
from ORION-1. Cardiovasc. Res. 117(1):284-291. 
Lowenstern A, Li S, Navar AM, et al (2018) Does clinician-reported lipid guideline adoption 
translate to guideline-adherent care? An evaluation of the Patient and Provider Assessment of 
Lipid Management (PALM) registry. Am. Heart J. 200:118-124. 
Mann DM, Woodward M, Muntner P, et al (2010) Predictors of nonadherence to statins: a 
systematic review and meta-analysis. Ann Pharmacother. 44(9):1410-1421. 
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):1349-1356. 
Novartis Pharmaceuticals Corporation (2020), Inclisiran (KJX839) Investigator's Brochure, 
15th edition. 


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Poluzzi E, Strahinja P, Lanzoni M, et al (2008) Adherence to statin therapy and patients' 
cardiovascular risk: a pharmacoepidemiological study in Italy. Eur. J. Clin. Pharmacol. 
64(4):425-432. 
Raal FJ, Kallend D, Ray KK, et al (2020) Inclisiran for the Treatment of Heterozygous 
Familial Hypercholesterolemia. N. Engl. J. Med. 382:1520-1530. 
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. 382:1507-1519. 
Roth GA, Johnson C, Abajobir A, et al (2017) Global, Regional, and National Burden of 
Cardiovascular Diseases for 10 Causes, 1990 to 2015. J. Am. Coll. Cardiol. 70(1):1-25. 
Rymer JA, Mues KE, Monda KL, et al (2020) Use of Low-Density Lipoprotein-Lowering 
Therapies Before and After PCSK9 Inhibitor Initiation 9(9):e014347. 
Sampson HA, Muñoz-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. 
Sampson HA, Muñoz-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(2): 391-7. 
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 
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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. 
Thorpe KE, Zwarenstein M, Oxman AD, et al (2009) A pragmatic-explanatory continuum 
indicator summary (PRECIS): a tool to help trial designers. J Clin Epidemiol 62(5):464-75. 
Virani SS, Alonso A, Benjamin EJ, et al (2020) Heart Disease and Stroke Statistics-2020 
Update: A Report From the American Heart Association. Circulation 141(9): e139-e596. 
Wong ND, Young D, Zhao Y, et al Prevalence of the American College of 
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Examination Survey 2011-2012. J Clin Lipidol 10(5):1109-18. 
Zimmermann TS, Lee AC, Akinc A, et al (2006) RNAi-mediated gene silencing in non- 
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Epidemiol 46(1): 96-102. 


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


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16.2 
Appendix 2: Liver event and laboratory trigger definitions & 
follow-up requirements 
Table 16-3 
Liver event and laboratory trigger definitions 
 
Definition/ threshold 
Liver laboratory triggers 
• 
ALT or AST > 5 × ULN 
If ALT, AST and total bilirubin normal at 
baseline: 
• 
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, CPK, 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: 
Normal 
None 
• 
Interrupt study 
drug 
1. Measure ALT, 
AST, ALP, 
GGT, TBL, 
direct and 
indirect 
bilirubin, PT/IN 
R, albumin, 
CPK, 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. 
ALT or AST > 5 x ULN 
for more than two 
weeks 
For patients with 
Gilbert’s syndrome: No 
change in baseline 
TBL 
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: 
Normal 
None 
ALT or AST > 8 x ULN 
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) 
None 
If elevated at 
baseline: 
ALT or AST > 2 x 
baseline 
For patients with 
Gilbert’s syndrome: 
Doubling of direct 
bilirubin 
or > 300 U/L 
(whichever occurs 
ﬁrst) 
If normal at baseline: 
Normal or elevated 
Severe fatigue, 
nausea, vomiting, right 
upper quadrant pain 
ALT or AST > 3 x ULN 
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 


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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 eCRF 
bilirubin, Alb, PT/INR, ALP and 
GGT) 
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin) 
> 10 x ULN 
• 
Discontinue the study 
treatment immediately 
• 
Hospitalize the participant 
• 
Establish causality 
• 
Record the AE and 
contributing factors(e.g. 
conmeds, med hx, lab) in 
the appropriate eCRF 
ALT, AST, total bilirubin, Alb, 
PT/INR, ALP and GGT until 
resolutionc (frequency at 
investigator discretion) 
Any AE potentially indicative of 
a liver toxicity* 
• 
Consider study treatment 
interruption or 
discontinuation 
• 
Hospitalization if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and 
contributing factors(e.g., 
conmeds, med hx, lab) in 
the appropriate eCRF 
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 increase (sCR) 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 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 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. Infants and children: low systolic blood pressure (age specific) or > 30% decrease in 
systolic blood pressure* 
b. Adults: systolic blood pressure <90 mmHg or >30% decrease from that person’s baseline 
*Low systolic blood pressure for children is age specific and defined as: <70 mmHg for age 
1 month to 1 year; <70 mmHg + [2 x age] for age 1 to years; <90 mmHg for age 11 to 17 years 
Source: (Sampson et al 2005) and (Sampson et al 2006) 


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Amended Clinical Trial Protocol (Version No. 02) 
 
 
 
 


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SAP_001.pdf: 
Clinical Development 
KJX839 
CKJX839A1US02 / NCT04929249
A randomized, multicenter, open-label trial comparing the 
effectiveness of an "inclisiran first" implementation 
strategy to usual care on LDL cholesterol (LDL-C) in 
patients with atherosclerotic cardiovascular disease and 
elevated LDL-C (≥70 mg/dL) despite receiving maximally 
tolerated statin therapy (VICTORION-INITIATE) 
Statistical Analysis Plan (SAP) 
Document type: 
SAP Documentation 
Document status: Final v3.0 
Release date: 
07-Nov-2023
Number of 
pages: 
45 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
 without the consent of Novartis 
Template Version 4.0, Effective from 23-Apr-2021


