Clinical trial NCT04652726
Conditions: Familial Hypercholesterolemia - Heterozygous
Keywords: Heterozygous familial hypercholesterolemia (HeFH) LDL-cholesterol (LDL-C) adolescents pediatric small interfering ribonucleic acid (siRNA)
Sponsor: Novartis Pharmaceuticals
Start date: 2021-01-27; Completion date: 2024-11-27
Enrollment: 141 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a pivotal phase III study designed to evaluate safety, tolerability, and efficacy of inclisiran in adolescents with heterozygous familial hypercholesterolemia (HeFH) and elevated low density lipoprotein cholesterol (LDL-C).

Detailed description:
This was a two-part (1 year double-blind inclisiran versus placebo / 1 year open-label inclisiran) multicenter study designed to evaluate safety, tolerability, and efficacy of inclisiran in adolescents with heterozygous familial hypercholesterolemia (HeFH) and elevated low density lipoprotein cholesterol (LDL-C) on stable standard of care background lipid-lowering therapy. The primary objective was to demonstrate superiority of inclisiran compared to placebo in reducing LDL-C (percent change) at Day 330.

Arms: arm 1: Year 1 - inclisiran sodium 300 mg subcutaneous injection (given at Days 1, 90, and 270) Day 360 only - placebo subcutaneous injection Year 2 - inclisiran sodium 300 mg subcutaneous injection (given at Days 450 and 630) arm 2: Year 1 - placebo subcutaneous injection (given at Days 1, 90 and 270) Year 2 - inclisiran sodium 300 mg subcutaneous injection (given at Days 360, 450, and 630)
Interventions: intervention 1: Inclisiran intervention 2: Placebo
Intervention descriptions: intervention 1: Inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) in 1.5 mL solution for subcutaneous injection intervention 2: Sterile normal saline (0.9% sodium chloride in water for subcutaneous injection)

Protocol documents:
Prot_000.pdf: 
Official Title:    Two Part (Double-blind Inclisiran Versus Placebo [Year 1] Followed by  
Open-label Inclisiran [Year 2]) Randomized Multicenter Study 
to Evaluate Safety, Tolerability, and Efficacy of Inclisiran in 
Adolescents (12 to Less Than 18 Years) With Heterozygous 
Familial Hypercholesterolemia and Elevated LDL-cholesterol 
(ORION-16)
NCT Number: 
 NCT04652726 
Document Date: 
Clinical Study Protocol (Amendment 2): 17-Feb-2023


Novartis Research and Development 
KJX839/inclisiran 
Clinical Trial Protocol CKJX839C12301 
Two part (double-blind inclisiran versus placebo [Year 1] 
followed by open-label inclisiran [Year 2]) randomized 
multicenter study to evaluate safety, tolerability, and 
efficacy of inclisiran in adolescents (12 to less than 18 
years) with heterozygous familial hypercholesterolemia 
and elevated LDL-cholesterol (ORION-16) 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2020-002757-18 
Version number: 
02 (Clean) 
Clinical Trial Phase: 
III 
Release date: 
17-Feb-2023 (Content Final)
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 10 
Amendment 2 (17-Feb-2023) ................................................................................................... 12 
Amendment 1 (28-Oct-2022) ................................................................................................... 13 
Protocol summary .............................................................................................................. 16 
1 
Introduction ....................................................................................................................... 18 
1.1 
Background ............................................................................................................ 18 
1.2 
Purpose .................................................................................................................. 20 
2 
Objectives and endpoints ................................................................................................... 20 
2.1 
Primary estimands ................................................................................................. 21 
2.2 
Secondary estimands ............................................................................................. 22 
3 
Study design ...................................................................................................................... 22 
4 
Rationale ............................................................................................................................ 24 
4.1 
Rationale for study design ..................................................................................... 24 
4.1.1 
Rationale for choice of background therapy ......................................... 25 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 25 
4.3 
Rationale for choice of control drugs (comparator/placebo) ................................. 26 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 26 
4.5 
Risks and benefits .................................................................................................. 27 
5 
Study Population ............................................................................................................... 28 
5.1 
Inclusion criteria .................................................................................................... 28 
5.2 
Exclusion criteria ................................................................................................... 29 
6 
Treatment ........................................................................................................................... 30 
6.1 
Study treatment ...................................................................................................... 30 
6.1.1 
Investigational and control drugs .......................................................... 30 
6.1.2 
Additional study treatments .................................................................. 31 
6.1.3 
Treatment arms/group ........................................................................... 31 
6.1.4 
Treatment duration ................................................................................ 32 
6.2 
Other treatment(s) .................................................................................................. 32 
6.2.1 
Concomitant therapy ............................................................................. 32 
6.2.2 
Prohibited medication ........................................................................... 33 
6.3 
Participant numbering, treatment assignment, randomization .............................. 34 
6.3.1 
Participant numbering ........................................................................... 34 


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6.3.2 
Treatment assignment, randomization .................................................. 34 
6.4 
Treatment blinding ................................................................................................ 34 
6.5 
Dose escalation and dose modification.................................................................. 35 
6.5.1 
Dose modifications ................................................................................ 35 
6.5.2 
Follow-up for toxicities ......................................................................... 36 
6.6 
Additional treatment guidance ............................................................................... 38 
6.6.1 
Treatment compliance ........................................................................... 38 
6.6.2 
Recommended treatment of adverse events .......................................... 38 
6.6.3 
Emergency breaking of assigned treatment code .................................. 38 
6.7 
Preparation and dispensation ................................................................................. 39 
6.7.1 
Handling of study treatment and additional treatment .......................... 39 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 39 
7 
Informed consent procedures ............................................................................................ 40 
8 
Visit schedule and assessments ......................................................................................... 41 
8.1 
Screening ............................................................................................................... 47 
8.1.1 
Information to be collected on screening failures ................................. 47 
8.2 
Participant demographics/other baseline characteristics ....................................... 47 
8.3 
Efficacy .................................................................................................................. 47 
8.3.1 
LDL-cholesterol .................................................................................... 48 
8.3.2 
Other efficacy biomarkers ..................................................................... 48 
 
 48 
8.3.4 
Appropriateness of efficacy assessments .............................................. 48 
8.4 
Safety ..................................................................................................................... 48 
8.4.1 
Laboratory evaluations .......................................................................... 49 
8.4.2 
Electrocardiogram (ECG) ..................................................................... 50 
8.4.3 
Pregnancy .............................................................................................. 51 
8.4.4 
Other safety evaluations ........................................................................ 51 
8.4.5 
Appropriateness of safety measurements .............................................. 53 
8.5 
Additional assessments .......................................................................................... 53 
 
 53 
8.5.2 
Biomarkers ............................................................................................ 53 
 
 53 
9 
Study discontinuation and completion .............................................................................. 54 
9.1 
Discontinuation and completion ............................................................................ 54 
9.1.1 
Study treatment discontinuation and study discontinuation.................. 54 
9.1.2 
Withdrawal of informed consent ........................................................... 55 
9.1.3 
Lost to follow-up ................................................................................... 56 


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9.1.4 
Early study termination by the sponsor ................................................. 56 
9.2 
Study completion and post-study treatment .......................................................... 57 
10 Safety monitoring and reporting ........................................................................................ 57 
10.1 
Definition of adverse events and reporting requirements ...................................... 57 
10.1.1 
Adverse events ...................................................................................... 57 
10.1.2 
Serious adverse events .......................................................................... 58 
10.1.3 
SAE reporting........................................................................................ 59 
10.1.4 
Pregnancy reporting .............................................................................. 60 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 61 
10.2 
Additional Safety Monitoring ................................................................................ 61 
10.2.1 
Liver safety monitoring ......................................................................... 61 
10.2.2 
Renal safety monitoring ........................................................................ 62 
10.2.3 
Other safety monitoring ........................................................................ 62 
10.2.4 
Data Monitoring Committee ................................................................. 62 
10.2.5 
Steering Committee ............................................................................... 63 
11 Data Collection and Database management ...................................................................... 63 
11.1 
Data collection ....................................................................................................... 63 
11.2 
Database management and quality control ............................................................ 63 
11.3 
Site monitoring ...................................................................................................... 64 
12 Data analysis and statistical methods ................................................................................ 65 
12.1 
Analysis sets .......................................................................................................... 65 
12.2 
Participant demographics and other baseline characteristics ................................. 65 
12.3 
Treatments ............................................................................................................. 65 
12.4 
Analysis of the primary endpoint(s)/estimand(s) .................................................. 66 
12.4.1 
Definition of primary endpoint and estimand ....................................... 66 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 66 
12.4.3 
Handling of remaining intercurrent events of primary estimand .......... 66 
12.4.4 
Handling of missing values not related to intercurrent event ............... 67 
12.4.5 
Sensitivity analyses for primary endpoint/estimand ............................. 67 
12.4.6 
Supplementary analysis ......................................................................... 67 
12.4.7 
Supportive analyses ............................................................................... 67 
12.5 
Analysis of secondary endpoints/estimands .......................................................... 67 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) .................................... 67 
12.5.2 
Safety endpoints .................................................................................... 68 
12.5.3 
Biomarkers ............................................................................................ 69 
 
 70 
 
 70 


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12.7 
Interim analyses ..................................................................................................... 70 
12.8 
Sample size calculation.......................................................................................... 71 
12.8.1 
Primary endpoint(s) ............................................................................... 71 
13 Ethical considerations and administrative procedures ...................................................... 71 
13.1 
Regulatory and ethical compliance ........................................................................ 71 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 71 
13.3 
Publication of study protocol and results............................................................... 72 
13.4 
Quality Control and Quality Assurance ................................................................. 72 
14 Protocol adherence ............................................................................................................ 72 
14.1 
Protocol amendments............................................................................................. 73 
15 References ......................................................................................................................... 74 
16 Appendices ........................................................................................................................ 77 
16.1 
Appendix 1: Diagnostic criteria for FH in adolescents / children ......................... 77 
16.2 
Appendix 2: Clinically notable laboratory values and vital signs ......................... 78 
16.3 
Appendix 3: Liver event and laboratory trigger definitions & follow-up 
requirements .......................................................................................................... 79 
16.4 
Appendix 4: Specific Renal Alert Criteria and Actions and Event Follow-up ...... 82 
16.5 
Appendix 5: Recommended Neurological Examination ....................................... 84 
16.6 
Appendix 6: Sampson Criteria for Diagnosing Anaphylaxis ................................ 88 
16.7 
Appendix 7: Reference table blood volume by weight ......................................... 89 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 20 
Table 6-1 
Investigational and control drug ............................................................ 31 
Table 6-2 
Prohibited medication ........................................................................... 33 
Table 6-3 
Guidance on specific clinical and diagnostic assessments which 
can be performed to rule out possible alternative causes of 
observed LFT abnormalities ................................................................. 37 
Table 8-1 
Assessment Schedule ............................................................................ 43 
Table 8-2 
Assessments & Specifications............................................................... 49 
Table 8-3 
Laboratory Assessments ........................................................................ 50 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 61 
 
 71 
Table 16-1 
Criteria for clinically notable vital signs ............................................... 78 
Table 16-2 
Clinically notable laboratory abnormalities for selected tests .............. 78 
Table 16-3 
Liver event and laboratory trigger definitions ...................................... 79 


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Table 16-4 
Follow up requirements for liver laboratory triggers with liver 
symptoms .............................................................................................. 80 
Table 16-5 
Follow up requirements for liver laboratory triggers ............................ 81 
Table 16-6 
Specific renal alert criteria and actions ................................................. 82 
Table 16-7 
Renal event follow-up ........................................................................... 82 
Table 16-8 
Grade Strength ...................................................................................... 84 
Table 16-9 
Reflex responses .................................................................................... 86 
Table 16-10 
Reference table – blood collection volumes by body weight ............... 89 
List of figures 
Figure 3-1 
Study Design ......................................................................................... 24 
 


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List of abbreviations 
ADA 
Anti-drug antibodies 
ADR 
Adverse Drug Reaction 
AE(s) 
Adverse event(s) 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
Apo A1 
Apolipoprotein A1 
Apo B 
Apolipoprotein B 
ASCVD 
Atherosclerotic cardiovascular disease 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical  
BfArM 
Federal Institute for Drugs and Medical Devices 
BMI 
Body Mass Index 
BUN 
Blood urea nitrogen 
C(P)K 
Creatine (phospho)kinase 
CFR 
Code of Federal Regulation 
CHD 
Coronary heart disease 
CMO&PS 
Chief Medical Office and Patient Safety 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CTFG 
Clinical Trials Facilitation and Coordination Group  
CTT 
Clinical trial team 
CV 
Cardiovascular 
CVD 
Cardiovascular disease 
DBP 
Diastolic Blood Pressure 
DILI 
Drug induced liver injury 
DIN 
Drug-induced nephrotoxicity 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
eGFR 
Estimated glomerular filtration rate 
EOS 
End of study 
ERCP 
Endoscopic retrograde cholangiopancreatography 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FAS 
Full Analysis Set 
FH 
Familial Hypercholesterolemia 
FPG 
Fasting plasma glucose 
GalNAc 
N-Acteylgalactosamine 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GLDH 
Glutamate dehydrogenase 
HbA1c 
Hemoglobin A1c 
HDL-C 
High density lipoprotein cholesterol 


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HeFH 
Heterozygous Familial Hypercholesterolemia  
HoFH 
Homozygous Familial Hypercholesterolemia 
 
 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation (of Technical Requirements for Pharmaceuticals for 
Human Use) 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISR(s) 
Injection site reaction(s) 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
kg 
Kilogram(s) 
LDL 
Low density lipoprotein 
LDL-C 
Low density lipoprotein cholesterol 
LDLR 
Low density lipoprotein receptor 
 
 
LFT(s) 
Liver function test(s) 
LLOQ 
Lower limit of quantification 
Lp(a) 
Lipoprotein (a) 
MCV 
Mean corpuscular volume 
mg 
milligram(s) 
MI 
Myocardial infarction 
mL 
milliliter(s) 
MMRM 
Mixed-effect model for repeated measures 
MRI 
Magnetic resonance imaging 
mRNA(s) 
Messenger ribonucleic acid(s) 
PCR 
Protein-creatinine ratio 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PD 
Pharmacodynamic(s) 
PEF 
Peak expiratory flow 
 
 
PT/INR 
Prothrombin Time / International Normalized Ratio 
RBC 
Red blood cell(s) 
RISC(s) 
Ribonucleic acid (RNA)-induced silencing complex(es) 
RNA 
Ribonucleic acid 
s.c. 
Subcutaneous 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SC 
Steering Committee 
sCr 
Serum creatinine 
SD 
Standard deviation 
siRNA(s) 
Small interfering ribonucleic acid(s) 


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SoC 
Standard of Care 
SOP(s) 
Standard Operating Procedure(s) 
SUSAR(s) 
Suspected Unexpected Serious Adverse Reaction(s) 
TBV 
Total blood volume 
TEAE 
Treatment emergent adverse event 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
VLDL-C 
Very low density lipoprotein cholesterol 
WBC 
White blood cell(s) 


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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  
Cohort 
A specific group of participants fulfilling certain criteria 
Control drug 
Any study drug (an active drug or an inactive drug, such as a placebo) which is used as a 
comparator to reduce assessment bias, preserve blinding of investigational drug, assess 
internal validity, and/or evaluate comparative effects of the investigational drug 
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; the point at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol). 
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. 
Investigational 
drug/ treatment 
The drug whose properties are being tested in the study. 
Medication 
number 
A unique identifier on the label of each study drug package in studies that dispense study 
drug using an IRT system. 
Mis-randomized 
participants 
Mis-randomized participants are those who were not qualified for randomization and who 
did not take study treatment, but have been inadvertently randomized into the study  
Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e. concomitant 
or rescue therapy) 
Part  
A sub-division of a study used to evaluate specific objectives or contain different 
populations. For example, one study could contain a single dose part and a multiple dose 
part, or a part in participants with established disease and in those with newly-diagnosed 
disease 
Participant 
A trial participant (can be a healthy volunteer or a patient) 
Participant number 
A unique number assigned to each participant upon signing the informed consent. This 
number is the definitive, unique identifier for the participant and should be used to identify 
the participant throughout the study for all data collected, sample labels, etc. 
Period 
A minor subdivision of the study timeline; divides phases into smaller functional segments 
such as screening, baseline, titration, washout, etc. 
Personal data 
Participant information collected by the Investigator that is coded and transferred to 
Novartis for the purpose of the clinical trial. This data includes participant identifier 
information, study information and biological samples. 
Premature 
participant 
withdrawal 
Point/time when the participant exits from the study prior to the planned completion of all 
study drug administration and/or assessments; at this time all study drug administration is 
discontinued and no further assessments are planned 


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Randomization 
number 
A unique identifier assigned to each randomized participant 
Screen Failure 
A participant who did not meet one or more criteria that were required for participation in 
the study 
Source 
Data/Document 
Source data refers to the initial record, document, or primary location from where data 
comes. The data source can be a database, a dataset, a spreadsheet or even hard-
coded data, such as paper or eSource 
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 administered to the study participants as part of the required study procedures; 
includes investigational drug(s), control(s) or background therapy 
Study treatment 
discontinuation 
When the participant permanently stops taking any of the study drug(s) prior to the 
defined study treatment completion date (if any) for any reason; may or may not also be 
the point/time of study discontinuation  
Treatment 
arm/group  
A treatment arm/group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts. 
Treatment of 
interest 
The treatment of interest and, as appropriate, the alternative treatment to which 
comparison will be made. These might be individual interventions, combinations of 
interventions administered concurrently, e.g. as add-on to standard of care, or might 
consist of an overall regimen involving a complex sequence of interventions. This is the 
treatment of interest used in describing the related clinical question of interest, which 
might or might not be the same as the study treatment. 
Variable (or 
endpoint) 
The variable (or endpoint) to be obtained for each participant that is required to address 
the clinical question. The specification of the variable might include whether the 
participant experiences an intercurrent event. 
Withdrawal of 
study consent 
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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Amended Protocol Version 02 (Clean)  
 
Protocol No. CKJX839C12301 
 
Amendment 2 (17-Feb-2023) 
Amendment rationale  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Changes to the protocol 
The revisions made to the protocol are listed in the Table below. 
Section 
Description of change 
List of abbreviations 
An abbreviation associated with the current amendment is added. 
 
 
 
 
 
 
 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.  
Institutional Review Boards (IRBs) / Independent Ethics Committees (IECs) 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 


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Amended Protocol Version 02 (Clean)  
 
Protocol No. CKJX839C12301 
 
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation.  
The changes herein do not affect the Informed Consent.  
Summary of previous amendments 
Amendment 1 (28-Oct-2022)  
Amendment rationale  
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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In addition 
, several small clarifications/corrections/additions are 
included in this protocol amendment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
• A minor spelling error is corrected. 
This amendment is issued after the release of the original protocol version 00. The first 
participant for this trial was screened on 27-Jan-2021.  
Changes to the protocol 
The revisions made to the protocol are listed in the Table below. 
Section 
Description of change 
Changes related to the sample size reduction 
List of abbreviations 
Abbreviations associated with the current amendment are added. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


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Section 
Description of change 
 
 
 
 
Other small clarifications/corrections/additions  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 15 References 
New references associated with the current amendment are added. 


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Protocol summary 
Protocol 
number 
CKJX839C12301 
Full Title 
Two part (double-blind inclisiran versus placebo [Year 1] followed by open-label inclisiran 
[Year 2]) randomized multicenter study to evaluate safety, tolerability, and efficacy of 
inclisiran in adolescents (12 to less than 18 years) with heterozygous familial 
hypercholesterolemia and elevated LDL-cholesterol (ORION-16) 
Brief title 
A multicenter study to evaluate safety, tolerability, and efficacy of inclisiran in adolescents 
(12 to less than 18 years) with heterozygous familial hypercholesterolemia  
Sponsor and 
Clinical Phase 
Novartis / Phase III 
Investigation 
type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
This is a pivotal phase III study designed to evaluate safety, tolerability, and efficacy of 
inclisiran in adolescents with heterozygous familial hypercholesterolemia (HeFH) and 
elevated low density lipoprotein cholesterol (LDL-C). The use of inclisiran for the treatment 
of HeFH in adolescent patients who require additional lipid lowering will be investigated in 
order to obtain needed pediatric information on inclisiran. 
Primary 
Objective(s)  
The primary objective of the study is to demonstrate superiority of inclisiran compared to 
placebo in reducing LDL-C [percent change] at Day 330 (Year 1) in adolescents (aged 12 
to <18 years) with HeFH and elevated LDL-C. 
Secondary 
Objectives 
Demonstrate superiority of inclisiran compared to placebo in reducing LDL-C [time-adjusted 
percent change] over Year 1 
Demonstrate superiority of inclisiran compared to placebo in reducing LDL-C [absolute 
change] at Day 330 (Year 1) 
Demonstrate superiority of inclisiran compared to placebo in reducing apolipoprotein B 
(Apo B), lipoprotein (a) [Lp(a)], non-high density lipoprotein cholesterol (non-HDL-C), and 
total cholesterol [percent change] at Day 330 (Year 1) 
Evaluate the effect of inclisiran, compared to placebo (for Year 1) and long-term (up to Day 
720), on lowering LDL-C, other lipoprotein and lipid parameters, and proprotein convertase 
subtilisin/kexin type 9 (PCSK9) over time 
Evaluate the safety and tolerability profile of inclisiran, compared to placebo (for Year 1) 
and long-term (up to Day 720), in adolescents (aged 12 to <18 years) with HeFH 
Study design 
Two part (double-blind inclisiran versus placebo [Year 1] followed by open-label inclisiran 
[Year 2]) randomized multicenter study  
Study 
population 
Adolescents (age 12 to <18 years) with HeFH; a minimum of 102 participants (actual 
expected number of participants: approximately 130); males and females 
Key Inclusion 
criteria 
• 
HeFH diagnosed either by genetic testing or on phenotypic criteria 
• 
Fasting LDL-C >130 mg/dL (3.4 mmol/L) at screening 
• 
Fasting triglycerides <400 mg/dL (4.5 mmol/L) at screening 
• 
On maximally tolerated dose of statin (investigator’s discretion) with or without other 
lipid-lowering therapy (e.g. ezetimibe). Maximum tolerated dose of statin is defined as 
the maximum dose of statin that, at the investigator’s discretion, can be taken on a 
regular basis without adverse events that would lead to a reduction in statin dose 
• 
Participants on lipid-lowering therapies (such as statin and/or e.g. ezetimibe) should be 
on a stable dose for ≥ 30 days before screening with no planned medication or dose 
changes during study participation 
• 
Participants on a documented regimen of LDL-apheresis will be allowed to continue the 
apheresis during the study, if needed. The apheresis schedule is not allowed to change 
during the double-blind period of the trial and must permit that an apheresis coincides 
with each study visit 
• 
Estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2 at screening 
Key Exclusion 
criteria 
• 
Previous treatment (within 90 days of screening) with monoclonal antibodies directed 
towards PCSK9 


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• 
Active liver disease or unexplained, confirmed alanine aminotransferase (ALT), 
aspartate aminotransferase (AST) elevation >3x ULN, or total bilirubin elevation >2x 
ULN (except patients with Gilbert’s syndrome) 
• 
Pregnant or nursing females 
• 
Homozygous familial hypercholesterolemia (HoFH) 
• 
Recent and/or planned use of other investigational medicinal products or devices 
• 
Secondary hypercholesterolemia, e.g. hypothyroidism or nephrotic syndrome 
• 
Major adverse cardiovascular events within 3 months prior to randomization 
Study 
treatment 
Part 1 (Year 1): 
• 
Inclisiran sodium 300 mg (equivalent to 284 mg inclisiran*) in 1.5 mL solution 
• 
Placebo 
Part 2 (Year 2): 
• 
Inclisiran sodium 300 mg (equivalent to 284 mg inclisiran*) in 1.5 mL solution 
• 
* Inclisiran is also referred to as KJX839. 
Treatment of 
interest 
The randomized treatment (the investigational treatment inclisiran or the control treatment 
placebo) as add-on to optimal standard of care lipid-lowering therapy for HeFH. The type 
and dose of the concomitant lipid-lowering therapy for HeFH must remain stable during 
Part 1 (Year 1) of the study. 
Efficacy 
assessments 
The primary efficacy assessment will be LDL-C 
Other efficacy assessments will include: 
• 
Apo B, Lp(a), non-HDL-C, total cholesterol, triglycerides, high density lipoprotein 
cholesterol (HDL-C), very low density lipoprotein cholesterol (VLDL-C), apolipoprotein 
A1 (Apo A1), PCSK9 
Key safety 
assessments 
Adverse event (AE) monitoring, vital signs, laboratory parameters (blood and urine), anti-
drug antibodies (ADA) measurement, growth, pubertal development 
 
  
 
 
Data analysis 
The analysis for the primary objective will test the null hypothesis of no difference between 
participants treated with inclisiran and placebo in the least squares mean percentage 
change from baseline to the Day 330 visit in LDL-C against an alternative hypothesis of 
superiority of inclisiran treatment. A one-sided significance level of 0.025 will be used in this 
test. The primary analysis will use an analysis of covariance (ANCOVA) model. The model 
will include the fixed effects of treatment group and baseline age group with baseline LDL-
C as a covariate. Multiple imputation will be used to impute missing data using a washout 
model. The difference in least squares means between treatment groups and 
corresponding 2-sided 95% confidence intervals will be calculated. 
A hierarchical testing strategy will be applied to control the family-wise type I error rate at 
the one-sided significance level of alpha=0.025 to assess superiority of inclisiran over 
placebo for key secondary endpoints: time-adjusted percent change in LDL-C from 
baseline after Day 90 and up to Day 330, absolute change in LDL-C from baseline to Day 
330, percent change in Apo B from baseline to Day 330, percent change in Lp(a) from 
baseline to Day 330, percent change in non-HDL-C from baseline to Day 330, and percent 
change in total cholesterol from baseline to Day 330. The analysis of key secondary 
endpoints will use ANCOVA with missing data imputed using the washout model. 
Safety analyses will include summaries of the incidence of AEs, laboratory parameters, 
ADA measurements, vital signs, and maturation. 
The sample size provides more than 90% power to detect a 30% reduction in the inclisiran 
group compared to the placebo group in percent change of LDL-C from baseline. 
Key words 
Heterozygous familial hypercholesterolemia (HeFH), LDL-cholesterol (LDL-C), adolescents, 
pediatric, small interfering ribonucleic acid (siRNA) 


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1 
Introduction 
1.1 
Background 
Despite advances in treatment, cardiovascular disease (CVD) is the leading cause of death 
worldwide, resulting in over 17 million deaths annually (WHO 2017). Eighty percent of all 
CVD deaths are due to coronary heart disease (CHD) or strokes. Elevated low density 
lipoprotein cholesterol (LDL-C) is a major risk factor for the development of CVD 
(Grundy et al 2004, Go et al 2014). Lowering LDL-C has been shown to reduce the risk of 
death or heart attack and within the range of effects achieved so far, the clinical risk reduction 
is 
linearly 
proportional 
to 
the 
absolute 
LDL-C 
reduction 
(Baigent et al 2005, 
Giugliano et al 2017). 
Millions of people worldwide are treated with lipid-lowering therapies, predominantly statins, 
to reduce LDL-C and the associated risk of death, nonfatal myocardial infarction (MI) and 
nonfatal stroke or associated events (Casula et al 2012). Despite the availability of statins alone 
or in combination with other lipid-lowering medications, with current therapies for the 
management of elevated LDL-C, many at-risk patients do not reach LDL-C goals 
(Jones et al 2012, Jameson et al 2014, Barkas et al 2015, Fitzgerald et al 2017). This is 
particularly true in patients with pre-existing CHD and/or diabetes or a history of familial 
hypercholesterolemia (FH), who are at the highest risk and require the most intensive 
management (Davidson et al 2005). 
FH is a genetic disorder that causes high levels of LDL-C in the blood and is characterized by 
premature cardiovascular (CV) disease. It is caused by mutations in genes encoding proteins 
which regulate low density lipoprotein receptor (LDLR)-mediated clearance of LDL-C, 
including (in decreasing order of prevalence) LDLR, apolipoprotein B (Apo B), and proprotein 
convertase subtilisin/kexin type 9 (PCSK9) (Santos et al 2016). There are two clinical 
manifestations depending on the presence of one or two affected alleles in these genes. The 
milder heterozygous form (heterozygous familial hypercholesterolemia [HeFH]) results from a 
single affected allele. The more severe homozygous form (homozygous familial 
hypercholesterolemia [HoFH]) results from biallelic pathogenic variants in one of these genes, 
or one pathogenic variant in each of two different genes (Santos et al 2016). 
Recent studies suggest that FH is more common than previously projected, with 1/160,000 to 1 
in 300,000 estimated to have HoFH and 1/200 to 1 in 250 people (instead of the historical 1/500) 
to have HeFH (Najam and Ray 2015, Wiegman et al 2015). There are an estimated 34 million 
people with FH worldwide, but the majority remain undiagnosed (~90%) and current treatment 
is often suboptimal (Wilemon et al 2020). 
Children with HeFH are usually asymptomatic in childhood and adolescence and are typically 
diagnosed by the established FH screening methods (Varghese 2014). The total cholesterol and 
LDL-C levels of these children are often over the 95th percentile of the recommended levels, 
and a positive family history corroborates the diagnosis. Some children with HeFH may present 
with tendon xanthoma or arcus lipoides (Varghese 2014). In FH, elevations in LDL-C occur 
from birth (Santos et al 2016). Although atherosclerosis resulting from FH manifests primarily 
in adulthood, growing evidence suggests that it may begin in childhood (as early as the first 
decade of life) and is directly associated with the same CVD risk factors that are well established 
in adults (Daniels et al 2011). 


