Clinical trial NCT04659863
Conditions: Familial Hypercholesterolemia - Homozygous
Keywords: Homozygous familial hypercholesterolemia (HoFH) LDL-cholesterol (LDL-C) adolescents pediatric small interfering ribonucleic acid (siRNA)
Sponsor: Novartis Pharmaceuticals
Start date: 2021-02-16; Completion date: 2024-11-18
Enrollment: 13 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 homozygous familial hypercholesterolemia (HoFH) and elevated low density lipoprotein cholesterol (LDL-C).

Detailed description:
This was a two-part (double-blind, inclisiran versus placebo \[Year 1\] followed by open-label inclisiran \[Year 2\]) multicenter study in adolescents (aged 12 to \< 18 years) with HoFH and elevated LDL-C (\> 130 mg/dL; 3.4 mmol/L) on stable, individualized, optimal standard of care (SoC) background lipid-lowering therapy (including maximally tolerated statin treatment, at the Investigator's discretion) to evaluate the safety, tolerability, and efficacy of inclisiran in this pediatric patient population.

Following an approximately 4-week screening/run-in period, the study had 2 sequential parts as follows:

Part 1/Year 1: 12 months double-blind, parallel group period, in which participants were randomized in a 2:1 ratio to receive either inclisiran sodium 300 mg subcutaneous (s.c.) or placebo. The primary endpoint was assessed at Day 330.

Part 2/Year 2: 12 months single arm, open-label follow-up period, with all participants receiving inclisiran sodium 300 mg s.c.

Arms: arm 1: Inclisiran sodium 300 mg subcutaneous (sc) injection (given at Days 1, 90 and 270) arm 2: Placebo sc injection (given at Day 1, 90 and 270) arm 3: Inclisiran sodium 300 mg sc injection (given at Days 450 and 630). In addition, participants assigned to placebo in Part 1 received inclisiran sodium 300 mg sc injection on Day 360, while participants assigned to inclisiran in Part 1 received placebo sc injection on Day 360.
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 injection) for subcutaneous injection

Protocol documents:
Prot_000.pdf: 


Novartis Research and Development 
KJX839/inclisiran 
Clinical Trial Protocol CKJX839C12302  
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 homozygous familial hypercholesterolemia 
and elevated LDL-cholesterol (ORION-13) 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2020-002755-38 
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 (01-Oct-2020) ................................................................................................... 14 
Protocol summary .............................................................................................................. 16 
1 
Introduction ....................................................................................................................... 18 
1.1 
Background ............................................................................................................ 18 
1.2 
Purpose .................................................................................................................. 20 
2 
Objectives and endpoints ................................................................................................... 21 
2.1 
Primary estimands ................................................................................................. 22 
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 ................................................................................................... 28 
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 ................................................................................ 31 
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 .............................. 33 
6.3.1 
Participant numbering ........................................................................... 33 


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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 ......................................................................... 35 
6.6 
Additional treatment guidance ............................................................................... 37 
6.6.1 
Treatment compliance ........................................................................... 37 
6.6.2 
Recommended treatment of adverse events .......................................... 38 
6.6.3 
Emergency breaking of assigned treatment code .................................. 38 
6.7 
Preparation and dispensation ................................................................................. 38 
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 ............................................................................................................... 46 
8.1.1 
Information to be collected on screening failures ................................. 46 
8.2 
Participant demographics/other baseline characteristics ....................................... 46 
8.3 
Efficacy .................................................................................................................. 46 
8.3.1 
LDL-cholesterol .................................................................................... 47 
8.3.2 
Other efficacy biomarkers ..................................................................... 47 
 
 47 
 
 47 
8.3.5 
Appropriateness of efficacy assessments .............................................. 47 
8.4 
Safety ..................................................................................................................... 48 
8.4.1 
Laboratory evaluations .......................................................................... 48 
8.4.2 
Electrocardiogram (ECG) ..................................................................... 50 
8.4.3 
Pregnancy .............................................................................................. 50 
8.4.4 
Other safety evaluations ........................................................................ 51 
8.4.5 
Appropriateness of safety measurements .............................................. 52 
8.5 
Additional assessments .......................................................................................... 52 
 
 52 
8.5.2 
Biomarkers ............................................................................................ 52 
 
 52 
9 
Study discontinuation and completion .............................................................................. 53 
9.1 
Discontinuation and completion ............................................................................ 53 
9.1.1 
Study treatment discontinuation and study discontinuation.................. 53 
9.1.2 
Withdrawal of informed consent ........................................................... 54 