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Study No. CKJX839A1US02 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted (Current) 
19-Jun-2021 
Prior to 
DB lock 
Creation of 
final version 
N/A - First version 
NA 
21-Dec-2021 
Prior to 
DB lock 
Updated after 
creation of 
TLF shells 
Secondary efficacy variable absolute 
change in LDL-C will also be 
analyzed by subgroup. Subgroups for 
subgroup analyses of primary efficacy 
variables and absolute change in LDL-
C added. 
Section 2.2.1 
 
List of demographic variables updated. Section 2.3.2 
 
Additional summaries added. 
Section 2.4.2 
 
Common adverse event tables using 
5% 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 
 
Summary tables for new onset or 
worsening of diabetes were added. 
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 
 
Other minor changes were made to the 
text. 
Various sections 
07-Nov-2023 
Prior to 
DB lock 
Updated after 
creation of 
TLF shells 
and further 
Novartis 
review 
Updated number of sites to 50 and 
added note that inclisiran is now 
commercially available. 
Section 1.1 
 
Added note clarifying that ‘absolute’ 
change from baseline is calculated as 
post-baseline value minus baseline 
value. Corrected inequality sign: 
Achievement of LDL-C <100 mg/dL 
Section 1.2 


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to be evaluated in participants with 
LDL-C ≥100 mg/dL at baseline. 
 
Clarified wording for population of 
primary estimand #2. 
Section 1.2.1 
 
 
 
 
Various updates made to clarify 
definitions. 
Section 2.1.1 
 
Clarifications added to analysis sets. 
Section 2.2 
 
Updates and clarifications added to 
subgroups. 
Section 2.2.1 
 
Clarifications added to analyses of 
patient disposition, demographics, and 
other baseline characteristics. Only 
summarizing FAS now. 
Sections 2.3, 2.3.1, 
and 2.3.2 
 
Clarifications added to analyses of 
study treatment/compliance and prior, 
concomitant and post therapies. 
Sections 2.4.1 and 
2.4.2 
 
Clarifications added for analyses 
supporting primary objectives. 
Sections 2.5.1, 2.5.2, 
2.5.3, 2.5.4, 2.5.5, 
and 2.5.6 
 
Clarifications added for analyses 
supporting secondary objectives. 
Removed handling of incurrent events 
section. Added supplementary 
analyses. 
Sections 2.6.1, 2.6.3, 
and 2.6.5 
 
Clarifications added for AE analyses. 
Updated MedDRA dictionary to 
v26.1. Updated common TEAE 
definition to 3%. Missing severity and 
relationship will not be imputed but 
will be identified as ‘missing’ in the 
tables. Updated sorting methods. 
Updated methods for identifying AEs 
of special interest. 
Sections 2.7.1 and 
2.7.1.1 
 
Clarified and updated laboratory data 
analyses. 
Section 2.7.3 
 
Updated vital signs analyses. 
Section 2.7.4.2 


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Updated text for potentially clinically 
significant and clinically significant 
laboratory tests 
Section 5.2.1 
 
Added updates to changes in protocol 
specified analyses. 
Section 4 
 
Moved concomitant medication data 
imputation to a new section. 
Section 5.1.3 
 
Added section on handling data with 
special symbols. 
Section 5.2.1 
 
Updated rule for excluding 
participants from the safety analysis 
set. 
Section 5.5 
 
Added a reference. 
Section 6 
 
Other minor changes were made to the 
text. 
Various sections 
 
 
 


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Table of contents 
Table of contents ................................................................................................................. 5 
List of tables ........................................................................................................................ 7 
List of figures ...................................................................................................................... 7 
List of abbreviations ............................................................................................................ 8 
1 
Introduction ....................................................................................................................... 10 
1.1 
Study design .......................................................................................................... 10 
1.2 
Study objectives, endpoints and estimands ........................................................... 13 
1.2.1 
Primary estimand(s) .............................................................................. 15 
1.2.2 
Secondary estimand(s) .......................................................................... 16 
2 
Statistical methods ............................................................................................................. 16 
2.1 
Data analysis general information ......................................................................... 16 
2.1.1 
General definitions ................................................................................ 17 
2.2 
Analysis sets .......................................................................................................... 19 
2.2.1 
Subgroup of interest .............................................................................. 20 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 21 
2.3.1 
Patient disposition ................................................................................. 21 
2.3.2 
Demographics and other baseline characteristics ................................. 21 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 22 
2.4.1 
Study treatment / compliance ................................................................ 22 
2.4.2 
Prior, concomitant and post therapies ................................................... 22 
2.5 
Analysis supporting primary objective(s) .............................................................. 23 
2.5.1 
Primary endpoint(s) ............................................................................... 23 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 24 
2.5.3 
Handling of intercurrent events ............................................................. 25 
2.5.4 
Handling of missing values not related to intercurrent event ............... 25 
2.5.5 
Sensitivity analyses ............................................................................... 25 
2.5.6 
Supplementary analyses ........................................................................ 26 
2.6 
Analysis supporting secondary objectives ............................................................. 26 
2.6.1 
Secondary endpoint(s) ........................................................................... 26 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 28 
2.6.3 
Handling of missing values ................................................................... 28 
2.6.4 
Sensitivity analyses ............................................................................... 29 
2.6.5 
Supplementary analyses ........................................................................ 29 
2.7 
Safety analyses....................................................................................................... 29 
2.7.1 
Adverse events (AEs) ............................................................................ 29 