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As the degree and duration of exposure to elevated LDL-C levels increases the atherosclerotic 
burden, early treatment of FH to lower LDL-C levels is vital (Varghese 2014). In accordance 
with recommendations from the Expert Panel on Integrated Guidelines for Cardiovascular 
Health and Risk Reduction in Children and Adolescents, a LDL-C target of ≤130 mg/dL is 
recommended in children/adolescents (Expert Panel 2011). Expert consensus recommends that 
lipid-lowering treatment consisting of lifestyle recommendations and pharmacological therapy 
should be started from 8 to 10 years of age in patients with FH and should be maintained for 
life (Wiegman et al 2015). Guidelines further recommend statins as first line drug therapy for 
lipid lowering in children (Daniels et al 2011, Expert Panel 2011, Gidding et al 2015, 
Newman et al 2019), however, multiple drug therapy is often needed (Youngblom et al 2016). 
Current treatment options are still limited for children with FH, and the known limitations of 
contemporary therapies are particularly relevant among children with FH who are at the highest 
risk of future CV events, and thus require the most intensive and aggressive management of 
hypercholesterolemia (Stone et al 2014). Thus, there remains a clear unmet medical need for 
treatments that will lower LDL-C, especially in pediatric populations. 
Proprotein convertase subtilisin/kexin type 9 (PCSK9), a member of the serine protease family, 
plays a key role in controlling the levels of LDLRs on the surface of hepatocytes 
(Khvorova 2017). PCSK9 is expressed and secreted into the bloodstream predominantly by the 
liver, binds LDLR both intracellularly and extracellularly and promotes the lysosomal 
degradation of these receptors in hepatocytes, (Lakoski et al 2009, Mousavi et al 2009) thereby 
increasing the circulating LDL-C levels. 
Recently developed and approved PCSK9-blocking monoclonal antibodies reduce PCSK9 and 
lower LDL-C levels, and were also shown to significantly reduce the risk of CV events 
(Sabatine et al 2017, Schwartz et al 2018). 
Small interfering ribonucleic acids (siRNAs) selectively and catalytically silence the translation 
of their complimentary target messenger ribonucleic acids (mRNAs) in a sequence specific 
manner through the formation of effector ribonucleic acid (RNA)-induced silencing complexes 
(RISCs), utilizing a highly specific endogenous mechanism for regulating gene expression 
(Ray et al 2019). Inclisiran is a chemically modified double-stranded small interfering RNA, 
conjugated on the sense strand with triantennary N-Acetylgalactosamine (GalNAc) to facilitate 
uptake by hepatocytes. In hepatocytes, the antisense strand is incorporated in the RISC and 
directs catalytic breakdown of mRNA for PCSK9. This inhibits translation of PCSK9 protein. 
Reduced intrahepatic PCSK9 increases LDLR recycling and expression on the hepatocyte cell 
surface, thereby increasing LDL-C uptake and lowering LDL-C levels in the circulation 
(Fitzgerald et al 2017). 
In the ORION clinical development program, 3660 participants with atherosclerotic CV disease 
(ASCVD), ASCVD risk equivalent, and/or HeFH were studied in three confirmatory 18-months 
phase III studies comparing inclisiran versus placebo adjunctive to maximally tolerated statin 
therapy, and an additional 681 participants were treated in phase I and phase II studies. In the 
phase III studies, treatment with inclisiran sodium 300 mg given by subcutaneous (s.c.) 
injection on Day 1, Day 90, and every 6 months thereafter, resulted in placebo-adjusted 
percentage reductions in LDL-C from baseline at Day 510 of 48% to 52%, with time-adjusted 
average reductions of 44% to 54% sustained over 18 months (Raal et al 2020, Ray et al 2020). 


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The efficacy of inclisiran was consistent across phase I, phase II and phase III studies, with no 
differences across a broad range of subpopulations. 
There were no clinically relevant differences in the safety profile of inclisiran compared with 
placebo, except for a higher incidence of treatment-emergent adverse events (TEAEs) at the 
injection site with inclisiran. However, all TEAEs at the injection site were localized, 
predominantly mild, transient, and resolved without sequelae. Inclisiran is not associated with 
an increased risk for hepatic or renal dysfunction, hypersensitivity, neurologic events and 
neurocognitive disorders, or ophthalmological events and there was no difference from placebo 
in new onset or worsening of diabetes. The potential for immunogenicity of inclisiran is low. 
Additional details on the efficacy and safety of inclisiran are available in the Investigator's 
Brochure (IB). 
Based on the established benefit-risk profile in adults, inclisiran may improve the treatment of 
children/adolescents with HeFH, with a low injection burden given the only twice yearly 
dosing. 
Study CKJX839C12301 (ORION-16) is planned to investigate inclisiran in adolescents aged 
12 to <18 years of age with HeFH. 
1.2 
Purpose 
Study CKJX839C12301 (ORION-16) is a pivotal phase III study designed to evaluate safety, 
tolerability, and efficacy of inclisiran in adolescents (aged 12 to <18 years) with HeFH and 
LDL-C >130 mg/dL (3.4 mmol/L). The use of inclisiran (as an adjunct to stable, optimal 
background lipid-lowering therapy) for the treatment of HeFH in adolescent patients who 
require additional lipid-lowering will be investigated in order to obtain needed pediatric 
information on inclisiran. The follow-up period (Part 2/Year 2) serves to collect longer-term 
data on inclisiran and also allows access of study participants to a potentially effective 
treatment. 
2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• The primary objective is to demonstrate 
superiority of inclisiran compared to placebo 
in reducing LDL-C [percent change] at Day 
330 (Year 1) in adolescents (aged 12 to <18 
years) with HeFH and elevated LDL-C  
• Percentage change in LDL-C from baseline to Day 330 
(Year 1) 
See Section 2.1 for primary estimand 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• Demonstrate superiority of inclisiran 
compared to placebo in reducing LDL-C 
[time-adjusted percent change] over Year 1 
• Time-adjusted percent change in LDL-C from baseline 
after Day 90 and up to Day 330 (Year 1) 
• Demonstrate superiority of inclisiran 
compared to placebo in reducing LDL-C 
[absolute change] at Day 330 (Year 1) 
• Absolute change in LDL-C from baseline to Day 330 
(Year 1) 


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Objective(s) 
Endpoint(s) 
• Demonstrate superiority of inclisiran 
compared to placebo in reducing Apo B, 
lipoprotein (a) [Lp(a)], non-high density 
lipoprotein cholesterol (non-HDL-C), and 
total cholesterol [percent change] at Day 
330 (Year 1) 
• Percent change in Apo B, Lp(a), non-HDL-C, and total 
cholesterol from baseline to Day 330 (Year 1) 
• Evaluate the effect of inclisiran, compared 
to placebo (for Year 1) and long-term (up to 
Day 720), on lowering LDL-C, other 
lipoprotein and lipid parameters, and 
PCSK9 over time 
• Percent change and absolute change in LDL-C, Apo B, 
Lp(a), non-HDL-C, total cholesterol, triglycerides, high 
density lipoprotein cholesterol (HDL-C), very low density 
lipoprotein cholesterol (VLDL-C), apolipoprotein A1 (Apo 
A1) and PCSK9 from baseline to each assessment time 
up to Day 720 (Year 2) 
• Evaluate the safety and tolerability profile of 
inclisiran, compared to placebo (for Year 1) 
and long-term (up to Day 720), in 
adolescents (aged 12 to <18 years) with 
HeFH 
• Incidence, severity and relationship to study drug of 
treatment-emergent adverse events (AEs) and serious 
adverse events (SAEs); vital signs; laboratory 
parameters; anti-drug antibodies (ADA) measurement; 
growth (height, weight, body mass index (BMI)); pubertal 
development (steroid hormones and Tanner staging) 
2.1 
Primary estimands 
The primary clinical question of interest is: What is the effect of the test treatment versus 
placebo on change in LDL-C after 330 days of treatment in adolescents with HeFH who are 
on stable, optimal standard of care (SoC) lipid-lowering therapy, regardless of treatment 
discontinuation for any reason and regardless of unforeseen change in the concomitant lipid-
lowering therapy. 
The justification for the primary estimand is that it will capture both the effect of the study drug 
and the effect of changes in additional medication(s) used for HeFH, if they occur, as would be 
the case in clinical practice.  
The primary estimand is described by the following attributes: 


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1. Population: Adolescents with the HeFH condition of interest and elevated LDL-C on stable 
optimal SoC lipid-lowering therapy. Further details about the population are provided 
in Section 5. 
2. Endpoint: Percentage change in LDL-C from baseline to Day 330 (Year 1). 
3. Treatment of interest: The randomized treatment (the investigational treatment inclisiran or 
the control treatment placebo) as add-on to optimal SoC lipid-lowering therapy for HeFH. 
The type and dose of the concomitant lipid-lowering therapy for HeFH must remain stable 
during Part 1 (Year 1) of the study. Further details about the investigational treatment and 
control treatment are provided in Section 6. 
The summary measure: difference between treatments in least squares mean percentage change 
at Day 330. 
2.2 
Secondary estimands 
Secondary estimands corresponding to key secondary efficacy endpoints are defined similarly 
to the primary estimand. These endpoints, and the corresponding summary measures, are listed 
below. Population, treatment of interest, endpoints, and intercurrent events are defined similarly 
as for the primary estimand. 
• Endpoint: time-adjusted percent change in LDL-C from baseline after Day 90 and up to Day 
330 (Year 1). Summary measure: difference between treatment groups in least squares mean 
time-adjusted percent change in LDL-C from baseline after Day 90 and up to Day 330 (Year 
1). 
• Endpoint: absolute change in LDL-C from baseline to Day 330 (Year 1). Summary 
measure: difference between treatment groups in least squares mean absolute change in 
LDL-C from baseline to Day 330 (Year 1). 
• Endpoint: percent change in Apo B from baseline to Day 330 (Year 1). Summary 
measure: difference between treatment groups in least squares mean percent change in Apo 
B from baseline to Day 330 (Year 1). 
• Endpoint: percent change in Lp(a) from baseline to Day 330 (Year 1). Summary 
measure: difference between treatment groups in least squares mean percent change in 
Lp(a) from baseline to Day 330 (Year 1). 
• Endpoint: percent change in non-HDL-C from baseline to Day 330 (Year 1). Summary 
measure: difference between treatment groups in least squares mean percent change in non-
HDL-C from baseline to Day 330 (Year 1). 
• Endpoint: percent change in total cholesterol from baseline to Day 330 (Year 1). Summary 
measure: difference between treatment groups in least squares mean percent change in total 
cholesterol from baseline to Day 330 (Year 1). 
3 
Study design 
This study is a two-part (double-blind, placebo-controlled / open-label) multicenter study in 
adolescents (aged 12 to <18 years) with HeFH and elevated LDL-C (>130 mg/dL / 3.4 mmol/L) 
on stable, individualized, optimal SoC background lipid-lowering therapy (including 
maximally tolerated statin treatment). 


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The overall study duration is 748 days (excluding a safety follow-up call 30 days after the end 
of study (EOS) visit). 
Following an approximately 4 weeks screening/run-in period, the study has two sequential parts 
(Figure 3-1). 
• Part 1 (Year 1): 12 months double-blind, parallel group period in which participants will 
be randomized to receive either inclisiran sodium 300 mg (equivalent to 284 mg inclisiran*) 
s.c. or placebo (given at Days 1, 90 and 270). 
• Part 2 (Year 2): 12 months single arm, open-label follow-up period with all participants 
receiving inclisiran sodium 300 mg (equivalent to 284 mg inclisiran*) s.c. Participants 
randomized to placebo in Part 1 will receive inclisiran starting on Day 360 (“Switch” Day 
360). Participants randomized to inclisiran in Part 1 will receive placebo on Day 360. This 
dose of inclisiran/placebo on Day 360 will remain blinded in order to maintain the blind for 
Part 1 of the study. All participants will receive subsequent doses of open-label inclisiran 
on Days 450 and 630. 
* Inclisiran is also referred to as KJX839. 
Informed consent will be obtained before initiation of any study-specific procedures (see 
Section 5.1 and Section 7 for details). Participants who meet the inclusion/exclusion criteria 
will be required to maintain their current lipid-lowering treatment unchanged for Part 1 (Year 
1) of the study (including the screening/run-in period). Investigators must ensure that each 
participant receives individualized, optimal SoC lipid-modifying treatment [including 
maximally tolerated statin treatment (investigator’s discretion) with or without other lipid-
lowering therapy (e.g. ezetimibe)], and that this treatment was stable for ≥ 30 days before 
screening. Maximum tolerated dose of statin is defined as the maximum dose of statin that, at 
the investigator’s discretion, can be taken on a regular basis without AEs that would lead to a 
reduction in statin dose. Intolerance to statin must be documented and enrollment of statin-
intolerant participants will be capped at approximately 15%. 
A minimum of 102 participants (actual expected number of participants: approximately 130) 
who meet the inclusion/exclusion criteria will be randomized in a 2:1 ratio to receive either 
inclisiran sodium 300 mg s.c. or placebo on Day 1 (baseline). Randomization will be stratified 
by age (≥12 to <15 years and ≥15 to <18 years to include a minimum of 40 participants in each 
of the two age strata). A second and third dose of inclisiran or placebo will be given on Day 90 
and Day 270, respectively. The primary endpoint will be measured at Day 330. 
Participants initially randomized to placebo will transition to inclisiran starting on Day 360 and 
the study will then change to an open-label, single arm follow-up period of inclisiran sodium 
300 mg s.c. (Part 2). In order to maintain the blind for Part 1 of the study, on the “switch” day 
(Day 360), participants randomized to placebo in Part 1 will receive blinded inclisiran, while 
participants randomized to inclisiran in Part 1 will receive blinded placebo. All participants will 
receive subsequent doses of open-label inclisiran on Day 450 and Day 630. 
The EOS visit will be on Day 720. In addition, a safety follow-up call will be conducted 30 
days after the last study visit or 90 days after the last administration of study drug, whatever is 
longer. 


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Figure 3-1 
Study Design 
  
* Primary endpoint assessed at Day 330. # "Switch Day": Participants randomized to placebo in Part 1 
will start to receive inclisiran on Day 360. Participants randomized to inclisiran in Part 1 will receive 
placebo on Day 360 only to maintain the blind for Part 1. 
Inclisiran and placebo will be administered exclusively by a health care provider at the study 
site. Participants will be observed in the clinic for at least 4 hours post injection on Day 1 and 
Day 360 (i.e. first dosing of inclisiran) and for at least 30 minutes post injection for all other 
dosing visits before being discharged. 
Participants on a documented regimen of low density lipoprotein (LDL)-apheresis will be 
allowed to continue their same regimen during the study, if needed. The apheresis schedule is 
not allowed to change during Part 1 (Year 1) of the study (including the screening/run-in 
period). The apheresis schedule must also allow that an apheresis coincides with each study 
visit. Study drug is to be administered the same day, after completion of apheresis (the next 
scheduled apheresis should not occur within 72 hours after an administration of study drug). 
Blood samples for LDL-C (and other laboratory assessments of efficacy and safety) must be 
obtained immediately before the scheduled apheresis treatment at each applicable study visit 
(including screening and baseline (Day 1)). 
4 
Rationale 
4.1 
Rationale for study design 
Part 1 of the study (Year 1) has a randomized, parallel group, placebo-controlled design to 
provide evidence for the efficacy, safety, and tolerability of inclisiran in adolescents with HeFH. 
This study design is the most appropriate trial design to answer the clinical questions of interest 
on the use of inclisiran in this pediatric patient population. 


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The open-label single-arm design for Part 2 of the study (Year 2) is appropriate to obtain 
additional long-term data, with a maximum number of participants exposed to the 
investigational drug. 
A screening/run-in period of approximately 4 weeks is used to ensure the entry criteria are met 
(allowing test results to be received) and to ensure stabilization of individualized, optimal SoC 
background lipid-lowering therapy prior to randomization. 
An unequal 2:1 randomization was chosen in agreement with regulatory authorities. This 
unequal randomization allows to maximize exposure to the active investigational drug and to 
enhance collection of corresponding efficacy/safety information in the pediatric study 
population. 
4.1.1 
Rationale for choice of background therapy 
It is required that all participants receive individualized, optimal SoC lipid-lowering treatment 
for HeFH at study entry, which must remain unchanged for Part 1 (Year 1) of the study 
(including the screening/run-in period). Optimal SoC for adolescents with HeFH comprises 
maximally tolerated statin treatment with or without additional lipid-lowering treatment (e.g. 
ezetimibe), in accordance with international/local practice and treatment guidelines as well as 
regulatory authorities. No specific background medication is required during the conduct of the 
study; any statin and other lipid-lowering therapies approved for use in this population may be 
used (unless specifically prohibited per protocol; see Section 5.2 and Section 6.2.2 for details). 
4.2 
Rationale for dose/regimen and duration of treatment 
The established dose regimen for inclisiran for adults is 300 mg s.c. on Day 1, Day 90 and every 
6 months thereafter. Based on nonclinical and clinical data, including phase I, II and III clinical 
studies as well as pharmacodynamic (PD) modeling in adult participants, the same dose and 
dose regimen will also be used in the present study in adolescents. 
In adult participants, maximum reductions in LDL-C and PCSK9 levels with inclisiran were 
achieved with single s.c. doses of 300 mg inclisiran sodium, with no additional meaningful 
benefit observed at higher doses. Three large pivotal phase III studies in adult participants with 
ASCVD, ASCVD risk equivalents, and/or HeFH demonstrated that the dose regimen used in 
the present study (300 mg inclisiran sodium s.c. on Day 1, Day 90 and every 6 months 
thereafter) resulted in placebo-adjusted percentage reductions in LDL-C from baseline at Day 
510 of 48% to 52%, with time-adjusted average reductions of 44% to 54% sustained over 18 
months. This dose and regimen also showed good tolerability of inclisiran, with a safety profile 
similar to placebo, except for a higher incidence of AEs at the injection site with inclisiran. No 
patient populations were identified that required an inclisiran dose adjustment. Doses up to 900 
mg (3-fold therapeutic dose) were studied which was safe and well tolerated in healthy adult 
subjects. 
Adult data has shown that the plasma PK of inclisiran does not predict PD effects. Inclisiran is 
rapidly cleared from plasma in 24 to 48 hours depending on the dose level, yet because of its 
site and mechanism of action, its LDL-C lowering effect is measurable for more than 6 months 
even after a single dose, the basis of the 6-monthly dosing interval. Inclisiran is delivered to 
hepatocytes due to its conjugated structure with GalNAc and stored intracellularly in RISC 
complexes, where target protein suppression occurs for months, resulting in the disconnect 


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between plasma PK and PD effects. In view of this time dissociation between PK and PD data, 
a plasma concentration vs. PD effect relationship cannot be established. From phase I study 
data, only a weak relationship was observed between inclisiran Cmax and minimum LDL-C 
levels, due to the indirect processes involved between s.c. administration of inclisiran and 
reduction of LDL-C in the bloodstream. Additionally, after multiple administrations in the 
phase I study, inclisiran plasma exposure ratios were close to one, indicating no PK 
accumulation. A modelling and simulation analysis based on phase II study (ORION-1) data in 
adults suggest that the PD effect of inclisiran neither strengthens nor attenuates over time after 
repeated administrations up to 2 years of treatment. 
In general, dosing and PK in adolescents are similar to those in adults (Momper et al 2013). 
Pharmacokinetics of inclisiran is expected to be similar in adolescents and adults as inclisiran 
is metabolized by exonuclease and endonuclease activity, with urinary excretion contributing 
to plasma elimination. Hence, the 300 mg dose, which has been shown to be efficacious, safe 
and well tolerated in adult phase III studies, as mentioned above, has been chosen as the dose 
for this study. 
 
 
The rationale for the approximately 1 year duration of the placebo-controlled Part 1 of the study 
is that it allows a reasonable number of 3 injections per participant (given the twice yearly 
dosing regimen) and is supported by the treatment effect observed in the phase III clinical trials 
(up to 18 months). The duration is also suitable to assess the longer-term efficacy as well as 
safety and tolerability, including safety areas of special interest. The additional approximately 
1-year duration of the uncontrolled Part 2 of the study is suitable to collect meaningful 
additional long-term data on inclisiran. 
4.3 
Rationale for choice of control drugs (comparator/placebo) 
Part 1 of the study (which includes assessment of the primary (Efficacy) endpoint) is placebo-
controlled, which is a standard design in drug development to assess efficacy and safety and 
ensures that differences in outcome will be a reliable/realistic measure of the treatment effect 
of inclisiran. The use of placebo as a comparator is justified since all enrolled participants will 
be treated with individualized, optimal SoC (including maximum tolerated statin ± other lipid-
lowering treatment, e.g. ezetimibe) prior to the addition of study treatment. 
Part 2 (1 year Safety follow-up) does not have a comparator arm; all patients will receive 
inclisiran, which represents a common and appropriate design to enable the collection of 
additional long-term safety data for the investigational drug for a maximum number of 
participants. 
4.4 
Purpose and timing of interim analyses/design adaptations 
An independent Data Monitoring Committee (DMC) will review safety data regularly during 
the study. A recommendation may be taken to stop or amend the study at any of these reviews. 
Further details are provided in Section 10.2.4 and Section 12.7. 
 
 


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4.5 
Risks and benefits 
It is widely recognized that LDL-C plays a major role in the initiation and progression of 
ASCVD, including in HeFH, and accumulated exposure of elevated LDL-C is causally related 
to the development of ASCVD. As the degree and duration of exposure to elevated LDL-C 
levels increases the atherosclerotic burden, early treatment of HeFH is vital. Published expert 
guidelines recommend a LDL-C target of ≤130 mg/dL in children/adolescents. Current 
treatment options to achieve these targets are still limited for children with FH and the well-
known limitations of contemporary therapies are particularly relevant among pediatric patients 
with FH. 
In adult studies in participants with ASCVD, ASCVD risk equivalents, and/or HeFH, inclisiran 
given on Day 1, Day 90 and every 6 month thereafter lowered LDL-C by ~50% versus placebo 
in participants on maximally tolerated statin therapy ± other lipid-lowering therapies. The effect 
was persistent over time and reversible on stopping inclisiran. 
In non-clinical toxicity studies, inclisiran was not carcinogenic or genotoxic, there was no effect 
on paternal performance, spermatogenesis, estrous cycle, and uterine or ovarian parameters and 
inclisiran did not show evidence of embryolethality, fetotoxicity, or teratogenicity. In addition, 
there were no effects of inclisiran on the development of the F1 generation, including survival, 
growth, physical and reflexological development, behavior, and reproductive performance. The 
safety profile of inclisiran in clinical studies was generally comparable to placebo. The only 
Adverse drug reaction (ADR) identified in clinical studies was a higher incidence of TEAEs at 
the injection site with inclisiran (preferred terms of injection site erythema, injection site 
hypersensitivity, injection site pruritus, injection site rash, and injection site reaction). However, 
all TEAEs at the injection site were localized, were predominantly mild or occasionally 
moderate, transient, and resolved without sequelae. The impact of this side effect is further 
mitigated by the infrequent dosing regimen of inclisiran. 
In general, the risk of participants in this trial may be minimized by compliance with the 
eligibility criteria and study procedures, close clinical monitoring of safety parameters, as well 
as periodic review of the safety data by an independent DMC. Participants will also be observed 
in the clinic for at least 4 hours post injection on Day 1 and Day 360 (i.e. first dosing of 
inclisiran) and for at least 30 minutes post injection for all other dosing visits before being 
discharged. 