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9.1.3 
Lost to follow-up ................................................................................... 55 
9.1.4 
Early study termination by the sponsor ................................................. 55 
9.2 
Study completion and post-study treatment .......................................................... 56 
10 Safety monitoring and reporting ........................................................................................ 56 
10.1 
Definition of adverse events and reporting requirements ...................................... 56 
10.1.1 
Adverse events ...................................................................................... 56 
10.1.2 
Serious adverse events .......................................................................... 58 
10.1.3 
SAE reporting........................................................................................ 59 
10.1.4 
Pregnancy reporting .............................................................................. 59 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 60 
10.2 
Additional Safety Monitoring ................................................................................ 60 
10.2.1 
Liver safety monitoring ......................................................................... 60 
10.2.2 
Renal safety monitoring ........................................................................ 61 
10.2.3 
Other safety monitoring ........................................................................ 61 
10.2.4 
Data Monitoring Committee ................................................................. 62 
10.2.5 
Steering Committee ............................................................................... 62 
11 Data Collection and Database management ...................................................................... 62 
11.1 
Data collection ....................................................................................................... 62 
11.2 
Database management and quality control ............................................................ 63 
11.3 
Site monitoring ...................................................................................................... 63 
12 Data analysis and statistical methods ................................................................................ 64 
12.1 
Analysis sets .......................................................................................................... 64 
12.2 
Participant demographics and other baseline characteristics ................................. 64 
12.3 
Treatments ............................................................................................................. 64 
12.4 
Analysis of the primary endpoint(s)/estimand(s) .................................................. 65 
12.4.1 
Definition of primary endpoint and estimand ....................................... 65 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 65 
12.4.3 
Handling of remaining intercurrent events of primary estimand .......... 65 
12.4.4 
Handling of missing values not related to intercurrent event ............... 65 
12.4.5 
Sensitivity analyses for primary endpoint/estimand ............................. 65 
12.4.6 
Supplementary analysis ......................................................................... 65 
12.4.7 
Supportive analyses ............................................................................... 65 
12.5 
Analysis of secondary endpoints/estimands .......................................................... 66 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) .................................... 66 
12.5.2 
Safety endpoints .................................................................................... 66 
12.5.3 
Biomarkers ............................................................................................ 68 
 
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 68 
 
 68 
12.7 
Interim analyses ..................................................................................................... 69 
12.8 
Sample size calculation.......................................................................................... 69 
12.8.1 
Primary endpoint(s) ............................................................................... 69 
13 Ethical considerations and administrative procedures ...................................................... 69 
13.1 
Regulatory and ethical compliance ........................................................................ 69 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 69 
13.3 
Publication of study protocol and results............................................................... 70 
13.4 
Quality Control and Quality Assurance ................................................................. 70 
14 Protocol adherence ............................................................................................................ 70 
14.1 
Protocol amendments............................................................................................. 71 
15 References ......................................................................................................................... 72 
16 Appendices ........................................................................................................................ 76 
16.1 
Appendix 1: Diagnostic criteria for HoFH ............................................................ 76 
16.2 
Appendix 2: Clinically notable laboratory values and vital signs ......................... 77 
16.3 
Appendix 3: Liver event and laboratory trigger definitions & follow-up 
requirements .......................................................................................................... 78 
16.4 
Appendix 4: Specific Renal Alert Criteria and Actions and Event Follow-up ...... 80 
16.5 
Appendix 5: Recommended Neurological Examination ....................................... 83 
16.6 
Appendix 6: Sampson Criteria for Diagnosing Anaphylaxis ................................ 87 
16.7 
Appendix 7: Reference table blood volume by weight ......................................... 88 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 21 
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 ................................................................. 36 
Table 8-1 
Assessment Schedule ............................................................................ 42 
Table 8-2 
Assessments & Specifications............................................................... 48 
Table 8-3 
Laboratory Assessments ........................................................................ 49 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 60 
Table 16-1 
Criteria for clinically notable vital signs ............................................... 77 
Table 16-2 
Clinically notable laboratory abnormalities for selected tests .............. 77 
Table 16-3 
Liver event and laboratory trigger definitions ...................................... 78 


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Table 16-4 
Follow up requirements for liver laboratory triggers with liver 
symptoms .............................................................................................. 78 
Table 16-5 
Follow up requirements for liver laboratory triggers ............................ 79 
Table 16-6 
Specific Renal Alert Criteria and Actions ............................................. 81 
Table 16-7 
Renal event follow-up ........................................................................... 82 
Table 16-8 
Grade Strength ...................................................................................... 83 
Table 16-9 
Reflex responses .................................................................................... 85 
Table 16-10 
Reference table – blood collection volumes by body weight ............... 88 
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 
PK 
Pharmacokinetic(s) 
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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Protocol summary 
Protocol 
number 
CKJX839C12302 
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 homozygous familial 
hypercholesterolemia and elevated LDL-cholesterol (ORION-13) 
Brief title 
A multicenter study to evaluate safety, tolerability, and efficacy of inclisiran in adolescents 
(12 to less than 18 years) with homozygous 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 homozygous familial hypercholesterolemia (HoFH) and 
elevated low density lipoprotein cholesterol (LDL-C). The use of inclisiran for the treatment 
of HoFH 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 evaluate the effect of inclisiran compared to placebo 
on reducing LDL-C [percent change] at Day 330 (Year 1) in adolescents (aged 12 to <18 
years) with HoFH and elevated LDL-C 
Secondary 
Objectives 
Evaluate the effect of inclisiran compared to placebo on reducing LDL-C [time-adjusted 
percent change] over 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 of inclisiran compared to placebo (for Year 1) and long-
term (up to Day 720), in adolescents (aged 12 to <18 years) with HoFH 
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 HoFH; approximately 12 participants; males and 
females 
Key Inclusion 
criteria 
• 
HoFH diagnosed by genetic confirmation 
• 
Fasting LDL-C >130 mg/dL (3.4 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 
• 
Documented evidence of a null (negative) mutation in both LDLR alleles 
• 
Previous treatment (within 90 days of screening) with monoclonal antibodies directed 
towards PCSK9 
• 
History of poor response to therapy with any monoclonal antibody directed towards 
PCSK9 