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2.7.2 
Deaths .................................................................................................... 31 
2.7.3 
Laboratory data ..................................................................................... 31 
2.7.4 
Other safety data ................................................................................... 33 
2.8 
Pharmacokinetic endpoints .................................................................................... 34 
2.9 
PD and PK/PD analyses ........................................................................................ 34 
 
 34 
2.11 
Biomarkers ............................................................................................................. 34 
 
 34 
2.13 
Interim analysis ...................................................................................................... 35 
3 
Sample size calculation ..................................................................................................... 35 
4 
Change to protocol specified analyses .............................................................................. 37 
5 
Appendix ........................................................................................................................... 38 
5.1 
Imputation rules ..................................................................................................... 38 
5.1.1 
Study drug ............................................................................................. 38 
5.1.2 
AE date imputation ............................................................................... 38 
5.1.3 
Concomitant medication date imputation ............................................. 40 
5.2 
Laboratory parameters derivations ........................................................................ 42 
5.2.1 
Handling data with special symbols ...................................................... 42 
5.2.2 
Criteria for Potentially Clinically Significant and Clinically 
Significant abnormal laboratory tests .................................................... 42 
5.3 
AEs coding/grading ............................................................................................... 43 
5.4 
Statistical models ................................................................................................... 44 
5.4.1 
Analysis supporting primary objective(s) ............................................. 44 
5.4.2 
Analysis supporting secondary objective(s).......................................... 44 
5.5 
Rule of exclusion criteria of analysis sets.............................................................. 44 
6 
References ......................................................................................................................... 45 
 


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List of tables 
Table 2-1 
Planned and Actual Treatment Definitions ........................................... 18 
Table 2-2 
Analysis Visit for Each Scheduled Visit ............................................... 19 
Table 3-1 
Same Size Calculations for Percent Change from Baseline in LDL-
C ............................................................................................................ 36 
Table 3-2 
Sample Size Calculations for Statin Statin Therapy Discontinuation ... 36 
Table 5-1 
Criteria Leading to Exclusion ............................................................... 44 
 
List of figures 
Figure 1-1 
Study Design ......................................................................................... 12 
 


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List of abbreviations 
ACC 
AE 
ALP 
AHA 
ApoB 
ALT 
ASCVD 
AST 
ATC 
 
CK 
CRF 
CSR 
CS 
DILI 
dL 
eGFR 
EHR 
ECG 
EOS 
American College of Cardiology 
Adverse Event 
Alkaline phosphatase 
American Heart Association 
Apolipoprotein B 
Alanine Aminotransferase 
Atherosclerotic cardiovascular disease 
Aspartate Aminotransferase 
Anatomical Therapeutic Chemical 
 
Creatine Kinase 
Case Report Form 
Clinical Study Report 
Clinically significant 
Drug induced liver injury 
Deciliter 
estimated Glomerular Filtration Rate 
Electronic Health Record 
Electrocardiogram 
End of Study 
FAS 
 
HDL-C 
HLGT 
HLT 
HRSA 
Full Analysis Set 
 
High density lipoprotein cholesterol 
High-Level Group Terms 
Highest Level Terms 
Health Resources and Services Administration 
ICF 
Informed consent form 
IRT 
Interactive Response Technology 
LDL-C 
Low density lipoprotein cholesterol 
Lp(a) 
Lipoprotein(a) 


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MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
mg 
Milligram(s) 
MI 
Myocardial Infarction 
mmHg 
millimeters of mercury 
MMRM 
Mixed-effects Model for Repeated Measures 
PCS 
Potentially clinically significant 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PD 
Pharmacodynamics 
PFS 
Prefilled syringe 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PT 
Preferred Term 
SAP 
SAE 
SAS 
Statistical Analysis Plan 
Serious Adverse Event 
Statistical Analysis System 
s.c. 
subcutaneous 
SMQ 
Standardised MedDRA Queries 
SOC 
System Organ Class 
TBL 
Total bilirubin 
TEAE 
Treatment-Emergent Adverse Event 
TESAEs 
Treatment-Emergent Serious AEs 
 
 
ULN 
Upper Limits Of Normal 
VLDL-C 
Very low density lipoprotein cholesterol 
WHO 
WHODDG 
World Health Organization 
World Health Organization drug dictionary 
 
 


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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 CKJX839A1US02.  
The aim of the trial and the described statistical analysis methodologies is to assess the 
effectiveness of an "inclisiran first" implementation strategy (addition of inclisiran to 
maximally tolerated statin therapy immediately upon failure to achieve acceptable LDL-C with 
maximally tolerated statin therapy alone) compared to usual care in an ASCVD population, 
enriched for minority and medically underserved patients. 
Analysis plans in this document refer to the related statistical analysis sections in Clinical Study 
Report (CSR). Data will be analyzed by 
 using 
 
 according to Section 12 (Data analysis and statistical methods) 
of the study protocol which is available in Appendix 16.1.1 of the CSR.  Additional detailed 
information regarding the analysis methodology will be contained in the Appendix Section 
16.1.9 of CSR. 
Please refer to the following documents: Clinical Protocol CKJX839A1US02 v02 (amended 
protocol dated 20-Oct-2022) and CRF v11.0 (dated 13-Jan-2023). 
1.1 
Study design 
The study design will be a randomized, two-arm, parallel-group, open-label, multicenter, 
clinical trial. Approximately 444 participants will be randomized 1:1 to "inclisiran first" 
implementation strategy or to usual care. Eligible participants have established ASCVD and 
elevated LDL-C (or non-HDL-C) despite treatment with maximally tolerated statin therapy (but 
without ezetimibe). The unit of randomization will be the participant. To address the bias that 
may arise due to differences in access to therapies, randomization will be stratified by 
status, and various statistical methods will be adjusted for 
 
. 
To minimize selection bias and increase generalizability of the results, potential study sites and 
potentially eligible participants will be identified using electronic data sets (EHR, claims and/or 
laboratory data). The goal in selecting study sites is to ensure a representative sample of sites 
in terms of geography, patient population, and lipid management practices. For example, the 
inclusion of specialized lipid clinics in the trial would lead to more intensive treatment than is 
typical and would therefore reduce the generalizability of the results. Several tactics will aim to 
enhance inclusion of minority and medically underserved populations, as these populations are 
traditionally underrepresented in clinical trials.
 