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Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study, and agree that in order 
to participate in the study they must adhere to the contraception requirements outlined in the 
exclusion criteria. If there is any question that the participant will not reliably comply, they 
should not be entered or continue in the study. 
The benefit a participant might have by participating in the study is the close monitoring of their 
condition and close adherence to SoC lipid-lowering treatment. 
5 
Study Population 
The study population consists of adolescents (12 to <18 years) with a genetic and/or clinical 
diagnosis of HeFH and LDL-C >130 mg/dL (3.4 mmol/L) on optimal SoC lipid-lowering 
therapy. 
A minimum of 102 participants (actual expected number of participants: approximately 130) 
meeting the eligibility criteria will be randomized. 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Written informed consent must be obtained from the participant’s parent(s)/legal 
representative(s) prior to the adolescent’s participation in the study. A consent or assent may 
also be required for some participants depending on their age and local requirements. An 
informed consent must be obtained from participants once they reach the local legal age of 
adulthood during the study.  
2. Male or female participants, ≥12 to <18 years of age at screening 
3. HeFH diagnosed either by genetic testing or on phenotypic criteria according to the 
European Atherosclerosis Society Consensus Panel (i.e. elevated LDL-C plus a family 
history of elevated LDL-C, premature coronary artery disease and/or genetic diagnosis); see 
Section 16.1 (Appendix 1) for details of the criteria including LDL-C cutoffs 
4. Fasting LDL-C >130 mg/dL (3.4 mmol/L) at the screening visit, measured at the central 
laboratory 
5. Fasting triglycerides <400 mg/dL (4.5 mmol/L) at the screening visit, measured at the 
central laboratory 
6. On maximally tolerated dose of statin (investigator’s discretion) with or without other lipid-
lowering therapy (e.g. ezetimibe). Maximum tolerated dose of statin is defined as the 
maximum dose of statin that, at the investigator’s discretion, can be taken on a regular basis 
without AEs that would lead to a reduction in statin dose 
7. Participants on lipid-lowering therapies (such as statin and/or e.g. ezetimibe) should be on 
a stable dose for ≥ 30 days before screening with no planned medication or dose changes 
during study participation 
8. Participants on a documented regimen of LDL-apheresis will be allowed to continue the 
apheresis during the study, if needed. The apheresis schedule is not allowed to change 
during the double-blind period of the trial and must permit that an apheresis coincides with 
each study visit 


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9. Estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2 at screening  
10. Willing to follow all study procedures including adherence to study visits, fasting blood 
draws, and compliance with study treatment regimens  
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. Previous treatment (within 90 days of screening) with monoclonal antibodies directed 
towards PCSK9 
2. (i) Active liver disease defined as any known current infectious, neoplastic, or metabolic 
pathology of the liver or (ii) unexplained alanine aminotransferase (ALT), 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 
1 week apart 
3. Females who are pregnant or nursing, or who are of child-bearing potential, defined as all 
women physiologically capable of becoming pregnant (e.g. are menarchal) unless they 
agree to abstinence or, if sexually active, agree to the use of effective methods of 
contraception during dosing of study treatment. Female participants of child-bearing 
potential, who are or might become sexually active, must be informed of the need to prevent 
pregnancy during the study. The effective contraception methods are: 
• Barrier method: Condom or Occlusive cap (e.g. diaphragm or cervical/vault caps). For 
UK sites only (if applicable): with spermicidal foam/gel/film/cream/ vaginal 
suppository 
• Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception 
• The decision on the contraceptive method should be reviewed at least every 3 months 
to evaluate the individual need and compatibility of the method chosen 
• If local regulations deviate from the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the informed consent form 
(ICF) 
• Adolescent females who have not reached menarche are exempt from the above 
requirements; however, to be eligible for inclusion in the study, they must be willing to 
comply with the above requirements if they gain child-bearing potential during the 
study 
4. Any uncontrolled or serious disease, or any medical or surgical condition, that may either 
interfere with participation in the clinical study, and/or put the participant at significant risk 
(according to investigator's [or delegate's] judgment) if he/she participates in the clinical 
study 
5. An underlying known disease, or surgical, physical, or medical condition that, in the opinion 
of the investigator (or delegate) might interfere with interpretation of the clinical study 
results 
6. Homozygous FH 


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7. Any condition that according to the investigator could interfere with the conduct of the 
study, such as but not limited to: 
• Participants who are unable to communicate or to cooperate with the investigator 
• Unlikely to comply with the protocol requirements, instructions, and study-related 
restrictions (eg, uncooperative attitude, inability to return for follow-up visits, and 
improbability of completing the study) 
• Have any medical or surgical condition, which in the opinion of the investigator would 
put the participant at increased risk from participating in the study 
• Persons directly involved in the conduct of the study 
8. Treatment with other investigational medicinal products or devices within 30 days or five 
half-lives, whichever is longer 
9. Planned use of other investigational products or devices during the course of the study 
10. Hypersensitivity to any of the ingredients of inclisiran 
11. Known history of alcohol and/or drug abuse 
12. Secondary hypercholesterolemia, e.g. hypothyroidism or nephrotic syndrome 
13. Major adverse cardiovascular events within 3 months prior to randomization 
14. Severe concomitant non-cardiovascular disease that carries the risk of reducing life 
expectancy to less than 2 years 
15. History of malignancy that required surgery (excluding local and wide-local excision), 
radiation therapy and/or systemic therapy during the 3 years prior to randomization 
16. Poorly controlled diabetes mellitus (i.e. hemoglobin A1c (HbA1c) >10.0 %) 
17. Previous participation in this study 
6 
Treatment 
6.1 
Study treatment 
Participants will be randomized 2:1 to double-blind s.c. injections of inclisiran sodium 300 mg 
or placebo in Part 1 (Year 1) of the study, and subsequently all participants will receive open-
label s.c. injections of inclisiran sodium 300 mg in Part 2 (Year 2) of the study. 
Investigational and control drugs will not be dispensed to the participants but administered by 
qualified personnel at the study site. 
6.1.1 
Investigational and control drugs 
The sponsor will provide the following investigational and control drugs as single-use pre-filled 
syringes for s.c. injection (Table 6-1). 
Part 1 (Year 1) including “Switch” Day 360: 
• Inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) in 1.5 mL solution 
• Placebo formulation to this active drug formulation 
Placebo will be supplied as sterile normal saline (0.9% sodium chloride in water for injection). 
Placebo will be administered as a 1.5 mL s.c. injection to match the dose in the inclisiran arm. 


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The placebo pre-filled syringes will be blinded and look identical to the corresponding inclisiran 
pre-filled syringes. 
Part 2 (Year 2): 
• Inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) in 1.5 mL solution 
Table 6-1 
Investigational and control drug 
Investigational/ 
Control Drug 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Sponsor (global 
or local) 
Inclisiran sodium 
300 mg (equivalent 
to 284 mg 
inclisiran*) in 1.5 
mL solution 
Solution for 
injection 
Subcutaneous 
injection 
Solution for 
injection in pre-filled 
syringe 
Sponsor (global) 
Placebo 
Solution for 
injection 
Subcutaneous 
injection 
Solution for 
injection in pre-filled 
syringe 
Sponsor (global) 
* Inclisiran is also referred to as KJX839 
6.1.2 
Additional study treatments 
No other treatment beyond investigational drug and control drug are included in this trial. 
6.1.3 
Treatment arms/group 
Part 1 (Year 1): 
Participants will be assigned at the baseline/randomization visit (Day 1) to one of the following 
two double-blind treatment groups in a 2:1 ratio: 
• Inclisiran sodium 300 mg s.c. 
• Corresponding placebo 
Each participant will receive one injection of blinded inclisiran or placebo on Day 1, a second 
injection of blinded inclisiran or placebo on Day 90 and a subsequent injection of blinded 
inclisiran or placebo on Day 270 (“6 months dosing”). 
Part 2 (Year 2): 
Following a “Switch” Day (Day 360), all participants will receive the same active open-label 
inclisiran treatment: 
• Inclisiran sodium 300 mg s.c. 
Participants randomized to placebo in Part 1 will receive inclisiran sodium 300 mg s.c. starting 
on Day 360 (“Switch” Day 360). Participants randomized to inclisiran in Part 1 will receive 
placebo on Day 360. This dose of inclisiran/placebo on Day 360 will remain blinded in order 
to maintain the blind for Part 1 of the study. 
All participants will receive subsequent doses of open-label inclisiran sodium 300 mg s.c. on 
Days 450 and 630. 


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6.1.4 
Treatment duration 
The expected duration of the participant’s involvement in the study will be approximately 748 
days, which includes a screening/run-in period (28 days) and subsequent treatment with study 
drug (1 year double-blind, placebo-controlled followed by 1 year open-label follow-up), with 
the EOS visit on Day 720 (Year 2). In addition, a safety follow-up call will be conducted 30 
days after the last study visit or 90 days after the last administration of study drug, whatever is 
longer. 
Participants may be discontinued from treatment earlier due to safety reasons and/or at the 
discretion of the investigator or the participant’s parent(s)/legal representative(s) / participant 
(if applicable). They will continue to be followed up in the study unless informed consent is 
withdrawn (Section 9.1.1 and Section 9.1.2). 
Participants who complete participation in this trial and continue to derive clinical benefit from 
the treatment based on the investigator’s evaluation may receive post-trial access (see 
Section 9.2). 
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
Concomitant lipid-lowering therapy 
Investigational and control drug will be given in addition to stable, individualized, optimal SoC 
for HeFH patients, which includes maximally tolerated dose of statin (investigator’s discretion) 
with or without other lipid-lowering therapy (e.g. ezetimibe). Maximum tolerated dose of statin 
is defined as the maximum dose of statin that, at the investigator’s discretion, can be taken on 
a regular basis without AEs that would lead to a reduction in statin dose. Intolerance to statin 
must be documented as medical history attributed to the statin in question in the source 
documentation and on an appropriate Electronic Case Report Form (eCRF). 
Participants are required to maintain their current lipid-lowering treatment unchanged for Part 
1 (Year 1) of the study, including the screening/run-in period (i.e. no medication or dose 
changes; see also Section 6.2.2). Lipid-lowering medications taken by the participant from 3 
months prior to randomization through the End of the Study must be recorded, including doses, 
on an appropriate eCRF. 
Participants on a documented regimen of LDL-apheresis will be allowed to continue their same 
regimen during the study, if needed. The apheresis schedule is not allowed to change during 
Part 1 (Year 1) of the study (including the screening/run-in period). The apheresis schedule 
must also allow that an apheresis coincides with each study visit. Study drug is to be 
administered the same day, after completion of apheresis (the next scheduled apheresis should 
not occur within 72 hours after an administration of study drug). Blood samples for LDL-C (and 
other laboratory assessments of efficacy and safety) must be obtained immediately before the 
scheduled apheresis treatment at each applicable study visit (including screening and baseline 
(Day 1)). LDL-apheresis, which the participant receives from 2 months prior to randomization 
through the End of the Study, must be recorded on an appropriate eCRF. 


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Other concomitant therapy 
All other medications, procedures and significant non-drug therapies used by the participant in 
the 3 months prior to randomization must be recorded on the appropriate eCRFs, independent 
of whether they will be continued during the study or not. Each concomitant drug must be 
individually assessed against all exclusion criteria. 
All other medications, procedures and significant non-drug therapies (including physical 
therapy and blood transfusions) administered after the participant was enrolled into the study 
must also be recorded on appropriate eCRF pages. A new concomitant drug must be assessed 
against all prohibited medications prior to its initiation. 
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 study medication. 
6.2.2 
Prohibited medication 
Participants need to be on stable background lipid-lowering therapy for Part 1 (Year 1) of the 
study (including the screening/run-in period), i.e. the type and dose of lipid-lowering therapy 
must not be altered during this time. Use of the treatments displayed in Part A of Table 6-2 
below are therefore not allowed to be newly added at any time during Part 1 (Year 1) of the 
study, including the screening/run-in period. 
In addition, use of the treatments displayed in Part B of Table 6-2 below are not allowed at any 
time during the entire study duration. 
Table 6-2 
Prohibited medication  
Medication 
Prohibition period 
Action taken with study 
treatment 
PART A: Medications not allowed to be newly added during Part 1 (Year 1) of the study 
Medications* prescribed to lower 
LDL-C (e.g., statins, ezetimibe, 
lomitapide, mipomersen, niacin, 
colesevelam, bile acid absorption 
inhibitors, LDL-apheresis) 
*For monoclonal antibodies 
directed towards PCSK9, see Part 
B 
Part 1 (Year 1) of the study 
(including screening/run-in period) 
None 
Any medication taken for the 
purpose of lipid-lowering, including 
over-the-counter or herbal 
therapies  
Part 1 (Year 1) of the study 
(including screening/run-in period) 
None 
PART B: Regular prohibited medications 
Monoclonal antibodies directed 
towards PCSK9 
Full Study Duration 
Discontinue study treatment 
Other investigational treatments 
Full Study Duration 
Discontinue study treatment  


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6.3 
Participant numbering, treatment assignment, randomization 
6.3.1 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her entire participation in the trial. 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 the participant’s parent(s)/legal representative(s) / participant 
(if applicable) signing the ICF, the participant is assigned to the next sequential Participant No. 
available. 
6.3.2 
Treatment assignment, randomization 
At the baseline/randomization visit (Day 1), all eligible participants will be randomized via 
Interactive Response Technology (IRT) to one of the treatment arms. The investigator or his/her 
delegate will contact the IRT after confirming that the participant fulfills all the 
inclusion/exclusion criteria. The IRT will assign a randomization number to the participant, 
which will be used to link the participant to a treatment arm and will specify a unique medication 
number for the first package of study treatment to be dispensed to the participant. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and investigator staff. A 
participant randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of participant numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the responsibility 
of Novartis Global Clinical Supply using a validated system that automates the random 
assignment of medication numbers to packs containing the study treatment. 
Randomization will be stratified by age (≥12 to <15 years and ≥15 to <18 years, to include a 
minimum of 40 participants in each of the two age strata). 
The randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Office. 
6.4 
Treatment blinding 
Part 1 (Year 1) 
Part 1 of the study is randomized, double-blind and placebo-controlled. Participants, 
investigator staff, persons performing the assessments, and the clinical trial team (CTT) will 
remain blind to the identity of the treatment from the time of randomization until at least 
database lock for all Part 1 (Year 1) data, using the following methods: (1) Randomization data 
are kept strictly confidential until the time of unblinding, and will not be accessible by anyone 
else involved in the study with the following exceptions: the independent statistician and 
programmer who need to have access to prepare interim analysis reports for the DMC and the 
 


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Unblinding will occur in the case of participant emergencies and at the conclusion of the study. 
Unblinding of the CTT and other parties (as needed) will also occur after the Year 1 database 
lock, which is planned after all participants have completed the Day 360 visit. 
Part 2 (Year 2) 
Due to the single-arm, open-label design, treatment in Part 2 of the study will be open to 
participants, investigator staff, persons performing the assessments, and the CTT. 
In order to maintain the blind for Part 1 of the study, on the “switch” day (Day 360), participants 
randomized to placebo in Part 1 will receive blinded inclisiran, while participants randomized 
to inclisiran in Part 1 will receive blinded placebo. 
6.5 
Dose escalation and dose modification 
Dose adjustments of study treatment are not permitted. 
6.5.1 
Dose modifications 
Dosing with study treatment should be temporarily interrupted as follows: 
Part 1 (Year 1): 
• If from the Day 150 visit onwards a participant’s LDL-C is below 25 mg/dL (0.65 mmol/L) 
at the last visit prior to the time of the next scheduled dose, the IRT will assign blinded 
placebo to be administered at the next scheduled dosing visit independent of which 
treatment group the participant was randomized to; i.e. if the participant was treated with 
inclisiran, study treatment will be interrupted in a blinded fashion via the IRT. 
Part 2 (Year 2): 
• If from the Day 450 visit onwards a participant’s LDL-C is below 25 mg/dL (0.65 mmol/L) 
at the last visit prior to the time of the next scheduled dose, the investigator should withhold 


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the dose at the next scheduled dosing visit. This will be flagged accordingly by the central 
laboratory. 
• These dose interruptions must be recorded on an appropriate eCRF. 
Treatment discontinuation is mandatory for specific events listed in Section 9.1.1. 
6.5.2 
Follow-up for toxicities 
6.5.2.1 
Follow up on potential drug-induced liver injury (DILI) cases 
Participants with transaminase increase combined with total bilirubin increase may be 
indicative of potentially severe DILI, and should be considered as clinically important events 
and assessed appropriately to establish the diagnosis. The required clinical information, as 
detailed below, should be sought to obtain the medical diagnosis of the most likely cause of the 
observed laboratory abnormalities. 
The threshold for potential DILI may depend on the participant’s baseline AST/ALT and total 
bilirubin value; participants meeting any of the following criteria will require further follow-up 
as outlined below: 
• For participants with normal ALT and AST and total bilirubin value at baseline: AST or 
ALT >3.0x ULN combined with total bilirubin >2.0x ULN 
• For participants with elevated AST or ALT or total bilirubin value at baseline: [AST or ALT 
>2.0x baseline] OR [AST or ALT >300 U/L] whichever occurs first combined with [total 
bilirubin >2.0x baseline AND >2.0x ULN] 
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered and their role clarified before DILI is assumed as the cause of liver injury. 
A detailed history, including relevant information such as review of ethanol consumption, 
concomitant medications, herbal remedies, supplement consumption, history of any pre-
existing liver conditions or risk factors, should be collected. 
Laboratory tests should include ALT, AST, total bilirubin, direct and indirect bilirubin, gamma-
glutamyl transferase (GGT), glutamate dehydrogenase (GLDH), prothrombin time 
(PT)/International Normalized Ratio (INR), alkaline phosphatase (ALP), albumin, and creatine 
(phospho)kinase (C(P)K). 
Perform relevant examinations (Ultrasound or Magnetic resonance imaging (MRI), Endoscopic 
retrograde cholangiopancreatography (ERCP)) as appropriate, to rule out an extrahepatic cause 
of cholestasis. Cholestasis (is defined as an ALP elevation >2.0x ULN with R value < 2 in 
participants without bone metastasis, or elevation of the liver-specific ALP isoenzyme in 
participants with bone metastasis). 
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R > 2 and < 5) liver injury. For children, 
there are caveats to calculating the R-ratio as normal levels of ALP are higher than in adults 
with standard ranges varying by developmental age. In clinical situations where it is suspected 
that ALP elevations are from an extrahepatic source, the GGT can be used if available. GGT 
may be less specific than ALP as a marker of cholestatic injury, since GGT can also be elevated 


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by enzyme induction or by ethanol consumption. It is more sensitive than ALP for detecting 
bile duct injury. 
Table 6-3 provides guidance on specific clinical and diagnostic assessments which can be 
performed to rule out possible alternative causes of observed liver function test (LFT) 
abnormalities. 
Table 6-3 
Guidance on specific clinical and diagnostic assessments which can 
be performed to rule out possible alternative causes of observed LFT 
abnormalities 
Disease 
Assessment 
Hepatitis A, B, C, E 
• IgM anti-HAV; HBsAg, IgM & IgG anti-HBc, HBV DNA; anti-HCV, HCV 
RNA, IgM & IgG anti-HEV, HEV RNA 
CMV, HSV, EBV infection 
• IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV 
Autoimmune hepatitis 
• ANA & ASMA titers, total IgM, IgG, IgE, IgA 
Alcoholic hepatitis 
• Ethanol history, GGT, MCV, CD-transferrin 
Nonalcoholic steatohepatitis 
• Ultrasound or MRI 
Hypoxic/ischemic hepatopathy 
• Medical history: acute or chronic CHF, hypotension, hypoxia, hepatic 
venous occlusion. Ultrasound or MRI. 
Biliary tract disease 
• Ultrasound or MRI, ERCP as appropriate 
Wilson disease (if <40 yrs old) 
• Ceruloplasmin 
Hemochromatosis 
• Ferritin, transferrin 
Alpha-1-antitrypsin deficiency 
• Alpha-1-antitrypsin 
ANA (antinuclear antibody), ASMA (anti-smooth muscle antibody), CD (carbohydrate-deficient), CHF (chronic 
heart failure), CMV (cytomegalovirus), EBV (Epstein-Barr virus), ERCP (Endoscopic retrograde 
cholangiopancreatography), HAV (hepatitis A virus), HBc (hepatitis B core), HBsAG (HBV surface antigen), 
HBV (hepatitis B virus), HCV (hepatitis C virus), HEV (hepatitis E virus), HSV (herpes simplex virus), Ig 
(Immunoglobulin), MCV (mean corpuscular volume), MRI (Magnetic Resonance Imaging) 
Other causes should also be considered based upon participants’ medical history 
(hyperthyroidism / thyrotoxic hepatitis – T3, T4, thyroid stimulating hormone (TSH); CVD / 
ischemic hepatitis – ECG, prior hypotensive episodes; type 1 diabetes / glycogenic hepatitis). 
In addition to the causes listed in Table 6-3, metabolic disorders should be excluded in children 
by measuring the following parameters: urinary ketones, ammonia, glucose, lactate, 
lactate:pyruvate ratio, alpha fetoprotein, arterial blood gas analysis. 
Following appropriate causality assessments, as outlined above, the causality of the treatment 
is estimated as “probable” i.e. >50% likely, if it appears greater than all other possible causes 
of liver injury combined. The term “treatment-induced” indicates probably caused by the 
treatment, not by something else, and only such a case can be considered a DILI case and should 
be reported as an SAE. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified, should be considered as “medically 
significant,” and thus, meet the definition of SAE and should be reported as SAE using the term 
“potential treatment-induced liver injury.” All events should be followed up with the outcome 
clearly documented. 


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6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
The investigator must promote compliance by informing the participant that compliance is 
necessary for the participant’s safety and the validity of the study. The investigator should also 
instruct the participant to adhere closely to the scheduled study visits. Study treatment will not 
be dispensed to the participant but will be administered at designated study visits at the study 
site by qualified personnel, facilitating compliance. Study drug dosing information should be 
captured within each designated visit on an appropriate eCRF. The investigator or designee 
must also maintain an inventory record of study drug (inclisiran/placebo) received and 
administered. 
 
  
6.6.2 
Recommended treatment of adverse events 
Adverse events should be treated according to local practice and guidelines, and is at the 
discretion of the investigator and treating physician. 
For participants with injection site reaction, antihistamines, local or systemic steroids can be 
used at the investigator’s discretion depending on the severity of the reaction. 
Medication used to treat AEs must be recorded on appropriate eCRF page(s). 
6.6.3 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
participant safely. Blinding codes may also be broken after a participant discontinues treatment 
due to disease progression if deemed essential to allow the investigator to select the participant’s 
next treatment regimen, and after discussion and agreement with the sponsor. Most often, study 
treatment discontinuation and knowledge of the possible treatment assignments are sufficient 
to treat a study participant who presents with an emergency condition. Emergency treatment 
code breaks are performed using the IRT. When the investigator contacts the system to break a 
treatment code for a participant, he/she must provide the requested participant identifying 
information and confirm the necessity to break the treatment code for the participant. The 
investigator will then receive details of the investigational drug treatment for the specified 
participant and a fax or email confirming this information. The system will automatically inform 
the Novartis monitor for the site and the study team that the code has been broken. 
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide: 
• protocol number 
• name 
• participant number 


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In addition, oral and written information to the participant must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time. 
After an emergency un-blinding, study drug should be permanently discontinued. The 
participant will continue to be followed up in the study unless informed consent is withdrawn 
(Section 9.1.1 and Section 9.1.2). 
6.7 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section. 
A unique medication number is printed on the study medication label.  
Investigator staff will identify the study medication kits to administer 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 using the medication kit, site personnel will 
detach the outer part of the label from the packaging and affix it to the source document. 
6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels. 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis Country Organization Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
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 
Investigational and control drugs will not be dispensed to the participants. Study drug injections 
will be performed exclusively at the study site by qualified clinical study site staff under the 
supervision of the investigator or designee. 


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The site of injection is the abdomen, alternating sides for each injection. Injections should not 
be done into areas of active skin disease or injury such as sunburns, skin rashes, inflammation, 
tattoos or skin infections. 
Participants will be administered one s.c. injection of study drug at pre-defined visits as 
specified in the Assessment Schedule (Table 8-1) and summarized below. 
• Part 1: Each participant will receive one injection of blinded inclisiran or placebo on Day 
1, a second injection of blinded inclisiran or placebo on Day 90 and a subsequent injection 
of blinded inclisiran or placebo on Day 270 (“6 months dosing”). 
• Part 2: Participants randomized to placebo in Part 1 will receive a single injection of blinded 
inclisiran on Day 360, while participants randomized to inclisiran in Part 1 will receive a 
single injection of blinded placebo on Day 360. All participants will receive subsequent 
doses of open-label inclisiran on Day 450 and Day 630. 
Injections will be administered after all other study assessments have been completed for the 
visit. At the Randomization (Day 1) and Day 360 visits, vital signs (blood pressure and pulse) 
and ADA (Day 1 only) will be assessed a second time 4 hours after injection.
 
Participants must be observed in the clinic for at least 4 hours post injection on Day 1 and Day 
360 (i.e. first dosing of inclisiran) and for at least 30 minutes post injection for all other dosing 
visits before being discharged. 
Should a participant develop signs or symptoms of anaphylaxis when study drug is injected, the 
investigator will need to collect a blood sample for tryptase within 30 minutes of the onset of 
anaphylaxis (or as soon as possible). 
All kits of study treatment assigned by the IRT will be recorded in the IRT system. 
All injections to the participant as well as study drug interruptions/discontinuations (i.e. no 
injection at a designated dosing visit) during the study must be recorded on an appropriate 
eCRF. 
7 
Informed consent procedures 
Eligible participants may only be included in the study after the participant’s parent(s)/legal 
representative(s) or the participant (if applicable) provides (witnessed, where required by law 
or regulation), Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-
approved informed consent. 
In cases where the participant's parent(s)/legal representative(s) give consent, 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 should indicate assent by personally signing and dating 
the written informed consent document or a separate assent form (as per local requirements). 
An informed consent must be obtained from the participant once he/she reaches the local legal 
age of adulthood during the study. 


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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 and 
participant assent where applicable must be documented in the participant’s source documents. 
Novartis will provide to investigators in separate documents proposed ICF(s) and age 
appropriate assent form(s) that comply with the International Council for Harmonisation (ICH) 
Good Clinical Practice (GCP) guidelines and regulatory requirements and are considered 
appropriate for this study. Any changes to the proposed consent/assent forms 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 IB. This information will be included in the informed consent and should be 
discussed with the participant’s parent(s)/legal representative(s) and, to the extent possible, 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/assent and then must be discussed with the 
participant’s parent(s)/legal representative(s) and, to the extent possible, the participant. 
Women of child bearing potential and her parent(s)/legal representative(s) 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/assent forms must be provided to Novartis after 
IRB/IEC approval. 
8 
Visit schedule and assessments 
The Assessment Schedule (Table 8-1) lists all of the assessments when they are performed. All 
data obtained from these assessments must be supported in the participant’s source 
documentation. 
Participants should be seen for all visits/assessments as outlined in the Assessment Schedule or 
as close to the designated day/time as possible. Missed or rescheduled visits should not lead to 
automatic discontinuation. 
Participants who prematurely and permanently discontinue from study treatment will continue 
to be followed up in the study according to the Assessment Schedule unless informed consent 
is withdrawn. 


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Participants who prematurely discontinue the study for any reason [e.g. if a participant’s 
parent(s)/legal representative(s) / a participant (if applicable) decide to prematurely and 
permanently discontinue the participant from study treatment and decline further follow-up 
visits] should be scheduled for an EOS visit as soon as possible. At this final visit, AEs and 
concomitant medications should be recorded in the corresponding eCRFs. 
Participants will have to comply with the following restrictions: 
• Participants should have fasted for at least 8 hours for all visits for fasting 
lipids/lipoproteins/PCSK9 and glucose blood samples (if the participant has not fasted, the 
collection of laboratory evaluations must be rescheduled) 
• Participants must refrain from unaccustomed strenuous physical exercise for 48 hours 
before the screening and any study visit until the follow-up has been completed 
• Blood donation will not be allowed at any time during the study 
If an extraordinary situation (like e.g. during the coronavirus disease (COVID)-19 pandemic) 
limits or prevents on-site study visits, alternative methods of providing continuing care may be 
implemented. Phone calls, virtual contacts (e.g. teleconsult) or visits by site staff / home nursing 
service to the participant´s home depending on local regulations and capabilities, can replace 
on-site study visits, for the duration of the extraordinary situation until it is safe for the 
participant to visit the site again. This also includes administration of study treatment by 
qualified study site personnel at a location other than the study site. 