 Second, investigators will explicitly be 
ority populations. Third, specific barriers to 
participation will be addressed, including rapid reimbursement (e.g., of transportation costs) 
and availability of trial materials (such as informed consent forms [ICFs]) in multiple 
languages). Selected sites will receive a list of patients who could qualify for the trial that is 
generated based on EHR, claims and/or laboratory data. All participants who meet the eligibility 
criteria are to be invited using a standardized invite.   


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Participants in both groups will remain on maximally tolerated statin therapy, unless they are 
statin-intolerant at baseline. In the usual care group, treating physicians are recommended to 
treat patients in accordance with the 2018 ACC/AHA guidelines (Grundy et al 2019). 
Treatment decisions will be at the discretion of the treating physician (including commercial 
prescription of inclisiran). In the "inclisiran first" implementation strategy group, inclisiran will 
be administered initially at randomization, 90 days later and six months thereafter. PCSK9-
inhibiting monoclonal antibodies are not to be used in the “inclisiran first” implementation 
strategy group post-randomization, but addition of other non-statin LDL-C lowering therapies 
(e.g., ezetimibe or bempedoic acid) is allowed to reach acceptable LDL-C levels. This could be 
the case, for example, if a patient has an LDL-C ≥70 mg/dL despite treatment with a maximally 
tolerated statin and inclisiran. The sponsor will not provide access to therapies other than 
inclisiran (only for patients randomized to the “inclisiran first” implementation strategy group). 
In both groups, laboratory assessments (including LDL-C) will be performed at screening, Day 
0, Day 90, Day 180, Day 270 and Day 330. The results of the laboratory assessments performed 
as part of the trial will be available to the participants' physicians in both study groups. Hence, 
to minimize reporting bias, participants in the "inclisiran first" implementation group and 
participants in the usual care group will have an equivalent number of study visits, and an 
equivalent number of blood draws (including LDL-C tests).  
The study will identify approximately 50 sites for participation. Each site will have a principal 
investigator (PI) who is responsible for study visits, while all aspects of the participants' routine 
care will remain the responsibility of the participants' own treating physician in both groups. 
While it is expected that most patients will have a treating physician who is distinct from the 
PI, a PI who wishes to include his or her own patients in the trial would have to (temporarily) 
transition routine care to a separate physician. This will reduce the effect that trial participation 
might have on treatment decisions if the PI and treating physician were the same individual 
(e.g., more aggressive treatment due to more frequent touchpoints).  
Since inclisiran is commercially available in the US as of late-2021, utilization of it in the usual 
care group at the sole discretion of the treating physician will not be encouraged, but will also 
not be prohibited to avoid withholding of appropriate care. If treatment with a PCSK9-inhibiting 
monoclonal antibody was initiated and a patient would have to be transitioned to inclisiran, the 
PCSK9-inhibiting monoclonal antibody should be discontinued.  
The collection of data from trial sites through eCRFs will be complemented with EHR data and 
claims data (e.g., lipid measurements and concomitant medications). 
Participants randomized to “inclisiran first” implementation strategy group will receive 
inclisiran at Day 0, Day 90 and Day 270, consistent with the dosing regimen studied in the 
Phase III trials. 
While study visits will be preferentially performed in-person at the study sites, phone or virtual 
visits are an acceptable alternative if in-person visits are not permitted or impractical 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. 
 


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Figure 1-1 
Study Design 
 
Additional important considerations of the study design include: 
Recruitment: Potentially eligible participants will be pre-screened using EHR, claims and/or 
laboratory databases. This will maximize the representativeness of the sample because it will 
reduce selection bias that occurs when investigators identify all participants by convenience 
sampling. Moreover, centrally identifying potential study sites and participants using EHR, 
claims and/or laboratory data will allow us to ensure that the study sites are representative while 
excluding sites that manage lipids more aggressively than is typical (for example specialized 
lipid clinics). Eligible participants will need to consent to having health records made available 
as part of the collection of medical and pharmacy claims. Several tactics will aim to enhance 
inclusion of minority and medically underserved populations, as these populations are 
traditionally underrepresented in clinical trials.  
Responsibilities of principal investigator / routine care physician: Study visits will be done 
by the PI while routine care is performed by the participant's own treating physician. 
Communication and coordination between the PI and treating physician is allowed. However, 
PIs are asked to refrain from influencing treatment decisions that are usually made by the 
treating physician to maximize external generalizability (i.e., the influence of study 
participation on routine care should be as limited as possible). The PI and treating physician 
can be from the same practice. 
Open-label: The study will be performed as an open-label study to mimic routine care decision-
making, 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 (a total of three inclisiran 
doses). 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) assessment of variables that likely 
require longer-term treatment to observe meaningful treatment differences, such as patient 
reported outcomes. 