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Table 8-1 
Assessment Schedule 
Period 
Screening1 
Part 1 (Double-blind, placebo-controlled) 
Part 2 (Open-label, single-arm) 
Follow-up 
Visit Name 
Screening 
Day 1 
(Baseline 
& 1st 
Treatment) 
Day 30 Day 90 Day 150 Day 270 Day 330 
Day 360 
("Switch 
Day")2 
Day 450 Day 510 Day 630 
Day 720 
(End of 
Treatment/ 
Study)3 
Safety 
follow-up 
(last visit 
+30 days)4 
Days 
-28 
1 
30 
90 
150 
270 
330 
360 
450 
510 
630 
720 
750 
Informed consent / 
assent (as applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
(serum)5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
(urine)5 
 
S 
 
 
 
 
 
S 
 
 
 
S 
 
Relevant medical 
history/current 
medical conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history Statin 
intolerance (if 
applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking & Alcohol 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight / waist 
circumference 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Body Height 
X 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
Vital Signs6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical Exam 
(complete) 
S 
 
 
 
 
 
S 
 
 
 
 
S 
 
Physical Exam 
(abbreviated) 
 
S 
S 
S 
S 
S 
 
S 
S 
S 
S 
 
 


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Period 
Screening1 
Part 1 (Double-blind, placebo-controlled) 
Part 2 (Open-label, single-arm) 
Follow-up 
Visit Name 
Screening 
Day 1 
(Baseline 
& 1st 
Treatment) 
Day 30 Day 90 Day 150 Day 270 Day 330 
Day 360 
("Switch 
Day")2 
Day 450 Day 510 Day 630 
Day 720 
(End of 
Treatment/ 
Study)3 
Safety 
follow-up 
(last visit 
+30 days)4 
Days 
-28 
1 
30 
90 
150 
270 
330 
360 
450 
510 
630 
720 
750 
12-lead ECG 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
Study drug 
administration7,8 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
 
IRT call 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Prior/Concomitant 
lipid-lowering therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
(Other) 
Prior/Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Surgical/Medical 
Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
LDL-apheresis 
recording (if 
applicable) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Fasting LDL-C 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Fasting PCSK9 
 
X 
 
X 
X 
 
X 
X 
 
X 
 
X 
 
Full fasting lipid / 
lipoprotein profile9 
 
X 
 
 
X 
 
X 
X 
 
X 
 
X 
 
Anti-drug antibodies10 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
Full chemistry11 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Limited chemistry11 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
Hematology 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
Sexual hormones 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Urinalysis 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
AEs/SAEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Injection site reaction 
assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Period 
Screening1 
Part 1 (Double-blind, placebo-controlled) 
Part 2 (Open-label, single-arm) 
Follow-up 
Visit Name 
Screening 
Day 1 
(Baseline 
& 1st 
Treatment) 
Day 30 Day 90 Day 150 Day 270 Day 330 
Day 360 
("Switch 
Day")2 
Day 450 Day 510 Day 630 
Day 720 
(End of 
Treatment/ 
Study)3 
Safety 
follow-up 
(last visit 
+30 days)4 
Days 
-28 
1 
30 
90 
150 
270 
330 
360 
450 
510 
630 
720 
750 
Neurological 
Examination 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Tanner staging / 
menarche 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
Safety Follow up 
Call14 
 
 
 
 
 
 
 
 
 
 
 
 
S 
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 Screening / run-in period 
2 Day 360 (“Switch Day”) is a shared visit, i.e. the end of Part 1 and the start of Part 2 of the study 
3 For participants who prematurely discontinue the study for any reason [e.g. if a participant’s parent(s)/legal representative(s) / a participant (if applicable) decide to 
prematurely and permanently discontinue the participant from study treatment and decline further follow-up visits] an EOS visit should also be scheduled as soon as 
possible. 
4 30 days after the last study visit or 90 days after the last administration of study drug, whatever is longer 
5 Only in females of child-bearing potential (prior to study treatment administration, if applicable) 
6 On Day 1 and Day 360 vital signs will be measured prior to injection and 4 hours post injection; at all other visits, vital signs will be measured only once (prior to 
injection, if applicable). 
7 Participants will be observed in the clinic for at least 4 hours post injection on Day 1 and Day 360 and for at least 30 minutes post injection for all other dosing visits. 
8 For any suspected episode of anaphylaxis, the investigator will need to collect a blood sample for tryptase within 30 minutes of an onset of anaphylaxis (or as soon as 
possible). 
9 Apo B, Lp(a), non-HDL-C, total cholesterol, triglycerides, HDL-C, VLDL-C and Apo A1 in addition to the separately listed LDL-C (see Section 8.3 for details). 


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Period 
Screening1 
Part 1 (Double-blind, placebo-controlled) 
Part 2 (Open-label, single-arm) 
Follow-up 
Visit Name 
Screening 
Day 1 
(Baseline 
& 1st 
Treatment) 
Day 30 Day 90 Day 150 Day 270 Day 330 
Day 360 
("Switch 
Day")2 
Day 450 Day 510 Day 630 
Day 720 
(End of 
Treatment/ 
Study)3 
Safety 
follow-up 
(last visit 
+30 days)4 
Days 
-28 
1 
30 
90 
150 
270 
330 
360 
450 
510 
630 
720 
750 
10 ADA serum samples will be collected on Day 1 prior to injection and 4 hours after injection. At all other visits, one sample only will be collected. 
11 Diagnosis of diabetes based on fasting plasma glucose (FPG) should be verified by a repeat FPG within 6 weeks of the initial observation 
 
 
14 SAEs to be reported to Novartis Safety (see Section 10.1.3 for details) 
 


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8.1 
Screening 
Screening activities (Table 8-1) must be initiated only after the ICF (and assent if applicable) 
has been signed. 
It is not permissible to re-screen a participant if s/he fails the initial screening. In the case where 
a safety laboratory assessment at screening is outside of the range specified in the exclusion 
criteria, the assessment may be repeated once prior to randomization. If the repeat value remains 
outside of the specified ranges, the participant is not eligible for the study. 
8.1.1 
Information to be collected on screening failures 
Participants for whom an ICF was signed and who are subsequently found to be ineligible prior 
to randomization will be considered a screen failure. The reason for screen failure should be 
recorded on an appropriate eCRF. The demographic information, informed consent, and 
inclusion/exclusion pages must also be completed for screen failure participants. If the screen 
failure participant experienced a SAE during the screening phase (see SAE section for reporting 
details), SAE information must additionally be collected. If the participant fails to be 
randomized, the IRT must be notified within 2 days of the screen fail that the participant was 
not randomized. 
Participants who are randomized and fail to start treatment, e.g. participants randomized in 
error, will be considered an early terminator. The reason for early termination should be 
recorded on an appropriate eCRF. 
8.2 
Participant demographics/other baseline characteristics 
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with eCRF. 
Participant demographic and baseline characteristic data to be collected on all participants 
include: age, sex, race, ethnicity, relevant medical history/current medical condition present 
before informed consent was signed (where possible, diagnoses and not symptoms will be 
recorded), concomitant lipid-lowering therapy, as well as relevant laboratory tests. 
Investigators will have the discretion to record abnormal test findings as medical history in an 
appropriate eCRF whenever, in their judgment, the test abnormality occurred prior to the 
informed consent signature. 
8.3 
Efficacy 
The efficacy assessments are specified below, with the Assessment Schedule (Table 8-1) 
detailing when each assessment is to be performed. 
All efficacy biomarkers will be analyzed at a Central laboratory(ies). Participants will be in a 
fasted state for all efficacy laboratory assessments. At dosing visits, specimens for the analysis 
of efficacy biomarkers must be collected prior to study drug administration. Details regarding 
the collection, processing, shipping and storage of the samples will be provided in a Laboratory 
Manual. The Laboratory Manual will also provide details about prioritization when blood 
volume is restrictive (Section 16.7 (Appendix 7)). 


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8.3.1 
LDL-cholesterol 
The primary efficacy assessment will be LDL-C. Samples for LDL-C will be collected at 
screening and on Days 1, 90, 150, 270, 330, 360, 450, 510, 630 and 720 (Table 8-1). 
After randomization (Day 1) until the Day 360 visit, the results from the LDL-C laboratory 
assessments must be blinded to participants, investigator staff, persons performing the 
assessments, and the CTT. 
8.3.2 
Other efficacy biomarkers 
Other efficacy assessments will include: 
• Apo B, Lp(a), non-HDL-C, total cholesterol, triglycerides, HDL-C, VLDL-C, Apo A1, 
PCSK9 
Samples for these additional efficacy biomarkers will be collected on Days 1, 90 (PCSK9 only), 
150, 330, 360, 510 and 720. (Table 8-1). 
After randomization (Day 1) until the Day 360 visit, the results from the efficacy laboratory 
assessments must be blinded to participants, investigator staff, persons performing the 
assessments, and the CTT.  
 
 
 
 
 
 
8.3.4 
Appropriateness of efficacy assessments 
LDL-C reduction, which is an effect of the mechanism of action of inclisiran, is a well-defined 
biomarker and standard assessment in clinical trials, and the primary endpoint of the study. 
LDL-C reduction is an accepted surrogate for CV risk reduction, e.g. for statins and PCSK9-
blocking monoclonal antibodies. While multiple factors contribute to the development of 
ASCVD, strong and consistent evidence from genetics, epidemiology, Mendelian 
randomization studies, and randomized trials, have established that among these factors, LDL-
C is not merely a biomarker of increased risk, but a causal and modifiable factor in ASCVD 
(Ference et al 2017). 
Laboratory and other assessments related to the secondary
are in line 
with the expected efficacy of inclisiran. 
8.4 
Safety 
Safety assessments are specified below, with the Assessment Schedule (Table 8-1) detailing 
when each assessment is to be performed. 
For details on AE collection and reporting, refer to the AE section. 


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A complete physical examination will be performed at the screening visit, the Day 330 visit and 
at the Study Completion (EOS) visit. An abbreviated physical examination will be performed 
at other study visits detailed in Table 8-1. Details on what is included in the complete and 
abbreviated physical exams and the requirements to perform vital signs assessment and height 
/ weight measurements are provided in Table 8-2. 
Table 8-2 
Assessments & Specifications 
Assessment 
Specification 
Physical 
examination 
A complete physical examination will include the examination of height, weight, general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, vital 
signs, abdomen, back, lymph nodes, extremities, vascular, and neurological. If indicated 
based on medical history and/or symptoms, rectal, external genitalia, breast, and pelvic 
exams will be performed. 
Tanner staging (Section 8.4.4.1) will additionally be performed at selected visits. 
A short physical examination will include the examination of general appearance and 
vital signs as well as other examinations based on Investigator discretion. Height and 
weight will additionally be assessed as per the Schedule of Assessment. 
Information for all physical examinations must be included in the source documentation at 
the study site. Clinically relevant findings that are present prior to informed consent 
signature must be recorded on the appropriate eCRF that captures Medical history. 
Significant findings made after informed consent signature, which meet the definition of an 
AE, must be recorded as an AE. 
Vital signs 
Vital signs include blood pressure and pulse measurements. After the participant has been 
sitting for five minutes, with back supported and both feet placed on the floor, systolic 
blood pressure (SBP) and diastolic blood pressure (DBP) will be measured three times 
using an automated validated device, e.g. OMRON, with an appropriately sized cuff. The 
repeat sitting measurements will be made at 1 - 2 minute intervals and the mean of the 
three measurements will be used. In case the cuff sizes available are not large enough for 
the participant's arm circumference, a sphygmomanometer with an appropriately sized cuff 
may be used. 
Clinically notable vital signs are defined in Section 16.2 (Appendix 2).  
Height and 
weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in indoor 
clothing, but without shoes) will be measured. Height should be taken using a calibrated 
stadiometer. 
8.4.1 
Laboratory evaluations 
Specimens will be obtained at the time points detailed in the Assessment Schedule (Table 8-1). 
Details on what is included in hematology, chemistry, sexual hormones, and urinalysis 
laboratory evaluations are provided in Table 8-3. Efficacy laboratory assessments (e.g. LDL-
C) are described in Section 8.3. 
Central laboratory(ies) will be used for analysis of all specimens collected, with the exception 
of urine pregnancy 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 notable laboratory findings are defined in Section 16.2 (Appendix 2). 
A table, which provides the maximum, allowable blood-draw volumes by weight, can be found 
in Section 16.7 (Appendix 7). The Laboratory Manual will also provide details about 
prioritization when blood volume is restrictive. 


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Table 8-3 
Laboratory Assessments 
Test Category 
Test Name 
Hematology 
Hemoglobin, hematocrit, red blood cell (RBC) count, mean cell hemoglobin 
(MCH), mean corpuscular volume (MCV), mean corpuscular hemoglobin 
concentration (MCHC), white blood cell (WBC) count with differential 
(neutrophils, basophils, eosinophils, monocytes, lymphocytes), platelet count 
Chemistry 
Full chemistry: 
AST, ALT, ALP, GGT, total bilirubin, direct and indirect bilirubin (if total 
bilirubin >2xULN), C(P)K, bicarbonate, uric acid, creatinine, blood urea 
nitrogen (BUN), eGFR*, sodium, potassium, calcium, phosphate, chloride, 
albumin, total protein, glucose (fasting)**, HbA1C 
Limited chemistry: 
ONLY: AST, ALT, ALP, GGT, total bilirubin [fractionated bilirubin (if total 
bilirubin >2x ULN)], C(P)K, creatinine, eGFR*, glucose (fasting)**, HbA1C 
Anti-drug antibodies 
see Section 8.4.1.1 
Sexual hormones 
Gonadal hormones (estradiol for females and testosterone for males), 
luteinizing hormone (LH), follicle-stimulating hormone (FSH), cortisol and 
dehydroepiandrosterone (DHEA) 
Urinalysis 
Dipstick measurements for: specific gravity, pH, glucose, protein (total), 
ketones, bilirubin, urobilinogen, nitrite, hemoglobin (blood), leukocytes 
esterase 
If dipstick measurement results are positive (abnormal), microscopic 
examination will be performed 
Pregnancy test 
Serum / Urine pregnancy test (see Section 8.4.3)  
Other 
Tryptase (only as required***) 
* eGFR will be calculated using the Schwartz age-specific eGFR formula as follows:  
• 
For height in cm and serum creatinine (sCr) in mg/dL: eGFR (mL/min/1.73 m2) = 0.413 x (height/sCr) 
• 
For height in cm and sCr in μmol/L: eGFR (mL/min/1.732) = 36.5 x (height/sCr) 
** Diagnosis of diabetes based on FPG should be verified by a repeat FPG within 6 weeks of the initial 
observation. 
*** Should a participant develop anaphylaxis on days when inclisiran is injected, the investigator will need to 
collect a blood sample for tryptase within 30 minutes of the onset of anaphylaxis (or as soon as possible). 
8.4.1.1 
Anti-drug antibodies 
Serum samples for the analysis of formation of ADA will be collected at the time points detailed 
in the Assessment Schedule (Table 8-1). 
On Day 1, ADA serum samples will be collected prior to injection and 4 hours after injection. 
At all other visits, one sample only will be collected. 
The results from ADA after the first administration of study drug until the Day 360 visit must 
be blinded to participants, investigator staff, persons performing the assessments, and the CTT. 
Instructions to be followed regarding sample collection, numbering, processing and shipment 
are outlined in a Laboratory Manual. 
8.4.2 
Electrocardiogram (ECG) 
ECGs will be done with local ECG machines. ECGs must be recorded (after 10 minutes rest in 
the supine position to ensure a stable baseline). The preferred sequence of CV data collection 
during study visits is ECG collection first, followed by vital signs, and blood sampling. The 
Fridericia QT correction formula (QTcF) should be used for clinical decisions. 


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Single 12 lead ECGs are collected. The original ECGs on non-heat-sensitive paper and a copy 
(if original ECG done on heat sensitive paper), appropriately signed, must be collected and 
archived at the study site. 
For any ECGs with participant safety concerns, two additional ECGs must be performed to 
confirm the safety finding. A monitoring or review process should be in place for clinically 
significant ECG findings throughout the study and especially before administration of study 
treatment. 
Any identifier details must be redacted e.g. participant initials, date of birth. 
Clinically significant abnormalities must be recorded on the eCRF as either Medical 
history/Current medical condition or AEs as appropriate. 
8.4.3 
Pregnancy 
Females of child-bearing potential are defined as all females physiologically capable of 
becoming pregnant. This includes female adolescent participants who are menarchal or who 
become menarchal during the study. 
Serum/urine pregnancy tests will be performed for all female adolescents of child-bearing 
potential according to the Assessment Schedule (Table 8-1). A positive urine pregnancy test 
should be confirmed with a serum pregnancy test. Additional pregnancy tests may be performed 
at the investigator’s discretion during the study and/or if requested by local requirements. 
Participants becoming pregnant must be discontinued from study drug. However, a participant 
may choose to remain in the study should she become pregnant, and be followed according to 
the protocol-defined study visits. 
All menarchal adolescents and their parent(s)/legal representative(s) should be informed about 
the potential risks of pregnancy and the need to prevent pregnancy during the study. 
It is important to be sensitive in introducing this issue, as understanding and comprehension of 
puberty, sexual activity, pregnancy and contraception is influenced by age as well as, factors 
such as precocity, socio(educational) economic and familial background. These discussions 
with the participant and her parent(s)/legal representative(s) are therefore best performed by 
investigators familiar with the adolescent participant and her family and should be guided by 
requirements of the local regulatory authorities. These discussions should take into account the 
socio-economic, cultural factors and religious beliefs of the adolescent participant and her 
family. The investigator should also discuss the management of the pregnancy test results with 
the participant and her parent(s)/legal representative(s). The privacy of the participant should 
be considered in accordance with the local law and ethics. 
8.4.4 
Other safety evaluations 
8.4.4.1 
Pubertal development 
In addition to the assessment of height, weight and sexual hormones (see Section 8.4.1), the 
following parameters will be monitored to evaluate pubertal development, at the time points 
detailed in the Schedule of Assessment (Table 8-1): 


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• Menarche (in females)  
• Tanner staging of sexual development (in males and females) 
Tanner staging will performed by a physician who (re-)familiarized him/herself with the Tanner 
stage assessment (in case needed). The results (stages 1-5 for the respective characteristics) will 
be recorded on an appropriate eCRF. Once a participant reaches Tanner stage 5, evaluations 
can be discontinued. For females, the date of menarche will also be recorded on an appropriate 
eCRF. 
8.4.4.2 
Neurological evaluation 
A full neurological evaluation will be performed as per the Schedule of Assessment  
(Table 8-1). This should include assessment of motor function, sensory function, tone and 
reflexes and cerebellar function as detailed in Section 16.5 (Appendix 5). 
Clinically significant abnormalities must be recorded on the eCRF as either Medical 
history/Current medical condition or AEs as appropriate. 
8.4.4.3 
Injection site reactions 
Injection site reactions (ISRs) should be monitored at each visit from the randomization (Day 
1) visit onwards (Table 8-1) and through additional contacts with the participant between visits 
as needed. 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. 
8.4.4.4 
Anaphylactic reactions 
Potential 
anaphylactic 
reactions 
should 
be 
assessed 
by 
Sampson 
criteria 
(see Section 16.6 (Appendix 6)). If Samson criteria are positive, confirmation by elevation of 
tryptase in blood plasma should be obtained within 30 minutes of the onset of anaphylaxis (or 
as soon as possible). 
8.4.4.5 
Hyperglycemia-related events 
Laboratory results and newly added concomitant medications should be checked for potential 
hyperglycemia-related AEs. 
‘New onset of diabetes’ should be reported as AE on the eCRF in participants with no medical 
history of diabetes when: 
• HbA1c becomes ≥6.5% and/or  
• Two consecutive values of FPG are ≥126 mg/dL (7.0 mmol/L) 
• If a new concomitant medication for control of plasma glucose is added, further information 
to assess for a diagnosis of new onset diabetes will need to be collected 
‘Worsening of glycemic control’ should be reported as AE on the eCRF in participants with a 
medical history of disease (HbA1c ≥6.5% at baseline) when: 
• HbA1c increases from baseline >0.5% 
• New concomitant medication or increase in dose of current antidiabetic therapy is initiated 
to improve the control of plasma glucose level 


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8.4.5 
Appropriateness of safety measurements 
The safety assessments selected for this trial are standard for this indication/adolescent 
population. They take into consideration safety data from adult studies and consultations with 
Health Authorities and are in accordance with guidelines (ICH Harmonised Guideline 
Addendum to ICH E11 (ICH E11 (R1) 2017)). 
8.5 
Additional assessments 
 
 
 
 
 
 
 
 
 
8.5.2 
Biomarkers 
No exploratory biomarkers will be evaluated in this study. The assessment of lipids/lipoproteins 
and PCSK9 is discussed in Section 8.3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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’s 
parent(s)/legal representative(s) / participant (if applicable) 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. After study treatment 
discontinuation, participants should remain in the study and complete other study visit 
procedures as per the Assessment Schedule, unless consent is withdrawn (Section 9.1.2), 
preferably in writing. 
Study treatment must be discontinued under the following circumstances: 
• Participant’s parent(s)/legal representative(s) / participant (if applicable) decision 
• Pregnancy 
• Use of prohibited treatment as per details in the prohibited treatment section (Table 6-2) 
• Following emergency unblinding 
• Any situation in which study participation might result in a safety risk to the participant 
• Severe and persistent (>14 days despite appropriate treatment) reactions at the injection site 
and any confirmed anaphylactic reactions 
• Unexplained increases in transaminases (ALT or AST) or total bilirubin as follows:  
• ALT or AST >5x ULN 
• ALT or AST >3x ULN for more than 2 weeks 
• ALT or AST >3x ULN and (total bilirubin >2x ULN or INR >1.5) 
• ALT or AST >3x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
• The investigator should evaluate to see if other causes for the laboratory abnormalities 
are immediately apparent, such as obstructive gall bladder or bile duct disease, viral or 
alcoholic hepatitis, malignancy involving the liver, congestive hepatopathy, other 
hepatotoxins or heritable disorders. 
• Unexplained C(P)K values >5x ULN confirmed by repeat test when the C(P)K elevation is 
associated with muscle pain, muscle tenderness and/or muscle weakness, or new onset renal 
dysfunction 
• Any other laboratory abnormalities that, in the judgment of the investigator, prevents the 
participant from continuing study treatment 
In addition, adolescent females who gain child-bearing potential during the study and are 
unwilling to comply with the requirements for contraception as outlined in Section 5.2 will be 
excluded from receiving further study drug. 


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If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s premature discontinuation of study 
treatment and record this information. 
Study treatment may be restarted at the discretion of the investigator, if the reason for 
discontinuation has resolved. Every effort should be made to restart study treatment, if deemed 
appropriate by the investigator. Study treatment is not allowed to be re-started following 
initiation of prohibited medication that requires study drug discontinuation (Table 6-2). 
Participants who discontinue study treatment or for whom the participant’s parent(s)/legal 
representative(s) / participant (if applicable) decide that they do not to wish the participant to 
participate in the study further, should NOT be considered withdrawn from the study UNLESS 
informed consent was withdrawn (see Withdrawal of informed consent, Section 9.1.2). 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’s parent(s)/legal representative(s) / 
participant / pre-designated contact as specified in the lost to follow-up section. This contact 
should preferably be done according to the study visit schedule. 
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, the participant’s parent(s)/legal representative(s) 
or with another pre-designated person. 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 and/or via telephone/email contact: 
• New / concomitant treatments 
• AEs/SAEs 
Where possible, all clinic visit assessments should be performed according to Table 8-1. 
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 
If discontinuation occurs because the treatment code has been broken, please refer to the 
Emergency breaking of treatment code section (Section 6.6.3). 
9.1.2 
Withdrawal of informed consent 
Participants’ parent(s)/legal representative(s) / participants (if applicable) may voluntarily 
withdraw consent for the participant to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a participant’s parent(s)/legal representative(s) / 
participant (if applicable): 
• Does not want the participant to participate in the study anymore, 
and 
• Does not want any further visits or assessments 
and 
• Does not want any further study related contacts 


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In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the decision to withdraw consent and record this 
information. 
Where consent to the use of personal and coded data is not required, participants’ parent(s)/legal 
representative(s) / participants (if applicable) therefore cannot withdraw consent. They still 
retain the right to object to the further use of personal data. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study discontinuation. A final 
evaluation at the time of the participant’s study discontinuation should be made as detailed in 
the Assessment Table (Table 8-1). 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation. 
Any adolescent’s (for whom the parent(s)/legal representative(s) provided informed consent) 
request to be withdrawn from the study should be respected and discussed in detail with the 
participant’s parent(s)/legal representative(s) and the local investigator before acting upon the 
request.  
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 / participant’s 
parent(s)/legal representative(s), e.g. dates of telephone calls, registered letters, etc. A 
participant should not be considered as lost to follow-up until the end of each study part while 
due diligence has been completed. 
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. 


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9.2 
Study completion and post-study treatment 
Study completion is defined as when the last participant finishes their Study Completion visit 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision. 
All treated participants should have a safety follow-up call conducted 30 days after their last 
study visit or 90 days after the last administration of study drug, whatever is longer. The 
information collected is kept as source documentation. All SAEs reported during this time 
period must be reported as described in Section 10.1.3. Documentation of attempts to contact 
the participant should be recorded in the source documentation. 
The decision whether there will be a post-study treatment with inclisiran in pediatric patients 
with HeFH will not occur before an adequate benefit-risk assessment. Should the assessment 
be positive and a post-study treatment be initiated, participants who complete the trial may have 
the opportunity to join such post-study treatment. 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An AE is any untoward medical occurrence (e.g. any unfavorable and unintended sign 
[including abnormal laboratory findings], symptom or disease) in a clinical investigation 
participant after written informed consent was provided for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual participant and 
identifying AEs. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of AEs must be sought by non-directive questioning of the participant at each 
visit during the study. Adverse events 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 in the AE eCRF 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 


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2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant 
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not recovered/not 
resolved must be reported 
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. Action taken regarding with study treatment 
All AEs must be treated appropriately. Treatment may include one or more of the following: 
• Dose not changed 
• Drug interrupted/withdrawn 
6. Its outcome (i.e. not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal or unknown) 
Conditions that were already present at the time of informed consent should be recorded in the 
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. 
Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent (e.g. continuing at the end of the study), and assessment must be made at each visit 
(or more frequently, if necessary) of any changes in severity, the suspected relationship to the 
study drug, the interventions required to treat it, and the outcome. 
Information about ADRs for the investigational drug can be found in the IB. 
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participants 
with the underlying disease. Alert ranges for laboratory abnormalities are included in 
Section 16.2 (Appendix 2). 
10.1.2 
Serious adverse events 
An SAE is defined as any AE [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: 


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• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (HeFH) 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
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 SAEs irrespective 
if a clinical event has occurred (Table 10-1). 
10.1.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after informed 
consent was provided and until 30 days after the last study visit (or 90 days after the last 
administration of study drug, whatever is longer) must be reported to Novartis Safety 
immediately, without undue delay, but under no circumstances later than within 24 hours of 
obtaining knowledge of the events (Note: If more stringent, local regulations regarding 
reporting timelines prevail). Detailed instructions regarding the submission process and 
requirements are to be found in the investigator folder provided to each site. 


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SAE reporting time frames are as follows: 
1. Screen failures: SAEs occurring after informed consent was provided until the time the 
participant is deemed a Screen Failure must be reported to Novartis. 
2. Randomized participants: SAEs collected between time informed consent was provided 
until 30 days after the last study visit (or 90 days after the last administration of study drug, 
whatever is longer) must be reported to Novartis. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, but under no circumstances later than within 24 hours of the 
investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail). An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event. 
If the SAE is not previously documented in the IB or Package Insert (new occurrence) and is 
suspected to be related to the study treatment, this event is considered a Suspected Unexpected 
Serious Adverse Reaction (SUSAR). A Chief Medical Office and Patient Safety (CMO & PS) 
Department associate may urgently require further information from the investigator for health 
authority reporting. Novartis may need to issue an Investigator Notification to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. 
SUSARs will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with European Union (EU) Guidance 2011/C 172/01 or as per 
national regulatory requirements in participating countries. 
Any SAE experienced after the 30 days period following the last study visit (or 90 days after 
the last administration of study drug, whatever is longer) should only be reported to Novartis 
Safety if the investigator suspects a causal relationship to study treatment. 
10.1.4 
Pregnancy reporting 
Pregnancies 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
participant’s parent(s)/legal representative(s) / participant (if applicable) must be asked to read 
and sign a pregnancy consent form to allow the Study Doctor ask about her pregnancy. To 
ensure participant safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up until one year after the baby was due to be born to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications. 
Pregnancy should be recorded and reported by the investigator to the Novartis CMO&PS. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the investigational treatment of any pregnancy outcome. Any 
SAE experienced during pregnancy must be reported. 


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10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (European Medicines Agency (EMA) definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
an appropriate dosing eCRF irrespective of whether or not associated with an AE/SAE and 
reported to Safety only if associated with an SAE. Misuse or abuse will be collected and 
reported in the safety database irrespective of it being associated with an AE/SAE within 24 
hours of Investigator’s awareness. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
eCRF (Yes/No) 
Document in AE eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with an 
AE 
Only if associated with an 
SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
10.2 
Additional Safety Monitoring 
10.2.1 
Liver safety monitoring 
To ensure participant safety and enhance reliability in determining the hepatotoxic potential of 
an investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
Please refer to Table 16-3 (Section 16.3 (Appendix 3)) 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 (Section 16.3 (Appendix 3)). Requirements for follow-up of potential DILI 
cases is provided in Section 6.5.2.1. 
• Repeat liver chemistry tests (i.e. ALT, AST, total bilirubin, direct and indirect bilirubin, 
PT/INR, ALP, GGT, GLDH, albumin and C(P)K) 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, 


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any local liver chemistry tests previously conducted that are associated with this event 
should have results recorded on an appropriate eCRF. 
• If the initial elevation is confirmed, close observation of the participant will be initiated, 
including consideration of treatment interruption if deemed appropriate. 
• Discontinuation of the investigational drug (refer to the Discontinuation of study treatment 
section), if appropriate 
• Hospitalization of the participant, if appropriate 
• Causality assessment of the liver event 
• Thorough follow-up of the liver event should include  
• These investigations can include based on investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy; obtaining more 
detailed history of symptoms and prior or concurrent diseases, history of concomitant 
drug use, exclusion of underlying liver disease 
All follow-up information and procedures performed must be recorded as appropriate in the 
eCRF. 
10.2.2 
Renal safety monitoring 
To ensure participant safety and enhance reliability in determining the nephrotoxicity potential 
of an investigational drug, a standardized process for identification, monitoring and evaluation 
of renal events has to be followed. 
Every renal laboratory trigger or renal event as defined in Table 16-6 (Section 16.4 (Appendix 
4)) should be followed up by the investigator or designated personnel at the trial site as 
summarized in Table 16-7 (Section 16.4 (Appendix 4)). 
10.2.3 
Other safety monitoring 
The frequency and severity of the AEs listed below will be monitored during the study. They 
will be reviewed by the DMC at regular intervals. 
• ISRs (see also Section 8.4.4.3), hypersensitivity reactions and immune-mediated reactions 
• Hepatobiliary AEs and liver-related biochemical abnormalities (see also Section 6.5.2.1 and 
Section 10.2.1) 
• Musculoskeletal AEs and muscle-related biochemical abnormalities (e.g. C(P)K) 
• Neurological or psychiatric AEs 
• New onset of diabetes or worsening of glycemic control in diabetics (see also 
Section 8.4.4.5) 
10.2.4 
Data Monitoring Committee 
This study will include a DMC, which will function independently of all other individuals 
associated with the conduct of this clinical trial, including the site investigators participating in 
the study. The DMC will assess at defined intervals the progress of the clinical trial, review 
safety data, and recommend to the sponsor whether to continue, modify or terminate the trial. 


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It is anticipated that the DMC will review safety data 90 days after the first 75 participants 
received the first injection of study drug and every 3 months thereafter until EOS, unless 
requested otherwise by the DMC. 
Specific details regarding composition, responsibilities, data monitoring and meeting 
frequency, and documentation of DMC reports, minutes, and recommendations will be 
described in a separate DMC charter that is established between the sponsor and the DMC. 
10.2.5 
Steering Committee 
The Steering Committee (SC) will be established comprising representatives associated with 
the trial, but not being members of the DMC. Novartis representatives from the Global Clinical 
Team can be present at the SC meetings. 
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical team, the SC will also develop 
recommendations for publications of study results including authorship rules. The details of the 
role of the SC will be defined in the SC charter. 
11 
Data Collection and Database management 
11.1 
Data collection 
Designated investigator staff will enter the data required by the protocol into eCRFs. The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 Code of 
Federal Regulation (CFR) Part 11 requirements, Investigator site staff will not be given access 
to the Electronic Data Capture (EDC) system until they have been trained. Automatic validation 
programs check for data discrepancies in the eCRFs, allow modification and/or verification of 
the entered data by the investigator staff. 
The investigator/designee is responsible for assuring that the data entered into the eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. The 
Investigator must certify that the data entered are complete and accurate 
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site. 
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
11.2 
Database management and quality control 
Novartis personnel (or designated Contract Research Organization (CRO)) will review the data 
entered by investigational staff for completeness and accuracy. Electronic data queries stating 
the nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated investigator 
site staff are required to respond promptly to queries and to make any necessary changes to the 
data. 


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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 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Dates of screenings, randomizations, screen failures and study completion, as well as 
randomization codes and data about all study treatment (s) dispensed and all dosage changes 
will be tracked using an IRT. The system will be supplied by a vendor, who will also manage 
the database. The data will be sent electronically to Novartis (or a designated CRO) at specific 
timelines. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of 
Novartis. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis. Any changes to the database after that time can only be made after 
written agreement by Novartis Development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eCRFs) with the 
investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and GCP compliance and the quality/integrity of the sites’ data. The field monitor will 
visit the site to check the completeness of participant records, the accuracy of data capture / data 
entry, the adherence to the protocol and to GCP, the progress of enrollment, and to ensure that 
study treatment is being stored, dispensed, and accounted for according to specifications. Key 
study personnel must be available to assist the field monitor during these visits. 
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, ECGs, 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 signed ICF and the original signed assent form, if 
applicable (a signed copy is given to the participant’s parent(s)/legal representative(s)/ 
participant (if applicable)). 
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. 


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12 
Data analysis and statistical methods 
Details of the statistical analysis and data reporting will be summarized in the Statistical 
Analysis Plan (SAP) document finalized before data lock. Any data analysis carried out 
independently by the investigator should be submitted to Novartis before publication or 
presentation. 
Efficacy and safety analyses of Part 1 data will be performed after all participants have 
completed the Day 360 visit or discontinued prior to the Day 360 visit. All available data from 
the clinical database will be included in the analysis. Formal testing of the primary and key 
secondary endpoints with full alpha level will be performed for the Part 1 data. This analysis 
will be unblinded and reviewed by the CTT. 
12.1 
Analysis sets 
The Full Analysis Set (FAS) comprises of all randomized participants with the exception of 
those mis-randomized participants who did not receive study drug. Mis-randomized participants 
are defined as not qualified for randomization and are inadvertently randomized into the study. 
According to the intent to treat principle, participants will be analyzed according to the 
treatment they have been assigned to during the randomization procedure. The FAS will be used 
in analyses for the primary, secondary, 
. 
The Safety Set includes all participants who received at least one dose of study treatment. 
Participants will be analyzed according to the study treatment received. This will be the primary 
population for the safety analyses. 
12.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including medical history will be summarized 
descriptively by treatment group for the FAS. 
Categorical data will be presented as frequencies and percentages by treatment group. For 
continuous data, non-missing observations, mean, standard deviation, median, minimum, and 
maximum will be presented. For continuous data, the 1st and 3rd quartile will also be presented 
by treatment group. 
Relevant medical histories and current medical conditions at baseline will be summarized 
separately by system organ class and preferred term, by treatment group. Histories of statin 
intolerance and underlying genetic mutation will be summarized by treatment group. 
12.3 
Treatments 
The Safety set will be used for the analyses below. 
The number of participants dosed at each dosing visit, number of study doses 
administered, duration of exposure in days, and dose administered will be summarized by 
treatment group. The number of study doses administered will be summarized by study part and 
overall (Parts 1 and 2 combined). 
Lipid-modifying therapy use and LDL-apheresis at screening and the baseline/Randomization 
visit (Day 1) will be summarized by treatment group. New or changed lipid-modifying therapy 
and LDL-apheresis after baseline will be summarized by treatment group and part. 


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Other concomitant medications and significant non-drug therapies prior to and after the start of 
the study treatment will be summarized according to the Anatomical Therapeutic Chemical 
(ATC) classification system, by treatment group and part. 
12.4 
Analysis of the primary endpoint(s)/estimand(s) 
12.4.1 
Definition of primary endpoint and estimand 
The primary estimand is defined in Section 2.1. The corresponding endpoint, i.e. primary 
analysis variable, is the percentage change in LDL-C from the pre-dose baseline measurement 
to the Day 330 visit. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
The primary objective of this study is to demonstrate superiority of inclisiran compared to 
placebo in reducing the percentage change from baseline in LDL-C to Day 330 in adolescents 
with HeFH and elevated LDL-C. The statistical hypotheses that will be tested are as follows: 
• H0: The difference (inclisiran minus placebo) between participants treated with inclisiran 
and placebo in the least squares mean percentage change from baseline to the Day 330 visit 
in LDL-C= 0 
• Ha: The difference (inclisiran minus placebo) between participants treated with inclisiran 
and placebo in the least squares mean percentage change from baseline to the Day 330 visit 
in LDL-C < 0 
The primary objective will be achieved if the null hypothesis is rejected using the one-sided 
significance level of 0.025 to test superiority of inclisiran treatment. 
The primary analysis will use an analysis of covariance (ANCOVA) model. The model will 
include the fixed effects of treatment group and baseline age group (≥12-<15 or ≥15-<18 years 
of age) with baseline LDL-C as a covariate. Multiple imputation will be used to impute missing 
data using a washout model. A total of 100 imputed datasets will be created. The ANCOVA 
model will be fit to each imputed dataset, and results will be combined using Rubin's 
combination rules. The difference in least squares means between treatment groups and 
corresponding 2-sided 95% confidence intervals will be calculated. The FAS will be used for 
this analysis. Full details on the model and imputation will be provided in the SAP. 
The washout model will be used to explore the assumption that missing Day 330 visit data are 
missing not at random in participants in the inclisiran group who discontinue the study treatment 
early before the Day 330 visit and cannot be followed for scheduled LDL-C assessments. Early 
terminating participants in the placebo group will have missing data imputed based on the 
missing at random assumption. Full details will be provided in the SAP. 
12.4.3 
Handling of remaining intercurrent events of primary estimand 
No remaining intercurrent events are expected. 


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12.4.4 
Handling of missing values not related to intercurrent event 
Other missing data are expected to be intermittent missing data and will be assumed to be 
missing at random. Imputation details for data missing at random in the washout model will be 
provided in the SAP. 
12.4.5 
Sensitivity analyses for primary endpoint/estimand 
The following sensitivity analyses will be performed for the primary estimand, to assess the 
robustness of the estimation in the presence of deviations from the assumptions specified in the 
primary analysis: 
• Linear mixed-effect model for repeated measures (MMRM) analysis without multiple 
imputation 
• MMRM analysis using a control-based pattern mixture model 
• ANCOVA using the washout model including the following fixed effects: concomitant 
lipid-modifying therapies, baseline age group, country, and a treatment-by-country 
interaction 
Analyses using the MMRM will include fixed effects for treatment, visits, interaction between 
treatment and visits, baseline LDL-C, and baseline age group. The Restricted Maximum 
Likelihood (REML) estimation approach will be used with covariance structure set as 
"Unstructured".  
The control-based pattern mixture model will be used to further explore the possibility of 
missing data being missing not at random. This approach will utilize placebo data for monotone 
missing inclisiran treatment data.  
Full details for sensitivity analyses will be provided in the SAP. 
12.4.6 
Supplementary analysis 
Supplementary analyses of LDL-C percent change from baseline to Day 330 will be performed 
in select subgroups. The MMRM will be used to evaluate the difference between inclisiran and 
placebo groups in each subgroup. Subgroups will include, but not be limited to, sex, age group, 
and baseline statin treatment. Additional subgroups will be specified in the SAP along with 
further details of supplementary analyses. 
12.4.7 
Supportive analyses 
No supportive analyses are planned. 
12.5 
Analysis of secondary endpoints/estimands 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) 
The following are key secondary efficacy endpoints: 
1. Time-adjusted percent change in LDL-C from baseline after Day 90 and up to Day 330 
(Year 1) 
2. Absolute change in LDL-C from baseline to Day 330 (Year 1) 
3. Percent change in Apo B from baseline to Day 330 (Year 1) 


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4. Percent change in Lp(a) from baseline to Day 330 (Year 1) 
5. Percent change in non-HDL-C from baseline to Day 330 (Year 1) 
6. Percent change in total cholesterol from baseline to Day 330 (Year 1) 
A hierarchical testing strategy will be applied to control the family-wise type I error rate at the 
significance level of 0.025 (one-sided test) to assess superiority of inclisiran over placebo. 
Hypotheses associated with the key secondary endpoints will be tested in the order listed above. 
The key secondary endpoints will be analyzed using ANCOVA with imputation performed 
using the washout model as discussed in Section 12.4.2. Details, including possible sensitivity 
analyses performed using the MMRM, will be provided in the SAP. 
Other secondary efficacy endpoints include the percent change and absolute change from 
baseline throughout the time course up to Day 720 (Year 2) in the following: 
• LDL-C 
• Apo B 
• Lp(a) 
• non-HDL-C 
• total cholesterol 
• triglycerides 
• HDL-C 
• VLDL-C 
• Apo A1 
• PCSK9 
Descriptive summaries by treatment group will be presented. 
12.5.2 
Safety endpoints 
For all safety analyses, the safety set will be used. All tables will be presented by treatment 
group. 
Safety summaries (tables, figures) include only treatment emergent events (events started after 
the first dose of study medication or events present prior to start of double-blind treatment but 
increased in severity based on preferred term) with the exception of baseline data which will 
also be summarized where appropriate (e.g. change from baseline summaries). In addition, a 
separate summary for deaths including on treatment and post treatment deaths will be provided. 
In particular, summary tables for adverse events (AEs) will summarize only treatment emergent 
AEs. 
Adverse events 
The number (and percentage) of participants with treatment emergent adverse events in Part 1 
and Part 2 will be summarized in the following ways: 
• by treatment, primary system organ class and preferred term alphabetically. 
• by treatment, primary system organ class, preferred term alphabetically and maximum 
severity. 


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• by treatment, primary system organ class and preferred term alphabetically for treatment 
emergent AEs leading to study drug discontinuation. 
• by treatment, primary system organ class and preferred term alphabetically for treatment 
emergent AEs related to study drug. 
The number (and percentage) of participants with treatment emergent serious adverse events in 
Part 1 and Part 2 will be summarized in the following ways: 
• by treatment, primary system organ class and preferred term alphabetically. 
• by treatment, primary system organ class and preferred term alphabetically for treatment 
emergent serious AEs related to study drug. 
A separate summary will be provided for adverse events leading to death. 
The number (and proportion) of participants with adverse events of special interest will be 
summarized by treatment. Categories of AEs used in this analysis will be specified in the SAP. 
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 (and relevant orthostatic changes) will be flagged. Summary 
statistics will be provided by treatment and visit/time. 
Baseline and change from baseline in height, weight, and BMI will be assessed using age- and 
sex-adjusted z-scores and summarized by treatment group. 
Clinical laboratory evaluations 
Summary statistics will be provided by treatment group and visit. Shift tables using the low, 
normal, or high classification will be used to compare baseline to the worst on-treatment value 
by treatment group for Part 1 and overall. The number (and percentage) of participants meeting 
clinically significant criteria will be provided by treatment group for Part 1 and overall. 
Immunogenicity 
ADA evaluations, including treatment emergent ADA findings, will be summarized by 
treatment group, participant, and visit. Additional analyses may be performed to describe the 
relationship between ADA and other study findings and will be detailed in the SAP. 
Other safety evaluations 
Baseline Tanner stage will be summarized by treatment group. Shift from baseline in Tanner 
stage and menarche in female participants without menarche at baseline will be summarized by 
treatment group.  
12.5.3 
Biomarkers 
Analyses of PCSK9 and lipids/lipoproteins are discussed in Section 12.5.1. No additional 
biomarkers will be evaluated in this study. 


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• 
 
• 
 
• 
 
• 
 
• 
 
 
 
  
 
 
 
12.7 
Interim analyses 
Interim analyses are planned for the monitoring of participants' safety and will be performed 
following the schedule specified in Section 10.2.4. Interim safety analyses before the 
unblinding for the analysis of Part 1 of the study will be performed by an independent 
statistician/programmer who will not be involved in the trial conduct. The interim results will 
be reviewed by the independent DMC. 
 
 
 


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12.8 
Sample size calculation 
12.8.1 
Primary endpoint(s) 
The sample size was calculated based on detecting a reduction of at least 
n the inclisiran 
group compared to the placebo group in percent change of LDL-C from baseline. The percent 
difference is assumed to have a standard deviation of 
 in the control group and 
 in the 
inclisiran group. These assumptions are based on observed results from adult inclisiran studies. 
The sample size of at least 
 total participants will provide more than 
 power to detect a 
 reduction with the
Furthermore, in the adult HeFH inclisiran study (ORION-9), a SD of 
 in the control group 
and 
 in the inclisiran group was observed. With a more conservative assumption of a SD 
of
 in the control group and
in the inclisiran group, the sample size of at least 
total 
participants will still provide more than
power to detect a
reduction with a one-sided 
significance level of 0.025. 
The revised sample size requires a minimum of
participants; however, the actual anticipated 
enrollment is approximately
participants.
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 GCP, 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 IRB/IEC for the trial protocol, written ICF(s), written assent form (if applicable), 
consent/assent form updates, participant recruitment procedures (e.g., advertisements) and any 
other written information to be provided to participants. Prior to study start, the investigator is 
required to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 


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


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14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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15 
References 
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Casula M, Tragni E, Catapano AL (2012) Adherence to lipid-lowering treatment: the patient 
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About_HMA/Working_Groups/CTFG/2020_09_HMA_CTFG_Contraception_guidance_Vers
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Giugliano RP, Pedersen TR, Park J-G, et al (2017) Clinical efficacy and safety of achieving 
very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a 
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plasma PCSK9 levels. J Clin Endocrinol Metab; 94:2537-43. 
Momper JD, Mulugeta Y, Green DJ, et al (2013) Adolescent dosing and labeling since the 
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subtilisin/kexin 9 in cholesterol homeostasis. J Intern Med; 266(6):507-19. 
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Familial Hypercholesterolemia. N Engl J Med; 382(16):1520-30. 
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Randomized Clinical Trial. JAMA Cardiol; 4(11):1067-75. 


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Ray KK, Wright RS, Kallend D, et al (2020) Two Phase 3 Trials of Inclisiran in Patients with 
Elevated LDL Cholesterol. N Engl J Med; 382(16):1507‐19. 
Sabatine MS, Giugliano RP, Keech AC, et al (2017) Evolocumab and Clinical Outcomes in 
Patients with Cardiovascular Disease. N Engl J Med; 376(18):1713-22. 
Sampson HA, Munoz-Furlong A, Bock SA, et al (2005) Symposium on the definition and 
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Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy 
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Santos RD, Gidding SS, Hegele RA, et al (2016) Defining Severe Familial 
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Santos RD, Ruzza A, Hovingh GK, et al (2020) Evolocumab in Pediatric Heterozygous Familial 
Hypercholesterolemia. N Engl J Med; 383(14):1317-27. 
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Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. A 
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Burden of Familial Hypercholesterolemia: A Global Call to Action. JAMA Cardiol; 5(2):217-
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posting: January 2, 2014; last update: December 8, 2016. In: Pagon RA, Adam MP, Ardinger 
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2020). 


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16 
Appendices 
16.1 
Appendix 1: Diagnostic criteria for FH in adolescents / children 
Diagnosis of FH in adolescents and children according to the European Atherosclerosis 
Society Consensus Panel: 
After ruling out secondary causes of hypercholesterolemia (for example hypothyroidism, 
nephrotic syndrome, obstructive liver disease, obesity, anorexia nervosa and treatments such as 
isoretinoids), FH is diagnosed either on phenotypic criteria, i.e. elevated LDL-C concentration 
plus a family history of elevated LDL-C, premature coronary artery disease and/or genetic 
diagnosis, or by positive genetic testing: 
• LDL-C ≥5 mmol/L (190 mg/dL*) twice after 3 months dietary intervention: highly probably 
FH 
• LDL-C ≥4 mmol/L (160 mg/dL*) twice and family history of premature CHD in close 
relative(s) and/or high cholesterol in one parent (untreated): highly probably FH 
• LDL-C ≥3.5 mmol/L (130 mg/dL*) twice and parent has a genetic diagnosis: highly 
probably FH 
• Proven pathogenic mutation in child: definitive FH 
Source: Wiegman et al 2015 and European Atherosclerosis Society 2015 
* Published mg/dL value by Wiegman et al 2015. Using the official conversion factor from SI 
to conventional unit for LDL-C (x 38.67): 5 mmol/L = 193 mg/dL, 4 mmol/L = 155 mg/dL, 3.5 
mmol/L = 135 mg/dL.  


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16.2 
Appendix 2: Clinically notable laboratory values and vital signs 
Criteria for clinically notable vital signs are defined in Table 16-1: 
Table 16-1 
Criteria for clinically notable vital signs 
Age 
SBP [mmHg] 
DBP [mmHg] 
Heart Rate [beats min-1] 
12 years* 
< 90, > 130 
< 50, > 80 
< 50, > 105 
>12 years 
< 90, > 145 
< 55, > 90 
< 45, > 95 
* criteria for 6-12 years 
Criteria for clinically notable laboratory values are defined in Table 16-2:  
Table 16-2 
Clinically notable laboratory abnormalities for selected tests 
Parameter 
Alert Value 
Hematology 
RBC count 
>50% increase, >30% decrease 
Hemoglobin 
>50% increase, >30% decrease or any value <70 g/L (<7 g/dL) 
Hematocrit 
>50% increase, >30% decrease 
WBC count 
>50% increase, >50% decrease 
Platelet count 
>75% increase, >50% decrease 
Clinical chemistry 
Albumin 
<20 g/L (<2 g/dL) 
ALT 
>150% increase 
AST 
>150% increase 
Bilirubin (Total) 
>100% increase 
BUN 
>50% increase 
Calcium 
>10% increase, >10% decrease 
C(P)K 
>300% increase 
Creatinine 
>50% increase 
Chloride 
>10% increase, >10% decrease 
eGFR 
>30% decrease 
Glucose 
>50% increase, >50% decrease, or any value <3.3 mmol/L (<60 mg/dL) 
Potassium 
>20% increase, >20% decrease, or any value >5.3 mmol/L (>5.3 mEq/L) 
Sodium 
>5% increase, or any value >150 mmol/L (>150 mEq/L) 
Uric acid 
>50% increase 


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16.3 
Appendix 3: Liver event and laboratory trigger definitions & 
follow-up requirements 
Table 16-3 
Liver event and laboratory trigger definitions 
  
Definition/ threshold 
Liver laboratory triggers 
If ALT, AST and total bilirubin normal at 
baseline: 
• ALT or AST > 5 × ULN 
• ALP > 2 × ULN (in the absence of known bone pathology) 
• Total bilirubin > 3 × ULN (in the absence of known Gilbert 
syndrome) 
• ALT or AST > 3 × ULN and INR > 1.5 
• Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and 
Total bilirubin > 2 × ULN [mainly conjugated fraction] without 
notable increase in ALP to > 2 × ULN) 
• Any clinical event of jaundice (or equivalent term) 
• ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash with 
eosinophilia 
• Any adverse event potentially indicative of a liver toxicity* 
If ALT or AST abnormal at baseline: 
• ALT or AST > 2x baseline or > 300 U/L (whichever occurs first) 
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; non-infectious hepatitis; benign, malignant and unspecified liver neoplasms. ULN: upper limit of 
normal 


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Table 16-4 
Follow up requirements for liver laboratory triggers with liver 
symptoms 
  
ALT or AST 
Total bilirubin 
Liver Symptoms 
Action 
ALT or AST increase without bilirubin increase: 
  
  
If normal at baseline: 
ALT or AST > 3 x ULN 
Normal 
For participants 
with Gilbert’s 
syndrome: No 
change in 
baseline total 
bilirubin 
None 
• No change to study 
treatment 
• Measure ALT, AST, ALP, 
GGT, total bilirubin, direct 
and indirect bilirubin, 
PT/INR, albumin, C(P)K, 
and GLDH in 48-72 hours 
• Follow-up for symptoms 
If elevated at baseline: 
ALT or AST > 2 x baseline 
or > 300 U/L (whichever 
occurs ﬁrst) 
  
If normal at baseline: 
ALT or AST > 5 x ULN for 
more than two weeks 
Normal 
For participants 
with Gilbert’s 
syndrome: No 
change in 
baseline 
total bilirubin 
None 
• Interrupt study drug 
• Measure ALT, AST, ALP, 
GGT, total bilirubin, direct 
and indirect bilirubin, 
PT/INR, albumin, C(P)K, 
and GLDH in 48-72 hours 
• Follow-up for symptoms 
• Initiate close monitoring 
and workup for competing 
etiologies 
• Study drug can be 
restarted only if another 
etiology is identiﬁed and 
liver enzymes return to 
baseline 
If elevated at baseline: 
ALT or AST > 3 x baseline 
or > 300 U/L (whichever 
occurs ﬁrst) for more than 
two weeks 
  
If normal at baseline: 
ALT or AST > 8 x ULN 
Normal 
None 
ALT or AST increase with bilirubin increase: 
  
If normal at baseline: 
ALT or AST > 3 x ULN 
Total bilirubin > 2 
x ULN (or INR > 
1.5) 
For participants 
with Gilbert’s 
syndrome: 
Doubling of direct 
bilirubin 
None 
If elevated at baseline: 
ALT or AST > 2 x baseline 
or > 300 U/L (whichever 
occurs ﬁrst) 
  
If normal at baseline: 
ALT or AST > 3 x ULN 
Normal or 
elevated 
Severe fatigue, 
nausea, vomiting, 
right upper 
quadrant pain 
If elevated at baseline: 
ALT or AST > 2 x baseline 
or > 300 U/L (whichever 
occurs ﬁrst) 