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Choice of non-inferiority margin for discontinuation of statin therapy: The sample size of 
the trial is partially based on the co-primary efficacy variable of discontinuation of statin 
therapy. The non-inferiority margin of 0.15 in the proportion of participants who discontinue 
statin therapy by Day 330 was chosen to reflect a clinically meaningful difference in statin 
discontinuation rates between the groups, while considering statin discontinuation rates 
described in other studies (Khunti et al 2018).   
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 an "inclisiran-
first" implementation strategy compared to usual 
care at Day 330 in participants with ASCVD and an 
LDL-C ≥70 mg/dL despite maximally tolerated 
statin therapy 
• 
Percent change from baseline in LDL-C 
• 
To assess the non-inferiority of an "inclisiran first" 
implementation strategy compared to usual care on 
discontinuation of background statin therapy at Day 
330 
• 
Discontinuation of statin therapy (i.e., no 
statin use ≥ 30 days before the end-of-study 
visit) (yes, no) 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To assess the absolute change in LDL-C of an 
"inclisiran first" implementation strategy compared 
to usual care at Day 330, as well as average of 
percent and absolute changes in LDL-C levels to 
each post-baseline visit 
 
• 
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 to each post-baseline visit  
• 
To assess the proportion of participants reaching 
pre-specified LDL-C targets among those receiving 
an "inclisiran first" implementation 
strategy compared to usual care at Day 330 
• 
Achieving ≥ 50% reduction from baseline in 
LDL-C (yes, no) 
• 
Achieving LDL-C < 100 mg/dL (among the 
subset of participants with LDL-C ≥100 
mg/dL at baseline) (yes, no) 
• 
Achieving LDL-C < 70 mg/dL (yes, no) 
• 
Achieving LDL-C < 55 mg/dL (yes, no) 
• 
To assess plasma lipids, lipoproteins and 
triglycerides in participants receiving an "inclisiran 
first" implementation strategy compared to usual 
care at Day 330 
• 
Percent change and absolute change from 
baseline in apoB 
• 
Percent change and absolute change from 
baseline in non-HDL-C 
• 
Percent change and absolute change from 
baseline in VLDL-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 


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Objective(s) 
Endpoint(s) 
• 
To assess changes in and adherence to background 
lipid-lowering therapy in participants receiving an 
"inclisiran first" implementation strategy compared 
to usual care 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, bempedoic 
acid or PCSK9 inhibiting monoclonal 
antibody therapies divided by total number of 
study days) 
• 
To assess visit-to-visit LDL-C variability from Day 
90 until Day 330  
• 
LDL-C measures of variability (standard 
deviation, coefficient of variation) 
• 
To assess overall safety and tolerability of inclisiran 
• 
Adverse events 
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). 
 
 


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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). 
The primary clinical question of interest is:   
What is the effectiveness of an "inclisiran first" implementation strategy compared to usual care 
in patients who have not reached their LDL-target despite treatment with a maximally tolerated 
statin? Inclisiran will be added to maximally tolerated statin therapy and will be compared to 
usual care. Eligible participants will have established ASCVD and elevated LDL-C despite 
being treated with maximally tolerated statin therapy and should not be on ezetimibe or PCSK9 
inhibiting monoclonal antibodies. Although at baseline there should be no plans to modify 
background lipid-lowering therapy, the participants’ treating physicians are recommended to 
treat patients in accordance with the 2018 ACC/AHA cholesterol guideline (Grundy et al 2019). 
The justification for the primary estimands is that these will capture both the effects of the 
inclisiran and the effect of changes in, adherence to, and discontinuation of additional 
medications, mirroring the conditions in clinical practice.  
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 first" implementation strategy 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 (in inclisiran participants).  This intercurrent event 
will be ignored in the analysis. 
• Summary measure: Least-squares mean difference between "inclisiran first" 
implementation strategy and usual care 
Primary estimand 2: The primary analysis of primary efficacy variable 2 (discontinuation of 
statin therapy) to address the primary objective will be based on the following estimand: 
• Population: Defined through appropriate inclusion/exclusion criteria to reflect the 
targeted population and if a participant did not have a medical history of statin 
intolerance 
• Variable: Discontinuation of statin therapy (yes, no) [The primary analysis time point is 
at Day 330.]  
• Treatment: "Inclisiran first" implementation strategy 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 (in inclisiran participants).  This intercurrent event 
will be ignored in the analysis. 
• Summary measure: Treatment difference ("inclisiran first" implementation strategy – 
usual care) in the proportion of participants who discontinue statin therapy 
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 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, 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. 
Lipid Parameters Units 
All tabular summaries, listings, and figures of lipid parameters will be provided in traditional 
units).   All other laboratory parameters will be analyzed in SI units.  Both traditional and SI 
units will be included in SDTM and ADaM datasets.  The lipid parameters include the 
following: 
1. LDL Cholesterol (mg/dL) 
2. Total Cholesterol (mg/dL) 
3. HDL Cholesterol (mg/dL) 
4. Non-HDL Cholesterol (mg/dL) 
5. VLDL Cholesterol (mg/dL) 




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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 First 
Received at least one dose of 
inclisiran 
Inclisiran First 
Inclisiran First 
Inclisiran First 
Never received inclisiran  
Inclisiran First 
Usual Care 
Usual Care 
Received at least one dose of 
inclisiran  
Usual Care 
Inclisiran First 
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 treatment start date is study Day -1 (i.e., no study Day 0). 
Baseline and post-baseline definitions 
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 planned 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 Visit for Each Scheduled Visit  
Analysis Visit 
Target 
Study 
Day* 
Analysis Window 
               From                                         To 
Baseline 
1 
 
Before 
randomization/First 
Study Treatment 
Day 90 
91 
1 
135 
Day 180 
181 
136 
225 
Day 270 
271 
226 
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 180, 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 180, 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, and do not have any major 
protocol deviations (including deviations from inclusion/exclusion criteria) in either treatment 
group.    




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Most recent ASCVD event (<1 year, >= 1 year) is derived from data recorded on the “Medical 
History Targeted” form. The derivation is based on the timing of the most recent percutaneous 
coronary intervention, myocardial infarction, cardiovascular arterial bypass graft, or ischemic 
stroke.  If a participant has multiple events with different timings, the earlier (<1 year) timing 
will be utilized. Participants without events are excluded from the subgroup. 
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 along with reasons for exclusion 
from each analysis population will be summarized by treatment group for all 
randomized participants. 
• The number of participants who completed the study or who discontinued 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. 
A summary of failed inclusion/exclusion criteria will be provided for all screened participants 
and by treatment group for the FAS. 
A summary of the number of participants by visit will be provided by treatment group 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 insurance type, income level, highest completed education, smoking 


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status by substance, body height, weight, 
 will be summarized by treatment for the 
FAS. 
Medical history (targeted medical history, other medical history, and medical history of statin 
intolerance) will be summarized by treatment group using the FAS.  Other medical history will 
be summarized by system organ class and preferred term. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
Study drug administration will be summarized overall for the Safety Set.  
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. See list of lipid-lowering 
therapies below. Medications will be coded using the World Health Organization (WHO) drug 
dictionary (WHODDG March 2021, B3 format) initially, and will be coded/re-coded with up-
version during the course of study. 
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.   
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 post baseline, a shift table from baseline statin 
intensity level to post-baseline lipid-lowering therapy addition group, and a shift table for statin 
intensity from baseline (study Day 1) to Day 330/End of Study (EOS) will also be provided.  
The statin intensity of the last statin taken on or prior to Day 330 (EOS) will be used for the 
post-baseline statin intensity. 
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. 
 
Medication 
Medications included 
Lipid Lowering Therapy 
ATCCODE2=C10 
Statin 
ATCCODE2=C10 and CMDECOD contains ‘statin’ 


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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 an "inclisiran-first" implementation 
strategy compared to usual care at Day 330 in participants with ASCVD and an LDL-C ≥70 
mg/dL despite maximally tolerated statin therapy and to assess the non-inferiority of an 
"inclisiran first" implementation strategy compared to usual care on discontinuation of 
background statin therapy at Day 330. 
2.5.1 
Primary endpoint(s) 
The primary efficacy variables are the following: 
1. Percent change from baseline in LDL-C  
2. Discontinuation of statin therapy (i.e., no statin use ≥ 30 days before the end-of-study visit) 
(yes, no) 
The primary analysis time point for both primary efficacy variables is at Day 330. 
The following provides additional details on the derivation of primary efficacy variable 2. 
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’). 


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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 first" implementation strategy and usual care groups are equal. The alternative 
hypothesis is that the mean percent change from baseline in LDL-C at Day 330 for "inclisiran 
first" implementation strategy group is not equal to that of the usual care group. 
Primary efficacy variable 1 will be analyzed using mixed-effects model repeated measures 
(MMRM) with treatment, visit (Day 90, Day 180, 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 effect at Day 330 is 
< 0.025 and the corresponding least squares mean treatment difference ("inclisiran first" 
implementation strategy – usual care) is less than 0, statistical significance in favor of "inclisiran 
first" implementation strategy 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 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 
The null hypothesis is that the difference ("inclisiran first" implementation strategy – usual care) 
in the proportion of participants who discontinue statin therapy at Day 330 is at least 0.15 (non-
inferiority margin). The alternative hypothesis is that the difference ("inclisiran first" 
implementation strategy – usual care) in the proportion of participants who discontinue statin 
therapy at Day 330 is less than 0.15.  
For primary efficacy variable 2, a one-sided 98.75% confidence interval for treatment difference 
("inclisiran first" implementation strategy – usual care) in the proportion of participants who 
discontinued statin therapy at Day 330 will be computed using the normal approximation to the 
binomial distribution. Non-inferiority of the "inclisiran first" implementation strategy to usual 
care will be declared if the upper limit of the confidence interval does not exceed the non-
inferiority margin of 0.15. The difference in proportions and associated two-sided 97.5% 
confidence interval will also be provided.  
The primary analysis of primary efficacy variable 2 will be based on the FAS excluding 
participants who had medical history of statin intolerance.  The primary analysis of this variable 
will be repeated for the Per-Protocol Set and Restricted Set 2. 


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2.5.3 
Handling of intercurrent events  
The remaining intercurrent events 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 participants).  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 for whom it cannot be 
ascertained that they are on statin therapy at the end of study will be assumed to have 
discontinued statin therapy (discontinued statin = ‘yes’).   
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 first" implementation strategy 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 (in inclisiran participants).  This intercurrent event 
will be ignored in the analysis. 
• Summary measure: Probability of observing the same or a more favorable response with 
"inclisiran first" implementation strategy 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 van Elteren test, adjusting for 
 
(Stokes et al 2012).  
The probability of observing the same or a more favorable response (θ0) with "inclisiran first" 
implementation strategy relative to usual care will be estimated using nonparametric methods, 
and the associated 97.5% confidence interval will also be reported (Chen and Kianifard 2000). 
For both primary efficacy variable 1 and primary efficacy variable 2, an additional sensitivity 
analysis will be performed where participants for whom 
 entered at 