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Table 16-5 
Follow up requirements for liver laboratory triggers 
Criteria 
Actions required 
Follow-up monitoring 
Total Bilirubin (isolated) 
>1.5 – 3.0 ULN 
• Maintain treatment 
• Repeat LFTs within 48-72 
hours 
Monitor LFTs weekly until 
resolutiona to ≤ Grade 1 or to 
baseline 
> 3 - 10 × ULN (in the absence of 
known Gilbert syndrome) 
• Interrupt treatment 
• Repeat LFT within 48-72 hours 
• Hospitalize if clinically 
appropriate 
• Establish causality 
• Record the AE and contributing 
factors (e.g. conmeds, medical 
history, lab) in the appropriate 
eCRF(s) 
Monitor LFTs weekly until 
resolutiona to ≤ Grade 1 or to 
baseline (ALT, AST, total bilirubin, 
albumin, 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, medical 
history, lab) in the appropriate 
eCRF(s) 
ALT, AST, total bilirubin, albumin, 
PT/INR, ALP and GGT until 
resolutiona (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, medical 
history, lab) in the appropriate 
eCRF(s) 
Investigator discretion 
a Resolution 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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16.4 
Appendix 4: Specific Renal Alert Criteria and Actions and Event 
Follow-up 
Table 16-6 
Specific renal alert criteria and actions 
Renal event 
Actions 
Confirmed serum creatinine (sCr) increase 25 – 49% 
Consider causes and possible interventions 
Follow up within 2-5 days 
Serum creatinine increase ≥ 50% + + OR if <18 years 
old, eGFR ≤ 35 mL/min/1.73 m2 + 
Consider causes and possible interventions 
Repeat assessment within 24-48h if possible 
Consider drug interruption or discontinuation unless 
other causes are diagnosed and corrected 
Consider participant hospitalization and specialized 
treatment 
New onset dipstick proteinuria ≥ 3+ 
OR 
Protein-creatinine ratio (PCR) ≥ 1g/g Cr (or mg/mmol 
equivalent as converted by the measuring laboratory) 
Consider causes and possible interventions 
Assess serum albumin & serum total protein 
Repeat assessment to confirm 
Consider drug interruption or discontinuation unless 
other causes are diagnosed and corrected 
New onset hematuria ≥ 3+ on urine dipstick 
Repeat assessment to confirm 
Distinguish hemoglobinuria from hematuria 
Urine sediment microscopy 
Assess sCr 
Exclude infection, trauma, bleeding from the distal 
urinary tract/bladder, menstruation 
Consider bleeding disorder 
+ Corresponds to KDIGO (Kidney Disease: Improving Global Outcomes) criteria for Acute Kidney Injury 
Additional specialized assessments are available to assess renal function or renal pathology. 
(Note: In exceptional cases, when a nephrologist considers a renal biopsy, it is recommended 
to make slide specimen available for evaluation by the RSG to potentially identify project-wide 
patterns of nephrotoxicity.) 
Whenever a renal event is identified, a detailed patient history and examination are indicated to 
identify and potentially eliminate risk factors that may have initiated or contributed to the event: 
• Blood pressure assessment (after 5-minute rest, with an appropriate cuff size) 
• Signs and symptoms like fever, headache, shortness of breath, back or abdominal pain, 
dysuria or hematuria, dependent or periorbital edema 
• Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output 
• Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic 
failure, contrast media or other known nephrotoxin administration, or other diseases or 
causes, e.g., dehydration due to delirium, tumor lysis  
Table 16-7 
Renal event follow-up 
Follow-up of renal events 
Assess, document and record in appropriate eCRF(s): 
Urine dipstick and sediment microscopy evidence of drug-induced nephrotoxicity (DIN): crystals, red blood cells 
(dysmorphic/glomerular vs. non-dysmorphic/non-glomerular), white blood cells, tubular epithelial cells 
Blood pressure and body weight 


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Follow-up of renal events 
Serum creatinine, BUN, electrolytes (sodium, potassium, phosphate, calcium), bicarbonate and uric acid 
Urine output 
Review and record possible contributing factors to the renal event (co-medications, other co-morbid conditions) 
and additional diagnostic procedures (MRI etc.) in the appropriate eCRF(s) 
Monitor participant regularly (frequency at investigator’s discretion) until – 
- Event resolution: (sCr within 10% of baseline or PCR < 1 g/g Cr, or albumin-to-creatinine ratio (ACR) <300 
mg/g Cr) 
or 
- Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio stabilization at 
a new level with ±50% variability over last 6 months. 
- Analysis of urine markers in samples collected over the course of the DIN event 


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16.5 
Appendix 5: Recommended Neurological Examination 
MOTOR FUNCTION 
When assessing motor function, from a neurological perspective, the assessment should focus 
on arm and leg movement. You should consider the following: 
1. Muscle size 
2. Muscle tone 
3. Muscle strength 
4. Involuntary movement 
5. Posture, gait 
Symmetry is the most important consideration when identifying focal findings. Compare one 
side of the body to the other when performing your assessment. 
Assessment of a Conscious Patient 
Limb assessment of a conscious patient usually involves a grading of strength. 
Table 16-8 
Grade Strength 
Grade strength 
Description 
5 
Full range of motion against gravity and resistance; normal muscle strength 
4 
Full range of motion against gravity and a moderate amount of resistance; slight 
weakness 
3 
Full range of motion against gravity only, moderate muscle weakness 
2 
Full range of motion when gravity is eliminated, severe weakness 
1 
A weak muscle contraction is palpated, but no movement is noted, very severe 
weakness 
0 
Complete paralysis 
NB: In a conscious patient, the single best test to quickly identify motor weakness is the 
“drift test”. Have the patient hold their arms outward at 90 degrees from the body. With 
palms up, have the patient close their eyes and hold the arms for a couple of minutes. 
“Drifting” will occur if one side is weak. 
Lower Extremities 
Assess the patient in a supine position. Ask him/her to separate both legs to test for hip 
abduction. Then ask the patient to bring the legs back together to test for hip adduction. Sit the 
patient on the side of the bed to assess knee flexion and extension. Ask the patient to flex and 
extend the knee. If able to do this, apply resistance as these movements are repeated. Test 
plantar and dorsiflexion by having the patient push down against your hand with their foot and 
then pull up against your hand with their foot. Remember to compare the left side to the right 
side. 
Upper Extremities 
Assess ability to flex elbow (biceps) and straighten (triceps). Assess ability to raise shoulders 
and return to a resting position. Assess wrist flexion and extension. Test each function with 
resistance. For focused upper extremity assessment, assess each digit for flexion, extension and 
lateral movement. 


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Assessment of an Unconscious Patient 
Upper Extremities 
1. Observe the patient for spontaneous/involuntary movement. 
2. Apply painful stimuli to elicit a motor response (start with central pain; move to peripheral 
pain if no response occurs). 
3. Assess for paralysis of the limb by lifting both arms and releasing them together. If one limb 
is paralysed it will fall more rapidly than the non paralysed arm. 
Lower Extremities 
1. Observe for spontaneous/involuntary movement. 
2. Apply painful stimuli to elicit a motor response. Begin with central pain. Nailbed or 
peripheral pain can be attempted if the patient doesn’t respond to central pain (caution needs 
to be used when interpreting peripheral pain as it may stimulate spinal reflex responses vs 
withdrawal or other more deliberate responses). 
3. To assess for paralysis of the one limb you can position the patient on their back and flex 
the knees so that both feet are flat on the bed. Release the knees simultaneously. If the leg 
falls to an extended position with the hip externally rotated, paralysis is present. The normal 
leg should stay in the flexed position for a few seconds and then gradually assume its 
previous position. 
SENSORY FUNCTION 
When assessing sensory function remember that there are three main pathways for sensation 
and they should be compared bilaterally: 
1. Pain and temperature sensation. 
2. Position sense (proprioception). 
3. Light touch. 
Pain can be assessed using a sterile pin. Light touch can be assessed with a cotton wisp. To test 
proprioception, grasp the patient's index finger from the middle joint and move it side to side 
and up and down. Have the patient identify the direction of movement. Repeat this using the 
great toe. 
Sensory Tests: 
A number of tests for lesions of the sensory cortex can be done. Examples include the following: 
• Stereognosis: The ability to recognize an object by feel. Place a common object in the 
persons hand and ask them to identify the object. 
• Graphesthesis: “Draw” a number in the palm of the person’s hand and ask them to identify 
the number. 
• Two-Point Discrimination: Simultaneously apply two pin pricks to the skin surface. 
Continually repeat the test while bringing the two pins closer together, until the individual 
can no longer identify two separate stimuli. The finger tips are the most sensitive location 
for recognizing two point differences while the upper arms, thighs and back are the least 
sensitive. 


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• Extinction: Touch the same spot on both sides of the body at the same time (eg, the left and 
right forearms. Ask the individual to describe how many spots are being touched. Normally, 
both sides are felt; with sensory lesions the individual will sense only one. 
• Point Locations: Touch the surface of the skin and remove the stimulus quickly. Ask the 
individual to touch the spot where the sensation was felt. Sensory lesions can impair 
accurate identification, even if they retain their sensation of light touch. 
TONE and REFLEXES 
Upper motor neuron problems (brain and spinal cord) are associated with increased tone. Lower 
motor neuron problems are associated with decreased tone. 
Look at the muscles on each side of the body in pairs. Assess for symmetry of bulk. 
Evaluation of the stretch reflexes assesses the intactness of the spinal reflex arc at various spinal 
cord levels. The limb should be relaxed while applying a short and snappy blow with a reflex 
hammer. Hold the hammer loosely in a relaxed manner, making a wrist action. Allow the 
hammer to bounce. 
Table 16-9 
Reflex responses 
Reflex responses 
Description 
0 
No response 
1+ 
Diminished, low normal 
2+ 
Average, normal 
3+ 
Brisker than normal 
4+ 
Very brisk, hyperactive 
Lower motor neuron disease is associated with 0 or 1+, upper motor neuron disease is associated with 3+ or 
4+. 
Biceps Reflex (C5 – C6): 
Support the forearm on the examiners forearm. Place your thumb on the bicep tendon (located 
in the front of the bend of the elbow; midline to the anticubital fossa). Tap on your thumb to 
stimulate a response. 
Triceps Reflex (C7-C8): 
Have the individual bend their elbow while pointing their arm downward at 90 degrees. Support 
the upper arm so that the arm hangs loosely and “goes dead”. Tap on the triceps tendon located 
just above the elbow bend (funny bone). 
Brachioradialis Reflex (C5-C6): 
Hold the person’s thumb so that the forearm relaxes. Strike the forearm about 2-3 cm above the 
radial styloid process (located along the thumb side of the wrist, about 2-3 cm above the round 
bone at the bend of the wrist). Normally, the forearm with flex and supinate. 
Quadriceps Reflex (Knee jerk) L2 – L4: 
Allow the lower legs to dangle freely. Place one hand on the quadriceps. Strike just below the 
knee cap. The lower leg normally will extend and the quadriceps will contract. 


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If the patient is supine: Stand on one side of the bed. Place the examiners forearm under the 
thigh closest to the examiner, lifting the leg up. Reach under the thigh and place the hand on 
the thigh of the opposite leg, just above the knee cap. Tap the knee closest to the examiner, (the 
one that has been lifted up with the examiners forearm). 
Achilles Reflex (ankle jerks) L5 – S2: 
Flex the knee and externally rotate the hip. Dorsiflex the foot and strike the Achilles tendon of 
the heel. In conscious patients, kneeling on a chair can help to relax the foot. 
Heel Lift: 
While the patient is supine, bend the knee and support the leg under the thigh. Have the leg “go 
dead”. Briskly jerk the leg to lift the heel of the bed. Normally, the leg will remain relaxed and 
the heel will slide upward; increased tone will cause the heel and leg to stiffen and lift off the 
bed. 
Babinski Response: 
Dorsiflexion of the great toe with fanning of remaining toes is a positive Babinski response. 
This indicates upper motor neuron disease. It is normal in infants. 
CEREBELLAR FUNCTION 
The cerebellum is responsible for muscle coordination and balance on the same side. To test 
cerebellar function use the following tests: 
1. Finger to finger test: have the patient touch their index finger to your index finger (repeat 
several times). 
2. Finger to nose test: perform with eyes open and then eyes closed. 
3. Tandem walking: heel to toe on a straight line 
4. Romberg test: stand with feet together and arms at their sides. Have patient close his/ her 
eyes and maintain this position for 10 seconds. If the patient begins to sway, have them open 
their eyes. If swaying continues, the test is “positive” or suggestive of cerebellum problems. 
Dizziness that occurs in response to position changes is usually blood pressure initiated. If the 
patient sways during a Romberg test, but stops when the eyes are opened, the problem is 
probably visual or CN VIII (vestibular). 


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16.6 
Appendix 6: Sampson Criteria for Diagnosing Anaphylaxis 
Anaphylaxis is highly likely when any one of the following three criteria is fulfilled: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips- tongue-uvula) 
AND AT LEAST ONE OF THE FOLLOWING: 
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow [PEF], hypoxemia) 
b. Reduced blood pressure or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence) 
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours): 
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen lips-
tongue-uvula) 
b. Respiratory compromise (eg, dyspnea, wheeze, bronchospasm, stridor, reduced PEF, 
hypoxemia) 
c. Reduced blood pressure or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence) 
d. Persistent gastrointestinal symptoms (eg, painful abdominal cramps, vomiting) 
3. Reduced blood pressure after exposure to a known allergen for that patient (minutes to several 
hours): 
a. Infants and children: low systolic blood pressure (age specific) or >30% decrease in systolic 
blood pressure* 
b. Adults: SBP <90 mmHg or >30% decrease from that person’s Day 1 reading 
*Low SBP for children is age specific and defined as: <70 mmHg from age 1 month to 1 year; 
<70 mmHg + [2 x age] for age 1 to 10 years; <90 mmHg from age 11 to 17 years. 
Source: Sampson et al 2005 and Sampson et al 2006 


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16.7 
Appendix 7: Reference table blood volume by weight 
Blood volume drawn for the purpose of this study is limited to a maximum of 2.5% of the 
circulating blood volume per sampling session and to a maximum of 5% over a 4-week period 
(Table 16-10) (Howie 2011). Investigators may further limit the volume of blood withdrawn 
based on local institutional guidelines and if the clinical condition of the participant may be 
adversely affected by removal of the blood volumes stated below. Details of blood volume 
requirement for 
 biomarker and safety samples are provided in the laboratory manual. 
Table 16-10 
Reference table – blood collection volumes by body weight  
Body Weight (kg) 
Total blood volume 
(TBV) of the participant 
(mL)1 
Maximum allowable 
volume (mL) in one 
blood draw (2.5% of 
TBV) 
Total maximum volume 
(mL) drawn in a 28-day 
period (5% of TBV) 
20 
1600 
40 
80 
21 
1680 
42 
84 
22 
1760 
44 
88 
23 
1840 
46 
92 
24 
1920 
48 
96 
25 
2000 
50 
100 
26 
2080 
52 
104 
27 
2160 
54 
108 
28 
2240 
56 
112 
29 
2320 
58 
116 
30 
2400 
60 
120 
31 
2480 
62 
124 
32 
2560 
64 
128 
33 
2640 
66 
132 
34 
2720 
68 
136 
35 
2800 
70 
140 
36 
2880 
72 
144 
37 
2960 
74 
148 
38 
3040 
76 
152 
39 
3120 
78 
156 
40 
3200 
80 
160 
41 
3280 
82 
164 
42 
3360 
84 
168 
43 
3440 
86 
172 
44 
3520 
88 
176 
45 
3600 
90 
180 
46 
3680 
92 
184 
47 
3760 
94 
188 
48 
3840 
96 
192 
49 
3920 
98 
196 
50 
4000 
100 
200 
51 
4080 
102 
204 
52 
4160 
104 
208 


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Body Weight (kg) 
Total blood volume 
(TBV) of the participant 
(mL)1 
Maximum allowable 
volume (mL) in one 
blood draw (2.5% of 
TBV) 
Total maximum volume 
(mL) drawn in a 28-day 
period (5% of TBV) 
53 
4240 
106 
212 
54 
4320 
108 
216 
55 
4400 
110 
220 
56 
4480 
112 
224 
57 
4560 
114 
228 
58 
4640 
116 
232 
59 
4720 
118 
236 
60 
4800 
120 
240 
61 
4880 
122 
244 
62 
4960 
124 
248 
63 
5040 
126 
252 
64 
5120 
128 
256 
65 
5200 
130 
260 
66 
5280 
132 
264 
67 
5360 
134 
268 
68 
5440 
136 
272 
69 
5520 
138 
276 
70 
5600 
140 
280 
71 
5680 
142 
284 
72 
5760 
144 
288 
73 
5840 
146 
292 
74 
5920 
148 
296 
75 
6000 
150 
300 
76 
6080 
152 
304 
77 
6160 
154 
308 
78 
6240 
156 
312 
79 
6320 
158 
316 
80 
6400 
160 
320 
1: Assuming a TBV of 80 mL per kg 
For body weights not listed in the Table, use the following formulas to calculate 2.5% and 5% 
of total blood volume: 
• 2.5% of total blood volume = body weight (in kg to the closest 0.5 kg) X 2 
• 5% of total blood volume = body weight (in kg to the closest 0.5 kg) X 4 

SAP_001.pdf: 
Official Title:    Two Part (Double-blind Inclisiran Versus Placebo [Year 1] Followed by 
Open-label Inclisiran [Year 2]) Randomized Multicenter Study 
to Evaluate Safety, Tolerability, and Efficacy of Inclisiran in 
Adolescents (12 to Less Than 18 Years) With Heterozygous 
Familial Hypercholesterolemia and Elevated LDL-cholesterol 
(ORION-16)
NCT Number: 
 NCT04652726 
Document Date: 
Statistical Analysis Plan (Amendment 4): 03-Dec-2024


Appendix 16.1.9
Documentation of statistical methods
History of changes
Version
Summary of changes
1.0
Original version
1
Statistical methods
The planned statistical analysis is described in Section 12 of the clinical study protocol. The 
most recent version of Statistical Analysis Plan (SAP) is included below.
Two post-hoc analyses were conducted:
1. After Part 1/Year 1 DBL, percentage change in PCSK9 from baseline to Day 330 using
ANCOVA with treatment as fixed effect and baseline PCSK9 and baseline age group as
covariates, was added, as only descriptive summary statistics of PCSK9 by treatment and visit
had been specified in the SAP before the Part 1/Year 1 DBL.
 
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Clinical Development
KJX839/inclisiran
CKJX839C12301 
Two part (double-blind inclisiran versus placebo [Year 1] followed 
by open-label inclisiran [Year 2]) randomized multicenter study to 
evaluate safety, tolerability, and efficacy of inclisiran in adolescents 
(12 to less than 18 years) with heterozygous familial 
hypercholesterolemia and elevated LDL-cholesterol (ORION-16)
Statistical Analysis Plan (SAP)
Author:
Trial statistician 
Document type:
SAP Documentation
Document status:
Amendment 4
Release date:
3-Dec-2024
Number of pages:
47
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
 
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Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for update
Outcome for update
Section and 
title impacted 
(Current)
05-
Oct-
2020
Prior to 
DB 
lock
Creation of final 
version
N/A - First version
NA
 
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Reason for update
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(Current)
 
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(Current)
 
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(Current)
 
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(Current)
 
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(Current)
 
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Table of contents
Table of contents..................................................................................................................9
List of tables.......................................................................................................................11
List of figures.....................................................................................................................11
List of abbreviations ..........................................................................................................12
1
Introduction........................................................................................................................14
1.1
Study design...........................................................................................................14
1.2
Study objectives and endpoints..............................................................................15
2
Statistical methods .............................................................................................................17
2.1
Data analysis general information..........................................................................17
2.1.1
General definitions ................................................................................17
2.2
Analysis sets...........................................................................................................19
2.2.1
Subgroup of interest ..............................................................................20
2.3
Disposition, demographics and other baseline characteristics...............................21
2.3.1
Disposition.............................................................................................21
2.3.2
Demographics and other baseline characteristics..................................21
2.3.3
Medical history/current medical condition............................................22
2.4
Treatments (study treatment, prior and concomitant therapies) ............................22
2.4.1
Study treatment......................................................................................22
2.4.2
Prior and concomitant therapies............................................................22
2.5
Analysis of the primary objective..........................................................................23
2.5.1
Primary endpoint ...................................................................................23
2.5.2
Statistical hypothesis, model, and method of analysis ..........................24
2.5.3
Handling of remaining intercurrent events of primary estimand ..........24
2.5.4
Handling of missing values not related to intercurrent event................24
2.5.5
Sensitivity analyses for primary endpoint/estimand..............................24
2.5.6
Supplementary analysis.........................................................................25
2.6
Analysis of the key secondary objective................................................................25
2.6.1
Key secondary endpoints.......................................................................25
2.6.2
Statistical hypothesis, model, and method of analysis ..........................26
2.6.3
Multiplicity adjustment .........................................................................26
2.6.4
Sensitivity analyses ...............................................................................27
2.6.5
Supplementary analyses ........................................................................27
2.7
Analysis of other secondary efficacy objective(s).................................................27
2.8
Safety analyses.......................................................................................................28
2.8.1
Adverse events (AEs)............................................................................28
 
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2.8.2
Deaths....................................................................................................30
2.8.3
Laboratory data......................................................................................30
2.8.4
Diabetes assessment ..............................................................................31
2.8.5
Vital signs..............................................................................................35
2.8.6
Immunogenicity.....................................................................................35
2.8.7
Other safety evaluation..........................................................................36
.36
2.10
Biomarkers.............................................................................................................36
36
2.12
Interim analysis......................................................................................................37
3
Sample size calculation......................................................................................................37
4
Change to protocol specified analyses...............................................................................38
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..............................................38
5.2
AEs coding/grading................................................................................................38
5.3
Analyses to be performed in Part 1 analysis (ANA1) and Part 2 analysis 
(ANA2) ..................................................................................................................39
5.4
Search criteria for AE of other safety topics..........................................................40
5.5
Laboratory parameters derivations.........................................................................41
5.6
Vital signs – definition of clinically notable values...............................................43
5.7
Statistical models ...................................................................................................43
5.7.1
Multiple Imputation Wash-out model ...................................................43
5.7.2
Control based Pattern-Mixture model ...................................................45
5.8
Rule of exclusion criteria of analysis sets..............................................................47
 
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List of tables
Table 1-1
Objectives and related endpoints...........................................................15
Table 2-1
Visit mapping ........................................................................................19
Table 2-2
Sub-group for efficacy analysis.............................................................20
Table 2-3
Sub-group for safety analysis................................................................21
38
Table 5-1
Clinical notable criteria for selected laboratory tests ............................41
Table 5-2
Notable liver function test values..........................................................42
Table 5-3
Clinical notable criteria for vital signs ..................................................43
List of figures
Figure 1-1
Study design ..........................................................................................15
 
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List of abbreviations
ADA
Anti-drug antibodies
AE(s)
Adverse event(s)
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
Apo A1
Apolipoprotein A1
Apo B
Apolipoprotein B
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical 
BMI
Body Mass Index
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
DBP
Diastolic Blood Pressure
DMC
Data Monitoring Committee
ECG
Electrocardiogram
eGFR
Estimated glomerular filtration rate
EudraCT
European Union Drug Regulating Authorities Clinical 
Trials
FAS
Full Analysis Set
FH
Familial Hypercholesterolemia
HbA1c
Hemoglobin A1c
HDL-C
High density lipoprotein cholesterol
HeFH
Heterozygous Familial Hypercholesterolemia 
LDL
Low density lipoprotein
LDL-C
Low density lipoprotein cholesterol
LFT(s)
Liver function test(s)
LLOQ
Lower limit of quantification
Lp(a)
Lipoprotein (a)
MMRM
Mixed-effect model for repeated measures
OAS
Open-label Phase Analysis Set
PCSK9
Proprotein convertase subtilisin/kexin type 9
PT
Preferred term
s.c.
Subcutaneous
SAE
Serious adverse event
SAF
Safety set
 
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SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SCR
Screened set
SD
Standard deviation
SOC
System Organ Class
TEAE
Treatment emergent adverse event
ULN
Upper limit of normal
WBC
White blood cell(s)
 
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1
Introduction
This document contains details of the statistical methods that will be used in the Phase 3 clinical 
trial CKJX839C12301 (ORION-16). The purpose of this Phase 3 study is to evaluate safety, 
tolerability, and efficacy of inclisiran in adolescents (aged 12 to <18 years) with heterozygous 
familial hypercholesterolemia (HeFH) and elevated LDL-cholesterol (LDL-C). The use of 
inclisiran (as an adjunct to stable, optimal background lipid-lowering therapy) for the treatment 
of HeFH in adolescent patients who require additional lipid lowering will be investigated to 
obtain needed pediatric information on inclisiran. Percentage change in LDL-C from baseline 
to Day 330 (Year 1) is the primary endpoint of this study.
The analysis plan has been prepared based on the ORION-16 study protocol version V02 
(protocol amendment 2), content final dated 17-Feb-2023.
Important information is given in the following sections and details are provided, as applicable, 
in Section 5. 
1.1
Study design
This study is a two-part (double-blind, placebo-controlled / open-label) multicenter study in 
adolescents (aged 12 to <18 years) with HeFH and elevated LDL-C (>130 mg/dL / 3.4 mmol/L) 
on stable, individualized, optimal SoC background lipid-lowering therapy (including 
maximally tolerated statin treatment). The overall study duration is 748 days.
Following an approximately 4 weeks screening/run-in period, the study has two sequential parts 
(Figure 1-1).
•
Part 1 (Year 1): 12 months double-blind, parallel group period in which participants will 
be randomized to receive either inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) 
s.c. or placebo (given at Days 1, 90 and 270).
•
Part 2 (Year 2): 12 months single arm, open-label follow-up period with all participants 
receiving inclisiran sodium 300 mg s.c. Participants randomized to placebo in Part 1 will 
receive inclisiran starting on Day 360 (“Switch” Day 360). Participants randomized to 
inclisiran in Part 1 will receive placebo on Day 360. This dose of inclisiran/placebo on Day 
360 will remain blinded in order to maintain the blind for Part 1 of the study. All participants 
will receive subsequent doses of open-label inclisiran on Days 450 and 630.
A minimum of 102 participants (actual enrolled number of participants: 141), who meet the 
inclusion/exclusion criteria were to be randomized in a 2:1 ratio to receive either inclisiran 
sodium 300 mg s.c. or placebo on Day 1 (baseline). Detailed information regarding sample size 
calculation is provided in Section 3.
Randomization was stratified by age group (≥12 to <15 years and ≥15 to <18 years) to include 
a minimum of 40 participants in each of the two age strata.
 
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Figure 1-1
Study design
* Primary endpoint assessed at Day 330.  # "Switch Day": Participants randomized to placebo in Part 1 
will start to receive inclisiran on Day 360. Participants randomized to inclisiran in Part 1 will receive 
placebo on Day 360 only to maintain the blind for Part 1.
The primary endpoint will be measured at Day 330.
1.2
Study objectives and endpoints
Section 2 of the study protocol lists the following primary, secondary, 
 
Table 1-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)
•
The primary objective is to demonstrate 
superiority of inclisiran compared to 
placebo in reducing LDL-C [percent 
change] at Day 330 (Year 1) in 
adolescents (aged 12 to <18 years) with 
HeFH and elevated LDL-C 
•
Percentage change in LDL-C from baseline to 
Day 330 (Year 1)
Secondary objective(s)
Endpoint(s) for secondary objective(s)
•
Demonstrate superiority of inclisiran 
compared to placebo in reducing LDL-C 
[time-adjusted percent change] over 
Year 1
•
Time-adjusted percent change in LDL-C from 
baseline after Day 90 and up to Day 330 (Year 
1)
 
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Objective(s)
Endpoint(s)
•
Demonstrate superiority of inclisiran 
compared to placebo in reducing LDL-C 
[absolute change] at Day 330 (Year 1)
•
Absolute change in LDL-C from baseline to Day 
330 (Year 1)
•
Demonstrate superiority of inclisiran 
compared to placebo in reducing Apo B, 
lipoprotein (a) [Lp(a)], non-high density 
lipoprotein cholesterol (non-HDL-C), and 
total cholesterol [percent change] at Day 
330 (Year 1)
•
Percent change in Apo B, Lp(a), non-HDL-C, 
and total cholesterol from baseline to Day 330 
(Year 1)
•
Evaluate the effect of inclisiran, 
compared to placebo (for Year 1) and 
long-term (up to Day 720), on lowering 
LDL-C, other lipoprotein and lipid 
parameters, and PCSK9 over time
•
Percent change and absolute change in LDL-C, 
Apo B, Lp(a), non-HDL-C, total cholesterol, 
triglycerides, HDL-C, very low density 
lipoprotein cholesterol (VLDL-C), apolipoprotein 
A1 (Apo A1) and PCSK9 from baseline to each 
assessment time up to Day 720 (Year 2)
•
Evaluate the safety and tolerability profile 
of inclisiran, compared to placebo (for 
Year 1) and long-term (up to Day 720), in 
adolescents (aged 12 to <18 years) with 
HeFH
•
Incidence, severity and relationship to study 
drug of treatment-emergent AEs and SAEs; vital 
signs; laboratory parameters; anti-drug 
antibodies (ADA) measurement; growth (height, 
weight, BMI); pubertal development (steroid 
hormones and Tanner staging)
 
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2
Statistical methods
2.1
Data analysis general information
All analyses will be performed by Novartis. The most recent version of SAS available in the 
statistical programming environment of Novartis will be used for the analysis.
Part 1 data are defined as all data collected starting from the screening visit up to the day 360 
visit date prior to dosing on this day/date. Part 1 data will be presented by two separate groups 
(inclisiran and placebo). The total column will be presented in all outputs of Part 1 as needed 
and will be specified in TFL shell document. 
Part 2 data analysis will include all data collected starting from after dosing on day 360. Part 2 
data will be presented in two separate groups, (1) inclisiran since Day 1 and (2) placebo-to-
inclisiran, unless otherwise specified. The column labels for these two groups will be inclisiran-
inclisiran and placebo-inclisiran. The total column will be presented in all outputs of Part 2 as 
needed and will be specified in TFL shell document.
For instances, where it will not be possible to distinguish whether data belong to Part 1 or Part 
2, based on the dosing time on the day 360 visit, all data collected from screening up to the day 
360 visit will be considered as Part 1 data and all data captured after the day 360 visit (starting 
from day 360 visit + 1 day) will be considered as Part 2.
Part 1 data analysis will be performed after all participants completed the day 360 visit (Part 1) 
or discontinued the study prior to the Day 360 visit. For each participant, data collected in the 
database till the end of study Part 1 (up-to Day 360 visit as mentioned above) will be included 
in this analysis. Hence the Day 360 visit of a participant will serve as data cut-off date for that 
participant. All events with start date before or on the cut-off date and for which the end date 
has not been reached yet or they are ongoing at final visit will be reported as ‘ongoing’. The 
same rule will be applied to events starting before or on the cut-off date and not having a 
documented end date. The assessment of study primary objective and key secondary objectives 
will be based on this analysis.
Part 2 data analysis will be conducted after all participants either completed the study or 
discontinued early.
Both Part 1 and Part 2 analyses will be reported in the CSR. For summary of the analyses that 
will be performed for Part 1 analysis and Part 2 analysis see Appendix 5.3.
Detailed information regarding DMC analysis will be provided in the DMC charter and a 
separate DMC SAP/TFL shells. 
2.1.1
General definitions 
Study day
Study day will be defined as the number of days since the date of first dose of double-blind 
treatment. The date of first dose of double-blind treatment will be defined as Day 1 and the day 
before the first dose of study drug will be defined as Day -1. 
 
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Therefore, for a particular date, study day will be calculated as follows:
For dates on or after the first date of double-blind treatment,
Study day = Assessment date – Date of first dose of double-blind treatment + 1;
For dates prior to the first date of double-blind treatment,
Study day = Assessment date – Date of first dose of double-blind treatment.
In case, participant has been randomized but has not received double-blind treatment then 
randomization visit day will be considered as Day 1.
Baseline definition
In general, for both Part 1 and Part 2, baseline value is defined as the last measurement collected 
on or prior to the first dose of double-blind treatment. 
Post-baseline measurement
Post-baseline values are defined as those measurements that were collected after the first dose 
of double-blind treatment.                                           
When change from baseline is of interest the following formula will be used for each scheduled 
visit and time-point where baseline and post-baseline values are both available:
Absolute change from baseline = post-baseline value – baseline value.
Percent change from baseline = (post-baseline value – baseline value) / baseline value*100.
Reflexive LDL-C
The endpoints involving LDL-C will use a reflexive LDL-C approach. The calculated LDL-C 
will be utilized unless triglycerides are greater than 400 mg/dL and/or calculated LDL-C is less 
than 40 mg/dL, in which case beta quantification LDL-C (i.e., LDL_C directly measured by 
ultracentrifugation) will be additionally performed and used for the analysis.
VLDL-C 
The endpoints involving VLDL-C will follow the same approach as reflexive LDL-C.
Re-derivation of age-strata for mis-stratified participants
If any subject will be mis-stratified for age-group during randomization, collected age of that 
participant will be used to re-derive the correct age-strata at analysis level and will be used for 
all analyses, as needed.
Discontinuation visit mapping
For patients who discontinued from the study and come to site for an early exit (EE) visit, the 
EE visit will be mapped to the next scheduled visit. The mapping details can be found as below:
 
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Table 2-1
Visit mapping
Status 
  Last attended scheduled visit prior
to EE
  
            Mapped visit for EE
Visit day 
Visit name 
Visit day
Visit name 
Visit day
Discontinued 
(Early exit)
1
Day 1
90
Day 90
Discontinued 
(Early exit)
90
Day 90
150
Day 150
Discontinued 
(Early exit)
150
Day 150
270
Day 270
Discontinued 
(Early exit)
270
Day 270
330
Day 330
Discontinued 
(Early exit)
330
Day 330
360
Day 360
Discontinued 
(Early exit)
360
Day 360
450
Day 450
Discontinued 
(Early exit)
450
Day 450
510
Day 510
Discontinued 
(Early exit)
510
Day 510
630
Day 630
Discontinued 
(Early exit)
630
Day 630
720
Day 720
Completed 
720
Fay 720
2.2
Analysis sets
The Screened Set (SCR) includes all participants who provided study informed consent.
The Randomized Set (RAN) consists of all participants who received a randomization number, 
regardless of whether double blind treatment received or not.
The Full Analysis Set (FAS) consists of all randomized participants with the exception of those 
mis-randomized participants who did not receive study drug. Mis-randomized participants are 
defined as not qualified for randomization and were inadvertently randomized into the study. 
According to the intent to treat principle, participants will be analyzed according to the 
treatment they have been assigned to during the randomization procedure. The FAS will be used 
in analyses for the primary, secondary, 
 objectives in Part 1.
The Safety Set (SAF) includes all participants who received at least one dose of study treatment. 
Participants will be analyzed according to the study treatment received. This will be the primary 
population for the safety analyses in Part 1. 
 
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Note that the Safety Set allows the inclusion of non-randomized participants who receive 
double-blind treatment in error. 
The Open-label Phase Analysis Set (OAS) includes all participants who entered study Part 2 
and received at least one dose of study drug in Part 2. The OAS will be used to analyze the data 
from participants who entered Part 2.
Note that in Part 1 the number of participants in FAS equals the number of participants in SAF, 
so only one open-label phase analysis set is defined for Part 2.
 
 
 
2.2.1
Subgroup of interest
Subgroup analyses of primary efficacy endpoint and key secondary efficacy endpoints will be 
performed on the FAS only. 
Table 2-2
Sub-group for efficacy analysis
Number Subgroup 
Categories 
1
Gender 
Male 
Female 
 
 
2
Age-group
≥ 12 - < 15  
 ≥ 15 - < 18
 
 
3
Race
White 
Black 
Asian 
Other 
4
Ethnicity
Hispanic or 
latino
Not Hispanic 
or latino
Other**
5
Body mass index
<= median
> median
6
Study center region*
North America 
Europe 
Other 
 
7
Baseline statin use 
Yes 
No 
 
 
8
Baseline LDL-C  
<= median
> median
 
 
9
Baseline PCSK9 
<= median
> median
*Region: 
North America: Canada, United States;
Europe: Czech Republic, France, Germany, Greece, Hungary, Italy, Netherlands, Norway, 
Poland, Russian Federation, Slovakia, Slovenia, Spain, Switzerland, Israel, Turkey, United 
Kingdom;
Other: Taiwan, South Africa, Malaysia, Lebanon, Jordan, Brazil, Argentina. 
**Other: Not reported and Unknown
Subgroup analyses of all treatment emergent adverse events (TEAE) including TEAE at 
injection site will be displayed by treatment, SOC, and PT. The number (and percentage) of 
 
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participants with TEAEs will be provided for each category of sub-group. The following sub-
group analyses will be performed on Safety Set.
Table 2-3
Sub-group for safety analysis
Number Subgroup 
Categories 
1
Gender 
Male 
Female 
 
 
2
Age-group
≥ 12 - < 15  
 ≥ 15 - < 18
3
Race
White 
Black 
Asian 
Other 
4
Body mass index
<= median
> median
2.3
Disposition, demographics and other baseline characteristics
2.3.1
Disposition
The overall number of participants who entered, completed, and discontinued the study will be 
summarized and listed, including the reasons for discontinuation for each period: screening, 
Study Part 1, Study Part 2. The screening disposition will be based on SCR. The RAN will be 
used for the summary and listing of patient disposition for Study Part 1 and 2. 
The number of participants in the FAS will be summarized by country, center, and treatment 
group for Part 1 analysis. 
Number of participants with protocol deviations will be tabulated by category (e.g., selection 
criteria not met, subject not withdrawn as per protocol, treatment deviation, prohibited 
concomitant medication, other), deviation and Part. Listing of participants with protocol 
deviation will be provided.
The number of participants included in each analysis set will be tabulated using SCR. 
2.3.2
Demographics and other baseline characteristics
Demographic and other baseline data including age, race, gender, ethnicity, country, region 
(North America, Europe, Other),  baseline characteristics such as body height, weight, BMI, 
waist circumference, smoking status, number of pack years, alcohol history; baseline disease 
characteristics including HeFH underlying genetic mutation(s), LDL-C, TC (total cholesterol), 
TG (triglycerides), PCSK9, baseline use of statins or other lipid-modifying therapies (yes, no), 
status of statin intolerance, baseline diabetes status as determined by fasting plasma glucose and 
HbA1C, baseline kidney function based on eGFR, baseline measurements of SBP, DBP, and 
pulse, will be summarized descriptively by treatment group. Listings will also be provided.
Categorical data will be presented as frequencies and percentages by treatment group. For 
continuous data, non-missing observations, mean, standard deviation, median, 1st and 3rd 
quartile, minimum, and maximum will be presented. For Part 1 analysis, these data will be 
summarized using RAN. 
No inferential statistics will be provided for baseline comparability among the treatment groups.
 
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2.3.3
Medical history/current medical condition
Medical history will be coded with the Medical Dictionary for Regulatory Activities 
terminology (MedDRA) using the most recent version at the time of database lock. Medical 
history/conditions will be summarized by primary system organ class, preferred term, and  
treatment group. Pre-specified solicited events selected Familial Hypercholesterolemia History 
and other targeted family history will be summarized separately by treatment. 
For Part 1 analysis, this data will be summarized using RAN. 
2.4
Treatments (study treatment, prior and concomitant therapies)
In general, all summaries of treatments of Part 1 will be performed on the SAF, and All 
summaries of treatments of Part 2 will be performed on the OAS.
2.4.1
Study treatment
The number of study doses administered, duration on study, duration of exposure, patient year 
of exposure will be summarized by treatment group and Part. The analysis of exposure will also 
be provided for overall i.e., Part 1 and 2 data combined. Listings will be provided.
The number of participants dosed, and the injection site location will also be summarized by 
study visit and treatment group.
Duration of exposure will be calculated as: minimum of (Date of last dose of treatment – Date 
of first dose of treatment + 180 + 1, Date of last known visit – Date of first dose of treatment + 
1). For Part 1 data analysis, duration of exposure will be truncated at data cut-off date.
Patient-year of exposure will be calculated as duration of exposure/365.25. 
Duration on study is defined as: date of last known visit on study – date of first dose of treatment 
+ 1. For Part 1 data analysis, duration on study will be truncated at data cut-off date.
The patients who will discontinue the treatment prematurely before discontinuing the treatment 
period will be summarized by treatment group and Part, including the reason of treatment 
discontinuation. Listing will also be provided.
2.4.2
Prior and concomitant therapies
Prior (pre-baseline) therapies are defined as any medication that was stopped ≥1 day before the 
first dose date of study medication. They will be summarized by treatment group.  
Concomitant therapies (any medication given at least once between the day of first dose of 
randomized study treatment and the date of the last study visit, including those which were 
started pre-baseline and continued into the period when study treatment is administered) will 
be summarized by treatment group and Part. Listings will be provided.
Lipid-modifying therapy (LMT) use, 
 will be summarized separately 
at screening and at the baseline/Randomization visit (Day 1) by treatment group using the 
following categories: 
•
Any LMT
 
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•
No LMT
•
Statins
•
Statins only
•
Other LMT
•
Other LMT only
•
Ezetimibe
•
Ezetimibe only
 
New or changed lipid-modifying therapy, 
 after baseline will be 
summarized by treatment group and Part.
Significant non-drug therapies prior to and after the start of the study treatment will be 
summarized according to the Anatomical Therapeutic Chemical (ATC) classification system 
and preferred term, by treatment group and Part. Significant non-drug therapies will be 
summarized similarly by primary system organ class, preferred term, treatment group and Part.
2.5
Analysis of the primary objective
The primary objective is to demonstrate superiority of inclisiran compared to placebo in 
reducing LDL-C [percent change] at Day 330 (Year 1) in adolescents (aged 12 to <18 years) 
with HeFH and elevated LDL-C.
2.5.1
Primary endpoint
The primary endpoint, i.e., primary analysis variable, is the percentage change in LDL-C from 
the baseline measurement to the Day 330 visit. 
The primary clinical question of interest is: What is the effect of the test treatment versus 
placebo on change in LDL-C after 330 days of treatment in adolescents with HeFH and elevated 
LDL-C who are on stable, optimal standard of care (SoC) lipid-lowering therapy, regardless of 
treatment discontinuation for any reason and regardless of unforeseen change in the 
concomitant lipid-lowering therapy.
The justification for the primary estimand is that it will capture both the effect of the study drug 
and the effect of changes in additional medication(s) used for HeFH, if they occur, as would be 
the case in clinical practice. 
The primary estimand is described by the following attributes:
1. Population: Adolescents with the HeFH condition of interest and elevated LDL-C on stable 
optimal SoC lipid-lowering therapy. Further details about the population are provided 
in Section 5 of the study protocol.
2. Endpoint: Percentage change in LDL-C from baseline to Day 330 (Year 1)
3. Treatment of interest: The randomized treatment (the investigational treatment inclisiran 
or the control treatment placebo) as add-on to optimal SoC lipid-lowering therapy for HeFH. 
 
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The type and dose of the concomitant lipid-lowering therapy for HeFH must remain stable 
during Part 1 (Year 1) of the study. Further details about the investigational treatment and 
control treatment are provided in Section 6 of the study protocol. Data collected regardless 
of treatment discontinuation for any reason, regardless of unforeseen change in the 
concomitant lipid-lowering therapy will be used for analysis [Treatment policy].
4. The summary measure: difference between treatments in mean percentage change from 
baseline to Day 330. 
2.5.2
Statistical hypothesis, model, and method of analysis
The statistical hypotheses that will be tested are as follows:
•
H0: The difference between inclisiran and placebo in the least squares mean percentage 
change from baseline to the Day 330 visit in LDL-C= 0
•
Ha: The difference (inclisiran minus placebo) between participants treated with inclisiran 
and placebo in the least squares mean percentage change from baseline to the Day 330 
visit in LDL-C < 0
The primary objective will be achieved if the null hypothesis is rejected at significance level of 
0.025 (One-sided test).
The primary analysis will use an analysis of covariance (ANCOVA) model. Due to probable 
heterogeneity of variances between treatment groups, ANCOVA model which assumes unequal 
variances for treatment group will be used. The model will include the fixed effects of treatment 
group and baseline age group (≥12-<15 or ≥15-<18 years of age), with baseline LDL-C as a 
covariate. Multiple imputation will be used to impute missing data using a washout model 
specified in Section 5.7.1. A total of 100 imputed datasets will be created. The ANCOVA model 
will be fit to each imputed dataset, and results will be combined using Rubin's combination 
rules. The estimate and corresponding 2-sided 95% confidence intervals of mean difference 
between treatment groups will be calculated. P-value for hypothesis test for mean difference 
will also be provided. The FAS will be used for this analysis. 
2.5.3
Handling of remaining intercurrent events of primary estimand
No remaining inter-current events are expected.
2.5.4
Handling of missing values not related to intercurrent event
Other missing data are expected to be intermittent missing data and will be assumed to be 
missing at random. Imputation details for data missing at random in the washout model has 
been provided in Section 5.7.1.
2.5.5
Sensitivity analyses for primary endpoint/estimand
The following sensitivity analyses will be performed for the primary estimand, to assess the 
robustness of the estimation in the presence of deviations from the assumptions specified in the 
primary analysis on the FAS only:
 
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•
Linear mixed-effect model for repeated measures (MMRM) analysis without multiple 
imputation
•
MMRM analysis on the imputed datasets, and multiple imputation will be based on a 
control-based pattern mixture model
•
ANCOVA using the washout model including the following fixed effects: baseline 
concomitant lipid-modifying therapies, baseline age group, region, and a treatment-by-
region interaction.
Due to the limited sample size of some countries, pooled regions will be used as the fixed effect 
for ANCOVA model. Analyses using the MMRM will include fixed effects for treatment, 
baseline age group (≥12-<15 or ≥15-<18 years of age), visits, interaction between treatment and 
visits, baseline LDL-C. Day 90, 150, 270, 330 and 360 will be included as visit. The Restricted 
Maximum Likelihood (REML) estimation approach will be used with covariance structure set 
as "Unstructured". If the model does not converge with unstructured covariance matrix, the 
compound symmetry covariance matrix will be used in the mixed model. 
The control-based pattern mixture model, as specified in Section 5.7.2, will be used to further 
explore the possibility of missing data being missing not at random. This approach will utilize 
placebo data for monotone missing inclisiran treatment data. Same MMRM as specified above 
will be used on analyze the imputed datasets.
2.5.6
Supplementary analysis
Supplementary analyses of LDL-C percent change from baseline to Day 330 will be performed 
in subgroups as specified in Section 2.2.1. The MMRM model (using control-based pattern 
mixture model for missing value imputation) will be used to evaluate the difference between 
inclisiran and placebo groups in each subgroup. Forest plot will be provided for sub-group 
analyses.
2.6
Analysis of the key secondary objective
2.6.1
Key secondary endpoints
The following are key secondary efficacy endpoints:
•
Time-adjusted percent change in LDL-C from baseline after Day 90 and up to Day 330 
(Year 1), defined as the average of percent changes from baseline to day 150, 270, and 
330.
•
Absolute change in LDL-C from baseline to Day 330 (Year 1)
•
Percent change in Apo B from baseline to Day 330 (Year 1)
•
Percent change in Lp(a) from baseline to Day 330 (Year 1)
•
Percent change in non-HDL-C from baseline to Day 330 (Year 1)
•
Percent change in total cholesterol from baseline to Day 330 (Year 1)
Secondary estimands corresponding to key secondary efficacy endpoints are defined similarly 
to the primary estimand. These endpoints, and the corresponding summary measures, are listed 
 
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below. Population, treatment of interest, endpoints, and intercurrent events are defined similarly 
as for the primary estimand.
•
Endpoint: time-adjusted percent change in LDL-C from baseline after Day 90 and up to Day 
330 (Year 1). Summary measure: difference between treatment groups in mean time-
adjusted percent change in LDL-C from baseline after Day 90 and up to Day 330 (Year 1).
•
Endpoint: absolute change in LDL-C from baseline to Day 330 (Year 1). Summary 
measure: difference between treatment groups in mean absolute change in LDL-C from 
baseline to Day 330 (Year 1).
•
Endpoint: percent change in Apo B from baseline to Day 330 (Year 1). Summary 
measure: difference between treatment groups in mean percent change in Apo B from 
baseline to Day 330 (Year 1).
•
Endpoint: percent change in Lp(a) from baseline to Day 330 (Year 1). Summary 
measure: difference between treatment groups in mean percent change in Lp(a) from 
baseline to Day 330 (Year 1).
•
Endpoint: percent change in non-HDL-C from baseline to Day 330 (Year 1). Summary 
measure: difference between treatment groups in mean percent change in non-HDL-C from 
baseline to Day 330 (Year 1).
•
Endpoint: percent change in total cholesterol from baseline to Day 330 (Year 1). Summary 
measure: difference between treatment groups in mean percent change in total cholesterol 
from baseline to Day 330 (Year 1).
2.6.2
Statistical hypothesis, model, and method of analysis
The key secondary endpoints will be analyzed using the same ANCOVA with multiple 
imputation using wash-out model as mentioned for primary endpoint except the time-adjusted 
percent change in LDL-C from baseline after Day 90 and up to Day 330. In the model baseline 
LDL-C will be replaced by baseline of respective endpoint. The estimate and corresponding 2-
sided 95% confidence intervals of mean difference between treatment groups will be calculated. 
P-value for hypothesis test for mean difference will also be provided. 
The time-adjusted percent change in LDL-C from baseline after Day 90 and up to Day 330 will 
be estimated using MMRM model. MMRM analysis (using control-based pattern mixture 
model for missing value imputation) will be performed on the percentage change in LDL-C 
from baseline over visits (Day 150, 270, 330) as specified for primary endpoint on each of the 
100 imputed dataset. Then, linear combinations of the estimated means from visits Day 150, 
270 and 330 will be used to compare treatment effects in terms of time-adjusted percent change 
in LDL-C. Treatment effects from these 100 MMRM analyses will then be combined using 
Rubin’s Method. The estimate and corresponding 2-sided 95% confidence intervals of mean 
difference between treatment groups will be calculated. P-value for hypothesis test for mean 
difference will also be provided.
2.6.3
Multiplicity adjustment
A hierarchical testing strategy will be applied to control the family-wise type I error rate at the 
one-sided significance level of alpha=0.025 to assess superiority of inclisiran over placebo. 
 
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Hypotheses associated with the key secondary endpoints will be tested in the order listed above 
in Section 2.6.1.
2.6.4
Sensitivity analyses
MMRM analysis using control-based pattern mixture model for missing value imputation will 
be performed for key secondary endpoints (except the time-adjusted percent change in LDL-C 
from baseline after Day 90 and up to Day 330) as specified for primary endpoint in Section 
2.5.5. In model corresponding baseline value will be used instead of baseline LDL-C.
For the time-adjusted percent change in LDL-C from baseline after Day 90 and up to Day 330, 
mixed model for repeated measurements (MMRM) analysis without multiple imputation, that 
assumes missing data are MAR, will be performed. The model will be same as MMRM model 
mentioned in Section 2.6.2. A linear combination of the estimated means from visits Day 150, 
270 and 330 will be used to compare treatment groups.
2.6.5
Supplementary analyses
Supplementary analyses of key secondary endpoints will be performed in subgroups as 
specified in Section 2.2.1. The MMRM model (using control-based pattern mixture model for 
missing value imputation) will be used to evaluate the difference between inclisiran and placebo 
groups in each subgroup.
Another supplementary analysis for Lp(a) will be applied in log-transformed scale using same 
MMRM without multiple imputation specified above. 
2.7
Analysis of other secondary efficacy objective(s)
Other secondary efficacy endpoints include the percent change and absolute change from 
baseline throughout the time course up to Day 720 (Year 2) in the following:
•
LDL-C
•
Apo B
•
Lp(a)
•
non-HDL-C
•
total cholesterol
•
triglycerides
•
HDL-C
•
VLDL-C
•
Apo A1
•
PCSK9
Descriptive summaries by treatment group and Part and Line-Plot displaying mean will be 
provided by treatment group and Part for all above endpoints. The overall (Part 1 and Part 2 
combined) descriptive summaries and Line-Plot of LDL-C, Apo B, Lp(a), non-HDL-C, total 
cholesterol and PCSK9 will additionally be provided. 
 
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Listings of all the above endpoints for all the available visits, including time-adjusted 
percent change in LDL-C will be provided. In addition, the absolute change in LDL-C and  
percent change in LDL-C, Apo B, Lp(a), non-HDL-C, total cholesterol and PCSK9 from 
baseline to Day 720 (Year 2) will be provided. 
2.8
Safety analyses
In general, for Part 1 safety analyses, the SAF will be used; for Part 2 safety analysis, the OAS 
will be used.  
Safety summaries will include only treatment emergent adverse events (TEAEs) by Part. For 
Part 1, TEAEs are defined as adverse events (AEs) starting on or after the first dose of double-
blind treatment or AEs that were present prior to start of double-blind treatment but increased 
in severity in Part 1. For Part  2, TEAEs are defined as AEs starting after the Day 360 dosing 
time or AEs that were present prior to the Day 360 dosing time but increased in severity in Part 
2. For Part 1, if the AE start date is the same as the date of the first dose of double-blind 
treatment but the time is not available for comparison, the AE will be considered as treatment 
emergent; for Part 2 if the AE start date is the same as the date of the Day 360 treatment but the 
time is not available for comparison, the AE will be considered as treatment emergent.
Vital signs values that have complete data and time values will be assigned to pre- or post-dose 
assessment (as per protocol) based on the actual date/time. For values with missing date/time, 
the scheduled visit date and time will be used. This rule will be applied to data from scheduled 
visits only. If a measurement scheduled as pre-dose is actually performed post-dose, or vice 
versa, the data will not be used for visit/time point summary.
2.8.1
Adverse events (AEs)
The number (and percentage) of participants with TEAEs will be summarized by Part in the 
following ways:
•
Overall summary. 
•
By treatment, primary system organ class (SOC) and preferred term (PT).
•
By treatment and PT.
•
By treatment and PT for most common TEAEs (For Part 1: occurring in >= 3% of 
participants in total; for Part 2: threshold to be determined before final database lock).
•
By treatment, SOC, PT and maximum severity.
•
By treatment, SOC and PT for TEAEs leading to study drug discontinuation.
•
By treatment, SOC and PT for TEAEs related to study drug.
The number (and percentage) of participants with treatment emergent serious adverse events 
(TESAEs) will be summarized by Part, in the following ways:
•
By treatment, SOC and PT.
•
By treatment and PT.
•
By treatment, SOC and PT for TESAEs related to study drug.
 
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Unless otherwise specified, SOCs will be sorted alphabetically and, within each SOC, the PTs 
will be sorted in descending order of frequency in the total column. If a participant reported 
more than one AE with the same PT, the AE will be counted only once. A participant with 
multiple AEs within a SOC is only counted once towards the total of the SOC. In case of 
summary by severity or relationship to study drug, summary will be done using the most severe 
or related occurrence respectively. Listing of all AEs and SAEs will be provided.
AE reporting for CT.gov and EudraCT
For the legal requirements of clinicaltrials.gov and EudraCT, two required tables on TEAEs 
which are not SAEs with an incidence greater than X% (X will be selected prior to final database 
lock) and on TESAEs and TESAEs suspected to be related to study treatment will be provided 
by system organ class and preferred term on the Safety Set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness, and severity) occurred with the same SOC and PT:
•
a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE.
•
more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE.
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non-SAE has to be checked in a block e.g., among AEs in a ≤ 1 day gap block, if 
at least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
These summaries will be provided after full study completion.
Injection site reactions 
The number and percentage of participants who reported injection site reaction TEAEs will be 
summarized in the following ways: 
•
SOC, PT, treatment group and Part.  
•
SOC, PT, severity, treatment group and Part.  
Listing will be provided for participants with injection site reactions.
The time to the first injection site reaction will also be summarized by treatment and Part using 
the following categories: ≤4h, 4h to ≤12h, >12h. The time (hours) to the event will be calculated 
from the most recent administration of study drug. The duration of the first and the longest 
injection site reaction will be summarized by treatment and Part using descriptive statistics. The 
outcome of the first and the longest injection site reaction will be summarized using the 
following categories: Resolved (≤4h, >4h to ≤7 days, >7 days to ≤14 days, >14 days), not 
resolved and unknown. The total number of injection site reactions per participant will be 
summarized in categories (e.g., 1, 2, 3, and >3 etc.). Symptoms of injection site reactions will 
be summarized by treatment group and Part.
 