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randomization (via Interactive Response Technology (IRT)) did not match 
 
entered at baseline (via CRF) were excluded from the analysis. 
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.]  
• Treatment: "Inclisiran first" implementation strategy or usual care 
• Remaining intercurrent events: 1. Potential use of inclisiran by participants in the usual 
care group. 2. Discontinuation of study treatment (in inclisiran participants).  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 first" 
implementation strategy and usual care 
2.6 
Analysis supporting secondary objectives  
The secondary objectives include the following: 
• To assess the absolute change in LDL-C of an "inclisiran first" implementation strategy 
compared to usual care at Day 330, as well as average of percent and absolute changes 
in LDL-C levels to each post-baseline visit 
• To assess the proportion of participants reaching pre-specified LDL-C targets among 
those receiving an "inclisiran first" implementation strategy compared to usual care at 
Day 330 
• To assess plasma lipids, lipoproteins and triglycerides in participants receiving an 
"inclisiran first" implementation strategy compared to usual care at Day 330 
• To assess changes in and adherence to background lipid-lowering therapy in participants 
receiving an "inclisiran first" implementation strategy compared to usual care at Day 
330 
• To assess visit-to-visit LDL-C variability from Day 90 until Day 330  
• To assess overall safety and tolerability of inclisiran 
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 


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3. Average absolute change from baseline in LDL-C levels to each post-baseline visit 
4. Achieving ≥ 50% reduction from baseline in LDL-C (yes, no) 
5. Achieving LDL-C < 100 mg/dL (yes, no) (among the subset of participants with LDL-
C ≥ 100 mg/dL at baseline) 
6. Achieving LDL-C < 70 mg/dL (yes, no) 
7. Achieving LDL-C < 55 mg/dL (yes, no) 
8. Percent change from baseline in apoB 
9. Absolute change from baseline in apoB 
10. Percent change from baseline in non-HDL-C 
11. Absolute change from baseline in non-HDL-C 
12. Percent change from baseline in VLDL-C 
13. Absolute change from baseline in VLDL-C 
14. Percent change from baseline in total cholesterol 
15. Absolute change from baseline in total cholesterol 
16. Percent change from baseline in Lp(a) 
17. Absolute change from baseline in Lp(a) 
18. Percent change from baseline in HDL-C 
19. Absolute change from baseline in HDL-C 
20. Percent change from baseline in triglycerides 
21. Absolute change from baseline in triglycerides 
22. 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 


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23. Proportion of days covered (total number of days on either statin, ezetimibe, bempedoic 
acid or PCSK9 inhibiting monoclonal antibody therapies prescribed taken during the 
study divided by total number of study days) 
If a participant did not take any of the four 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). 
2.6.2 
Statistical hypothesis, model, and method of analysis 
Analyses of secondary efficacy variables 1 and 8 - 21 will be similar to the primary analysis of 
primary efficacy variable 1 (using MMRM, but with a two-sided 95% confidence interval for 
all applicable estimates). 
Secondary efficacy variable 2, 3, and 23 will be analyzed using a linear model with treatment, 
baseline LDL-C, and 
 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. 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 180, Day 
270, and Day 330. The outcome value for variable 23 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 - 7 will be analyzed at each applicable post-baseline visit using 
a logistic regression model with treatment, baseline LDL-C, and 
 
 as explanatory variables (Stokes et al 2012). The odds ratio, 95% confidence intervals 
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 22 will be analyzed at each post-baseline visit using a proportional 
odds model with treatment, baseline LDL-C, and 
 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. 
Visit-to-visit LDL-C variability from Day 90 until Day 330 will be reported, using various 
measures of variability (standard deviation and coefficient of variation) (Bangalore et al 2015). 
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 8-21, the MMRM implicitly imputes 
missing data under a missing at random assumption. 
For the analysis of secondary efficacy variables 4 – 7, participants with missing data will be 
imputed using “non-responder” (i.e., “negative” outcome) imputation. 
For the analysis of secondary efficacy variables 2, 3, 22 and 23, missing data will not be 
imputed. 


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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. 
2.7 
Safety analyses 
All safety analyses will be performed on the Safety Set. 
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 study. The final MedDRA version used in this 
study was v26.1. 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. 
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 TEAEs (≥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.  


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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. 
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  
o PTs ‘infusion site %’ (e.g., ‘'infusion site dermatitis', 'infusion site eczema’, 
'infusion site hypersensitivity', 'infusion site rash', 'infusion site urticaria', 
'infusion site vasculitis) and  


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o PTs ‘injection site %’ (e.g., 'injection site dermatitis', 'injection site eczema’, 
'injection site hypersensitivity', 'injection site rash', 'injection site urticaria' and 
'injection site vasculitis')  
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). 
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. 
A shift analysis using the normal range (except for eGFR 
) 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 estimated Glomerular Filtration Rate (eGFR) 
 
 
• 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. 
 
 
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. 
New onset of diabetes during the study will be identified by evaluating different components: 
1) adverse events, 
 
 3) initiation of antidiabetic medication. This analysis will only be conducted in 
participants who do not have diabetes at baseline (determined by either targeted medical history, 
prior concomitant therapies, 
 and fasting plasma glucose).  Additionally, new 
onset or worsening of diabetes will be identified using SMQ and AE terms for diabetic treatment 
emergent adverse events (TEAEs).  The analysis will be performed for all participants and then 
by baseline diabetes status.   
A participant will be identified as being diabetic at baseline if ANY of the following conditions 
are met: 
• Targeted medical history of diabetes (using targeted medical history CRF). 
• Anti-diabetic medication (ATC level 2 code: A10) at baseline. 
• 
 AND fasting glucose ≥126 mg/dL at baseline. 
For this analysis, 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. 