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Other safety topics
The number and percentage of participants who reported TEAEs of other safety topics will be 
summarized by PT, treatment group and Part. PTs will be sorted in descending order of 
frequency in the total column. If a participant reported more than one AE with the same PT, the 
AE will be counted only once. If a participant reported more than one AE within the same safety 
topic, the participant will be counted only once at that safety topic. Listing of participants with 
AEs of other safety topics will be provided.
The Compound Case Retrieval Strategy (CRS) will be used to determine the MedDRA search 
criteria to be used to identify events of other safety topics. 
AEs of other safety topics will include the following:
•
Hepatic events
•
Renal events 
•
Hypersensitivity events
•
Neurological events 
•
Psychiatric events
•
Musculoskeletal events
•
Cardiac events
•
New onset diabetes and worsening of glycemic control 
For search criteria of AE of other safety topics, refer to Appendix 5.4.
For detailed analysis of new onset diabetes and worsening of glycemic control, please see 
Section 2.8.4.
Any immune-related events will be identified in the SOC of immune system disorders.
The percentage of participants with abnormal ECG findings reported as AEs will be 
summarized by treatment group and Part.
2.8.2
Deaths
Summary for deaths will be provided by SOC and PT of cause of death, treatment group, and 
Part. Listing of all deaths will be provided.
2.8.3
Laboratory data
Laboratory data consist of hematology, biochemistry, sexual hormones, urinalysis 
measurements and ADA (see Section 2.8.6) . Absolute values and change from baseline will be 
summarized for continuous laboratory parameters by visit and box plots will also be provided 
by visit. Frequency table of results for categorical laboratory parameters will be presented by 
visit. This analysis will be performed by treatment group and Part.
Shift tables using the low, normal, high/low, or high classification (except for eGFR and HbA1c 
where the categories outlined below will be applied) will be used to compare baseline to the 
worst on-treatment value by treatment group and Part. All data collected after first dose of 
 
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double-blind treatment, from scheduled, unscheduled, and premature discontinuation visits in 
each part will be used to determine the worst on-treatment value.
The following categories will be used for eGFR and HbA1c:
•
For eGFR, the categories will be <30 mL/min/1.73m2; ≥ 30 to <60 mL/min/1.73m2; ≥ 60 
to <90 mL/min/1.73m2; and ≥90 mL/min/1.73m2.
•
For HbA1c, the categories will be <5.7%; ≥5.7% to <6.5%; and ≥6.5%.
The shift table dealing with the fasting plasma glucose parameter will require the lab sample to 
be taken fasting. Samples taken while the subject was not fasted will not be analyzed.
For selected laboratory tests, the number and percentage of patients meeting the clinically 
notable criteria at any time, considering all data collected after first dose of double-blind 
treatment, from scheduled, unscheduled, and premature discontinuation visits, will be 
summarized by laboratory parameter and treatment group and Part. The worst post-baseline 
value will be used for this analysis. Notable criteria are defined in Appendix 5.5. Clinically 
notable criteria will be considered met when both of the following occur:
•
Post-baseline value meets the clinically notable criteria. 
•
Baseline value does not meet the clinically notable criteria.
Furthermore, the number and percentage of participants meeting notable criteria in liver 
function tests (LFT) will be summarized by treatment and Part considering on-treatment data 
from scheduled, unscheduled, and premature discontinuation visit. LFT criteria are defined in 
Appendix 5.5.
The baseline value is the last value prior to the first dose of double-blind treatment.
All laboratory data will be listed by treatment group, participant, and visit/time and if normal 
ranges are available, abnormalities will be flagged.
2.8.4
Diabetes assessment
Diabetes will be assessed by the analysis of: 
•
TEAEs, 
•
Change in glucose-related laboratory values over time,
•
Shifts from baseline in glucose control category and,  
•
Incidence of post-baseline new onset of diabetes. 
Note that diabetes related tables dealing with the fasting plasma glucose parameter will require 
the lab sample to be taken fasting. Samples taken while the subject was not fasted will not be 
analyzed. 
Unless otherwise specified, baseline of fasting plasma glucose will be defined as the average of 
Screening and Day 1 assessments. If one fasting plasma glucose value is missing (Screening or 
Day 1), the baseline will be based on the available data. For HbA1c, the Day 1 assessment will 
be considered as baseline. If missing, then the baseline will be based on the assessment at 
screening.
Diabetes TEAE
 
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New onset/worsening of diabetes will be identified by the search criteria specified in Appendix 
5.4. The analysis will be performed for all subjects and then by baseline diabetes status. A 
participant will be identified as being diabetic at baseline if the medical history notes that the 
subject is diabetic or the baseline HbA1c value is ≥ 6.5% or the baseline fasting plasma glucose 
is ≥126 mg/dL. This summary will be provided by treatment and Part.
Change in Glucose-related Laboratory Values over Time
This analysis only utilizes laboratory data (fasting plasma glucose and HbA1c). The change from 
baseline to the last on-treatment observation and the worst on-treatment observation will be 
summarized by treatment and Part, separately for fasting plasma glucose and HbA1c for all 
participants and then by baseline glucose control status. Baseline glucose control status will be 
identified separately for fasting plasma glucose and HbA1c using the values provided in the 
table below (note that medical history will not be considered for this analysis). Figures will also 
be created showing change in mean fasting plasma glucose and HbA1c values over time by 
baseline glucose control status. 
Parameter 
Baseline Glucose Control Status (Laboratory 
Values) 
<100 mg/dL 
≥100 to <126 mg/dL 
 
Fasting Plasma Glucose 
≥126 mg/dL 
<5.7% 
≥5.7 to <6.5% 
 
HbA1c
≥6.5% 
Shifts from Baseline in Glucose Control Category  
Shifts from baseline in glucose control category will be summarized by treatment and Part in 
two different ways. The change from baseline to the worst-on-treatment and the last-on-
treatment laboratory values will be used to classify the on-treatment glucose control category.  
Medical history will not be considered for this analysis. 
 
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Shift Category* 
Baseline Category 
Post-baseline Category**
 Normal to Normal (no 
change) 
Fasting plasma glucose <100 
mg/dL 
AND 
HbA1c <5.7% 
Fasting plasma glucose <100 
mg/dL on two consecutive 
occasions 
AND 
HbA1c <5.7% 
 Normal to Impaired 
Fasting plasma glucose <100 
mg/dL 
AND 
HbA1c <5.7% 
Fasting plasma glucose ≥100 and 
<126 mg/dL on two consecutive 
occasions 
OR 
HbA1c ≥5.7 and <6.5%  
 Normal to Diabetes
Fasting plasma glucose <100 
mg/dL 
AND 
HbA1c <5.7% 
Fasting plasma glucose ≥126 
mg/dL on two consecutive 
occasions 
OR 
HbA1c ≥6.5% 
Impaired to Normal 
Fasting plasma glucose ≥100 and
<126 mg/dL 
OR 
HbA1c ≥5.7 and <6.5% 
Fasting plasma glucose <100 
mg/dL on two consecutive 
occasions 
AND 
HbA1c <5.7% 
Diabetes to Normal 
Fasting plasma glucose ≥126
mg/dL 
OR 
HbA1c ≥6.5% 
Fasting plasma glucose <100 
mg/dL on two consecutive 
occasions 
AND 
HbA1c <5.7% 
Impaired to Impaired
(no change)
Fasting plasma glucose ≥100 and
<126 mg/dL OR HbA1c ≥5.7 and
<6.5%
Fasting plasma glucose ≥100 and 
<126 mg/dL on two consecutive 
occasions OR HbA1c ≥5.7 and 
<6.5%
Impaired to Diabetes
Fasting plasma glucose ≥100 and
<126 mg/dL 
OR 
HbA1c ≥5.7 and <6.5%
Fasting plasma glucose ≥126 
mg/dL on two consecutive 
occasions 
OR 
HbA1c ≥6.5%
 
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Diabetes to Impaired 
Fasting plasma glucose ≥126
mg/dL 
OR 
HbA1c ≥6.5% 
Fasting plasma glucose ≥100 and 
<126 mg/dL on two consecutive 
occasions 
OR
HbA1c ≥5.7 and <6.5%
Diabetes to Diabetes 
(no change) 
Fasting plasma glucose ≥126
mg/dL 
OR 
HbA1c ≥6.5% 
Fasting plasma glucose ≥126 
mg/dL 
two consecutive occasions 
OR 
HbA1c ≥6.5%
*No change (Normal to Normal, Impaired to Impaired, and Diabetes to Diabetes), Worsened 
(Normal to Impaired, Normal to Diabetes, and Impaired to Diabetes), and Improved (Impaired 
to Normal, Diabetes to Impaired, and Diabetes to Normal) categories will also be summarized. 
**For post-baseline categories, if the post-baseline two consecutive fasting plasma glucose 
measurements fall in separate categories, or if only one post-baseline fasting plasma glucose 
measurement is available, then the post-baseline glucose control category will be defined based 
on the HbA1c measurement only. If HbA1c value is missing and two consecutive fasting 
plasma glucose measurements fall in separate categories, the lower category will be used to 
determine the post-baseline category. 
Incidence of Post-baseline New-Onset of Diabetes
The number of participants who shift from no diabetes at baseline to post-baseline new onset 
of diabetes will be summarized. 
The participants with no diabetes at baseline are those who had no medical history of diabetes 
in the medical history CRFs, had baseline HbA1c <6.5%, and had baseline fasting plasma 
glucose <126 mg/dL prior to the start of study treatment.  
A 4-component analysis will be utilized to detect post-baseline new onset of diabetes.  The 4 
components are provided below:
•
Diabetic TEAEs identified by the SMQ search (see Section 5.4), or 
•
Post-baseline fasting plasma glucose ≥126 mg/dL on two consecutive occasions, or 
•
Initiation of anti-diabetic medication at any time post-baseline, or 
•
At least one post-baseline HbA1c ≥6.5%. 
The number of participants who have any of the 4 components will be summarized (post-
baseline new onset of diabetes) by treatment and Part.  
This analysis will be performed separately for participants who had normal and impaired 
glucose control categories at baseline.
•
Subjects with normal glucose control status at baseline are those with all the following:
 
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•
No medical history of diabetes.
•
HbA1c < 5.7% and fasting plasma glucose < 100 mg/dL at baseline.
•
Subjects with impaired glucose control status at baseline are those with all the following:
•
No medical history of diabetes.
•
HbA1c ≥5.7% and <6.5% (and fasting plasma glucose<126 mg/dL) or fasting 
plasma glucose ≥100 mg/dL and <126 mg/dL (and HbA1c <6.5%) at baseline.
The time to new onset diabetes will also be summarized by treatment and Part. Only participants 
without diabetes at baseline will be included in the analysis. The time (weeks) to new-onset 
diabetes will be calculated from the date of the first administration of study drug. 
2.8.5
Vital signs
Absolute values and change from baseline will be summarized for vital sign parameters by visit, 
time point, treatment group and Part. For SBP and DBP, average of 3 readings will be used for 
analysis while all 3 readings will be provided in the listing. Baseline and change from baseline 
in height, weight, and BMI will be assessed with/without using age- and sex-adjusted z-scores 
and summarized by visit treatment group and Part. 
The number and percentage of patients meeting clinically notable criteria at any time, 
considering all data collected after first dose of double-blind treatment, from scheduled, 
unscheduled, and premature discontinuation visits will be summarized by treatment group and 
Part. The worst post-baseline value in each part will be used for this analysis. Notable criteria 
are defined in Appendix 5.6. Clinically notable criteria will be met when both of the following 
occur: 
•
Post-baseline value meets the clinically notable criteria. 
•
Baseline value does not meet the clinically notable criteria.
The baseline value is the last value prior to and up to Day 1 of the double-blind treatment.
All vital signs data will be listed by treatment group, participant, and visit/time and if clinically 
notable criteria are met, abnormalities will be flagged.
2.8.6
Immunogenicity
Number and percentage of subjects with treatment-induced transient and persistent ADA and 
no treatment-induced ADA will be summarized. Listing will be provided.
Treatment-induced ADA will be defined as a negative ADA sample at baseline and at least one 
positive ADA sample post-baseline. Persistent will be defined as negative ADA at baseline and 
confirmed positive ADA on 2 or more timepoints where the first and last were separated by a 
period of at least 16 weeks or positive ADA at the last timepoint or at a timepoint less than 16 
weeks before an ADA negative last sample. Transient will be defined as treatment-induced 
ADA detected at only 1 time point post-baseline, or 2 or more sampling time points where the 
first and last ADA-positive samples are separated by a period less than 16 weeks, and the 
subject’s last sampling time point is ADA-negative.
 
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In addition, further ADA details will be assessed and will be listed in a separate ADA report. If 
applicable, additional analyses may be conducted.
2.8.7
Other safety evaluation
Shift from baseline in Tanner stage will be summarized by sex, treatment, visit and Part. 
Additionally, shift in menarche status from baseline will be summarized by visit and treatment 
group and Part.  Mean and SD of age of the participants in each of category of shift table will 
be provided. Listing will be provided.
In cases where following a Tanner stage 5 the data of the next visit are missing, they will be 
imputed as Tanner stage 5 (as the protocol does not mandate to repeat the Tanner stage 
assessment once Tanner stage 5 has been reached). Similarly, menarche data will be imputed 
as yes if the previous assessment was yes for menarche and data are missing at the next visit.
  
 
 
 
 
 
 
 
 
 
2.10
Biomarkers
Analyses of PCSK9 and lipids/lipoproteins are discussed in Section 2.7. No additional 
biomarkers will be evaluated in this study.
 
 
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2.12
Interim analysis
Interim safety analyses are planned for the monitoring of participants' safety and will be 
performed as determined by the DMC  (see DMC charter). Interim safety analyses before the 
unblinding for the analysis of Part 1 of the study will be performed by an independent 
statistician/programmer who will not be involved in the trial conduct. The interim results will 
be reviewed by the independent DMC.
 
 
 
3
Sample size calculation
The sample size was calculated based on detecting a reduction of at least
in the inclisiran 
group compared to the placebo group in percent change of LDL-C from baseline to day 330. 
The primary efficacy variable is assumed to have a standard deviation of
n the control 
group and
in the inclisiran group. These assumptions are based on observed results from 
adult inclisiran studies.
The sample size of at least 
total participants will provide more than
power to detect a 
reduction at significance level of 
in a 2:1 (Inclisiran vs placebo) 
randomization ratio. 
Furthermore, in the adult HeFH inclisiran study (ORION-9), a SD of 
in the control group 
and
n the inclisiran group was observed. With a more conservative assumption of a SD 
of
in the control group and
in the inclisiran group, the sample size of at least
total 
 
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participants will still provide more than 
 power to detect a 
 with a 
 
significance level of 
The revised sample size requires a minimum of
articipants; however, the actual enrollment 
is
participants.
4
Change to protocol specified analyses
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
Missing/partial start date or end date of treatment will not be imputed.
5.1.2
AE date imputation
Partial AE start and end dates will be imputed. If there is uncertainty whether an AE occurred 
on-treatment or not, imputation will be performed, such that AE will be considered as on-
treatment. Rules for imputing AE end date or start date will be provided in Programming 
Dataset Specification (PDS) document in details.
5.1.3
Concomitant medication date imputation
Rules for imputing the CM end date or start date will be provided in Programming Dataset 
Specification (PDS) document in details.
5.2
AEs coding/grading
The MedDRA version which will be available at the time of database lock, will be used for the 
coding purpose of the adverse events.
 
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5.3
Analyses to be performed in Part 1 analysis (ANA1) and Part 2 
analysis (ANA2)
Data to be included 
(ANA1 and ANA2 analysis)
Comment
Part 1
Part 2
Part 1 & Part 2 
combined 
Disposition
ANA1
ANA2
Protocol Deviations
ANA1
ANA2
Demography and baseline 
characteristics
ANA1
Concomitant therapies
(Including lipid modifying 
therapy 
)
ANA1
ANA2
SAF for ANA1;
OAS for ANA2.
CM will be counted in 
both parts when starting 
from part 1 and continuing 
to part 2.
New or changed lipid-
modifying therapy 
ANA1
ANA2
Doses, Duration on study, 
Exposure
ANA1
ANA2
For exposure
Efficacy (Primary & key 
secondary endpoints)
ANA1
Efficacy (other Secondary 
 endpoints)
ANA1
ANA2
For selected 
efficacy 
parameters
AEs
ANA1
ANA2
SAF for 
ANA1; 
OAS forANA2
Diabetes assessment 
ANA1
ANA2
SAF for 
ANA1;
OAS for ANA2
Lab and Vital signs
ANA1
ANA2
SAF for 
ANA1;
 
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OAS for ANA2
5.4
Search criteria for AE of other safety topics
The most recent eCRS available during database lock will be used.
 
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5.5
Laboratory parameters derivations
The following table shows the criteria for clinically notable laboratory values. Not all 
parameters have notable criteria defined:
Table 5-1
Clinical notable criteria for selected laboratory tests
Notable post-baseline value
Hematology
Hemoglobin
≤10 g/dL 
Hematocrit
≤ 0.8 x LLN
WBC count / 
Leukocytes
≤ 2.8 x 10ˆ9/L  or ≥16 x 10ˆ9/L
Platelet count
≤ 75 x 10ˆ9/L  or ≥700 x 10ˆ9/L
Clinical chemistry
C(P)K 
>5 x ULN
>5 and ≤10 x ULN
>10 and ≤20 x ULN
>20 x ULN
Creatinine 
≥50% increase from baseline (not >2 mg/dL)
>2 mg/dL
≥50% increase from baseline or >2 mg/dL
eGFR
<30 mL/min/1.73m2
≥ 30 to <60 mL/min/1.73m2
≥ 60 to <90 mL/min/1.73m2
Glucose
≥100 to <126 mg/dL
≥126 mg/dL
HbA1C
≥5.7% to <6.5% 
≥6.5%
 
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Table 5-2
Notable liver function test values
Criterion
ALT > 3 x the upper limit of normal range (ULN)
ALT > 5 x ULN
ALT > 8 x ULN
ALT > 10 x ULN
ALT > 20 x ULN
AST > 3 x ULN
AST > 5 x ULN
AST > 8 x ULN
AST > 10 x ULN
AST > 20 x ULN
ALT or AST > 3 x ULN
ALT or AST > 5 x ULN
ALT or AST > 8 x ULN
ALT or AST > 10 x ULN
ALT or AST > 20 x ULN
Total bilirubin > 2 x ULN
TBL >2xULN & DBL >ULN
TBL >2xULN & DBL >2xULN
ALP > 2 x ULN
ALT or AST > 3 x ULN and total bilirubin > 2 x ULN
ALT or AST > 5 x ULN and total bilirubin > 2 x ULN
ALT or AST > 8 x ULN and total bilirubin > 2 x ULN
ALT or AST > 10 x ULN and total bilirubin > 2 x ULN
ALT or AST > 20 x ULN and total bilirubin > 2 x ULN
ALT or AST > 3 x ULN and Total Bilirubin > 2 x ULN and ALP < 2 x ULN (Hy's law)
ALT = alanine aminotransferase, AST = aspartate aminotransferase, ALP = alkaline 
phosphatase, DBL = Direct bilirubin
When a criterion contains multiple laboratory parameters, the criterion will only be considered 
to have been met when all conditions occur within a 3-day window. 
 
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5.6
Vital signs – definition of clinically notable values
The following table shows the clinical notable criteria for vital signs.
Table 5-3
Clinical notable criteria for vital signs 
Age
SBP [mmHg]
DBP [mmHg]
Heart Rate [beats 
min-1]
>=12 years
< 90, > 145
< 55, > 90
< 45, > 95
 
5.7
Statistical models
5.7.1
Multiple Imputation Wash-out model
A multiple imputation washout model will be utilized for the primary efficacy analysis of the 
percentage change in LDL-C from baseline to Day 330 endpoint. The washout model can be 
thought of as a modified control-based PMM that will be used to explore the possibility of 
missing data being MNAR for subjects who discontinued the study early. For subjects who 
discontinued the study early, their missing values will be imputed under the assumption that 
their outcome would be similar to those in the placebo group with similar background 
characteristics. For subjects in the inclisiran group only missing Day 330 values will be imputed. 
For subjects in the placebo group their missing values over all visits after early termination will 
be imputed based on the missing at random (MAR) assumption. Multiple imputation will be 
used to account for uncertainty in the imputation process and results from the imputed datasets 
will be combined using Rubin’s method. Further details are provided below. 
For the placebo group the following variables will be included in a multiple imputation 
procedure (SAS PROC MI), this assumes missing data are MAR: 
•
Baseline value of efficacy measurement (continuous) 
•
Observed value of efficacy measurement at Day 90 (continuous) 
•
Observed value of efficacy measurement at Day 150 (continuous) 
•
Observed value of efficacy measurement at Day 270 (continuous) 
•
Observed value of efficacy measurement at Day 330 (continuous)  
•
Observed value of efficacy measurement at Day 360 (continuous)  
For the subjects in the inclisiran group who completed first 3 doses and have data available 
after Day 330 (considered to have completed the Study Part 1) the following variables will be 
included in a multiple imputation procedure (SAS PROC MI), this assumes missing data are 
MAR: 
•
Baseline value of efficacy measurement (continuous) 
•
Observed value of efficacy measurement at Day 330 from the inclisiran group 
(continuous) 
For the remaining subjects in the inclisiran group the following variables will be included in a 
multiple imputation procedure (SAS PROC MI), this assumes missing data are MNAR: 
•
Baseline value of efficacy measurement (continuous) 
 
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•
Observed value of efficacy measurement at Day 330 from the placebo group (continuous) 
1. Intermittent missing data in the placebo treatment group will be imputed using Markov Chain 
Monte Carlo (MCMC) methods, assuming MAR. SAS PROC MI will be utilized for this step 
using the MCMC impute=monotone option. A total of 100 datasets will be created. These 
datasets will be utilized in Step #2. 
2. The remaining missing values in the placebo group with a monotone missing data pattern will 
be imputed in this step. Missing data will be imputed assuming data are MAR. Only subjects in 
the placebo group will be utilized in this step. SAS PROC MI will be used to impute missing 
values utilizing the monotone reg option. Baseline age group will be included in the regression 
model. This will be performed for the 100 datasets. After this step, the 100 datasets will be fully 
imputed for the placebo treatment group. These datasets will be utilized in Step #4. 
3. Subjects in the inclisiran group who received first 3 doses of study medication, have the Day 
330 value missing, and have evaluable data after Day 330 will be included in this step.  Missing 
values at Day 330 will be imputed assuming data are MAR.  Only subjects in the inclisiran 
group will be included in this step.  Observed Baseline data, Day 330 data and baseline age 
group will be utilized to impute missing Day 330 data utilizing SAS PROC MI.  This will be 
performed 100 times to create 100 datasets that are fully imputed at Day 330. 
4. The remaining missing values at Day 330 in the inclisiran group will be imputed in this step. 
Note that the subjects with imputed inclisiran Day 330 data from Step #3 will not be utilized in 
this step. Control-based PMM imputation will be performed. With this imputation model, the 
missing efficacy measurements in the inclisiran group will not be constructed from the observed 
data in the inclisiran group but rather from the observed and imputed data in the placebo group 
at Day 330. Baseline data and age group will also be utilized in the imputation. The MNAR 
statement in SAS PROC MI will be used to impute missing values. This will be performed for 
the 100 datasets. 
5. The imputed data from Step #3 will be combined with the imputed data from Step #4 to create 
100 fully imputed datasets. 
6. A total of 100 fully imputed datasets will be created (M=100). Since multiple imputation is a 
stochastic method, slight differences in output can be expected for different initial states of the 
random number generator. The seed numbers will be identified in the SAS programs to allow 
for reproducibility. 
7. After the missing data imputation is completed using the above steps, absolute 
change/percentage change values will be calculated in each of the imputed datasets at each visit. 
8. These 100 datasets will be analyzed using ANCOVA models with fixed effects of treatment 
group: baseline age group and baseline LDL-C as a covariate for the percent change of LDL-C 
from baseline to Day 330 primary efficacy endpoint. PROC MIXED with (repeated / 
group=treatment) statement which allows separate variance to estimate for treatment groups 
will be used.
 
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9. Treatment effects (difference in least squares (LS) means between treatments) from these 100 
analyses will then be combined using Rubin’s Method via SAS PROC MIANALYZE 
procedure for each endpoint. 
5.7.2
Control based Pattern-Mixture model
A control-based PMM will be used to explore the possibility of missing data being MNAR for 
subjects who discontinued the study. For subjects who discontinued the study without any 
further follow-up data, their missing values after study discontinuation will be imputed under 
the assumption that their outcome would be the similar to those in the placebo group with 
similar background characteristics. For subjects who did not discontinue the study, their 
intermittent missing values will be imputed based on the MAR assumption. Multiple imputation 
will be used to account for uncertainty in the imputation process and results from the imputed 
datasets will be combined using Rubin’s method. Further details are provided below. 
The covariates and baseline characteristics which can be predictive of the response will be 
included in a multiple imputation procedure (SAS PROC MI) and will include the following: 
•
Baseline value of efficacy measurement (continuous) 
•
Observed value of efficacy measurement at Day 90 (continuous) 
•
Observed value of efficacy measurement at Day 150 (continuous) 
•
Observed value of efficacy measurement at Day 270 (continuous) 
•
Observed value of efficacy measurement at Day 330 (continuous) 
•
Observed value of efficacy measurement at Day 360 (continuous) 
1. Intermittent missing data will be imputed using MCMC methods, assuming MAR, within 
each treatment group. SAS PROC MI will be utilized for this step using the MCMC 
impute=monotone option. A total of 100 datasets will be created. These datasets will be 
utilized in Step #2. 
2. The remaining missing values with a monotone missing data pattern will be imputed in this 
step. Control-based PMM imputation will be performed. With this imputation model, the 
missing efficacy measurements in the inclisiran group will not be constructed from the 
observed data in the inclisiran group but rather from the observed data in the placebo group. 
We will also use this model to impute missing efficacy measurements in the placebo group. 
The MNAR statement in SAS PROC MI will be used to impute missing values under the 
aforementioned assumptions. Baseline age group will be included in the imputation model. 
This will be performed for the 100 datasets. After this step, the 100 datasets will be fully 
imputed. 
3. A total of 100 fully imputed datasets will be created (M=100). Since multiple imputation is 
a stochastic method, slight differences in output can be expected for different initial states 
of the random number generator. The seed numbers will be identified in the SAS programs 
to allow for reproducibility. 
 
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4. After the missing data imputation is completed using the above steps, absolute 
change/percentage change values will be calculated in each of the imputed datasets at each 
visit. 
5. These 100 datasets will be analyzed using the MMRM for the primary and key secondary 
efficacy endpoints. 
6. Treatment effects (difference in LS means between treatments) from these 100 analyses will 
then be combined using Rubin’s Method via SAS PROC MIANALYZE procedure for each 
endpoint. 
 
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5.8
Rule of exclusion criteria of analysis sets 
The protocol deviations (PD) and other criteria leading to complete exclusion from analyses 
sets may be included in this section and would be finalized before study DBL.
 
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