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New onset or worsening of diabetes is defined if ANY of the following conditions 
 
• Laboratory results indicating diabetes, which can be any of the following:   
o The participant has 
 on two consecutive tests.  
o The participant has fasting glucose ≥126 mg/dL on two consecutive fasted tests.  
o The participant has 
 and fasting glucose ≥126 mg/dL on the same 
occasion.  
o The participant has 
 on one occasion and has fasting glucose ≥126 
mg/dL on the succeeding occasion.  
o The participant has fasting glucose ≥126 mg/dL on one occasion and has 
 
 on the succeeding occasion. 
• Diabetic TEAEs identified by the search terms:  
o Hyperglycaemia/new onset diabetes mellitus (SMQ, narrow) 
o Diabetic complications (HLGT) 
o Diabetes mellitus (incl subtypes) (HLT) 
o 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 subjects with potentially clinically significant (PCS) laboratory 
values or clinically significant (CS) laboratory values (refer to Appendix 5.2.2 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 following two categories will also be presented in addition to the CS 
criterion: 
1) Subjects with the baseline value ≤ 2 mg/dL and any post-baseline value > 2 mg/dL. 
2) Subjects who are not in the first category but has ≥ 50% increase from baseline.  
For liver chemistry parameters (ALT, AST, ALP, TBIL), the number and percentage of subjects 
whose PCS/CS value returned to baseline level at the last measurement will also be 
summarized. Here the baseline level is defined as a value of the same category as the baseline 
category or a value of a better category than the baseline. For example, if a subject’s baseline 
ALT is >3 and <=5 x ULN and the subject’s ALT elevated to >5 and <=10 x ULN at the worst 
measurement post baseline, the subject is considered to have returned to baseline level at the 
last measurement if the last ALT value of that subject is <=5 x ULN. 
Listings of all subjects with PCS or CS laboratory values will be presented. Subjects will appear 
once per lab parameter but may appear under multiple lab parameters.  


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The number and percentage of participants satisfying Hy’s Law will also be tabulated by 
treatment group based on the following lab findings: 
• 
Any elevated post-baseline aminotransferases defined as:  
 ALT > 3 x ULN or  
 AST > 3 x ULN 
• 
Elevated post-baseline serum total bilirubin (TBL) > 2 x ULN and serum 
alkaline phosphatase (ALP) levels < 2 x ULN 
Participants must meet all of the criteria listed above at the same time point and have normal 
lab variables (ALT, AST, TBL) at baseline to be considered a Hy’s Law case. The same analysis 
will be performed excluding the normal baseline value requirement. 
2.7.4 
Other safety data 
2.7.4.1 
ECG and cardiac imaging data 
ECG results will be listed. 
2.7.4.2 
Vital signs 
Observed value, change, and percent change from baseline in vital signs (pulse rate, blood 
pressure, weight, 
 will be summarized descriptively at each analysis visit (including 
Day 330/Last Visit) by treatment group.  
Blood pressure categories will be summarized at each analysis visit (including Day 330/Last 
Visit) by treatment group.  The categories are summarized below. The worst category at an 
analysis visit will be used in the analysis.  A shift table from baseline to each visit will also be 
created. 
 
Blood Pressure Category 
Systolic Blood 
Pressure (mmHg) 
 
Diastolic Blood 
Pressure (mmHg) 
Normal 
<120 
and  
<80 
Elevated 
120-129 
and  
<80 
High Blood Pressure Stage 1 
130-139 
or 
80-89 
High Blood Pressure Stage 2 
140-180  
or  
90-120  
Hypertensive Crisis 
>180 
or 
>120 
Reference: Whelton et al 2017. 
 


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2.8 
Pharmacokinetic endpoints   
Not applicable. 
2.9 
PD and PK/PD analyses 
Not applicable. 
 
 
 
2.11 
Biomarkers 
See Section 2.6. 


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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 




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approximately 444 participants (222 participants per treatment group) to be randomized. This 
will also allow examination of subgroups with reasonable sample sizes. 
4 
Change to protocol specified analyses 
Changes from Protocol version 01 (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. 
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. 
Changes from Protocol version 02 (amended protocol) include the following: 
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 
#22 (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. 
 








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Concomitant Medication End Date Imputation 
If not ongoing then - 
• Imputed date = date part of CMENDTC, if complete date 
• Imputed date = min(completion/discontinuation visit date,  DEC 31) , if month is 
missing, (C2, D, E) 
• Imputed date = min(completion/discontinuation visit date, last day of the Month) , 
if day is missing. (A, B, C1) 
 
Concomitant Medication Date Flag 
If not a complete date then 
• Y - If year of the imputed date is not equal to YYYY  
• Else M – If month of the imputed date is not equal to MON  
• Else D. 
 
5.1.3.1 
Prior therapies date imputation 
Same as above. 


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5.1.3.2 
Post therapies date imputation 
Same as above. 
5.1.3.3 
Other imputations 
Same as above. 
5.2 
Laboratory parameters derivations 
5.2.1 
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). 
5.2.2 
Criteria for Potentially Clinically Significant and Clinically Significant 
abnormal laboratory tests 
 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: 
o The baseline value is ≤ 2 mg/dL and any post-baseline value is > 2 mg/dL. 
o Any post-baseline value is ≥ 50% increase from baseline, regardless of whether 
the baseline value is ≤ 2 mg/dL. 
 
Variable 
Unit 
Lower 
Boundary 
Upper Boundary  
Hematology 
Hematocrit 
% 
≤0.8 × LLN 
N/A 


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Variable 
Unit 
Lower 
Boundary 
Upper Boundary  
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 
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* 
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. 
 
5.3 
AEs coding/grading 
Not applicable. 


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5.4 
Statistical models 
5.4.1 
Analysis supporting primary objective(s)  
Not applicable. 
5.4.2 
Analysis supporting secondary objective(s) 
Not applicable. 
5.5 
Rule of exclusion criteria of analysis sets  
Table 5-1 
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 first” implementation 
strategy 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.