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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). 
Patients with HoFH have an extremely high risk of CVD. They often have LDL-C levels 
ranging between 3- to 6-fold higher than normal (> 13 mmol/L (500 mg/dL)) 
(Nordestgaard et al 2013, Wiegman et al 2015), and, if untreated, many will manifest coronary 
or other CV disease in childhood or adolescence (Wiegman et al 2015). The severity of the 
HoFH phenotype depends on the residual LDLR activity; HoFH patients who are LDLR-
negative (<2% activity) have higher LDL-C levels and poorer clinical prognosis, and also tend 
to present earlier than LDLR-defective patients (2-25% residual activity) (Bertolini et al 2013, 
Kolansky et al 2008, Moorjani et al 1993, Varghese 2014). Children with HoFH primarily 
present with dermatological manifestations such as tendon xanthomas and interdigital 


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xanthomas. Ocular manifestations include xanthelasma and corneal arcus (Varghese 2014). 
Most individuals with HoFH experience severe atherosclerotic vascular disease by their mid 
twenties and aortic stenosis is common (Youngblom et al 2016). 
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) and lipid-
lowering therapy is therefore recommended to be started as early as possible in HoFH 
(Cuchel et al 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). Lifestyle 
intervention and maximal statin therapy are the mainstays of treatment in HoFH, often in 
combination with ezetimibe and other lipid-modifying therapy (Cuchel et al 2014, 
Wiegman et al 2015). Even at the highest doses of the most efficacious statins, however, only 
modest reductions in LDL-C plasma levels of 10-25% are observed in most patients with HoFH. 
Where available, low density lipoprotein (LDL)-apheresis is regarded an important adjunctive 
treatment for HoFH, however, it is recognized that its use, including the age for initiation and 
frequency of treatment, represent a compromise between access to centers, the severity of the 
disease, affordability, and the patient’s choice (Cuchel et al 2014). 
Despite recent advances, current treatment options are still limited for children with HoFH, 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). 


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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). 
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 HoFH, with a low injection burden given the only twice yearly 
dosing. 
Study CKJX839C12302 (ORION-13) is planned to investigate inclisiran in adolescents aged 
12 to <18 years of age with HoFH. 
1.2 
Purpose 
Study CKJX839C12302 (ORION-13) is a pivotal phase III study designed to evaluate safety, 
tolerability, and efficacy of inclisiran in adolescents (aged 12 to <18 years) with HoFH 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 HoFH 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. 


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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 evaluate the 
effect of inclisiran compared to placebo 
on reducing LDL-C [percent change] at 
Day 330 (Year 1) in adolescents (aged 12 
to <18 years) with HoFH 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) 
• Evaluate the effect of inclisiran compared 
to placebo on 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) 
• 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, 
lipoprotein (a) [Lp(a)], non-high density lipoprotein 
cholesterol (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 of 
inclisiran compared to placebo (for Year 
1) and long-term (up to Day 720), in 
adolescents (aged 12 to <18 years) with 
HoFH 
• 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) 


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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 HoFH 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 HoFH, 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 HoFH 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 
HoFH. The type and dose of the concomitant lipid-lowering therapy for HoFH 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 mean percentage change at Day 330. 
2.2 
Secondary estimands 
Not applicable. 
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 HoFH 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 (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 


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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. 
Approximately 12 participants 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). 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. 
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 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)). 


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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. 
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 HoFH. 
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. 
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. 


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4.1.1 
Rationale for choice of background therapy 
It is required that all participants receive individualized, optimal SoC lipid-lowering treatment 
for HoFH 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 HoFH 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). 
LDL-apheresis is also allowed as adjunctive treatment per protocol in line with current practice 
and guidelines. 
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 
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. 






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5 
Study Population 
The study population consists of adolescents (12 to <18 years) with a genetic diagnosis of HoFH 
and LDL-C >130 mg/dL (3.4 mmol/L) on optimal SoC lipid-lowering therapy. 
Approximately 12 participants 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. HoFH diagnosed by genetic confirmation; see Section 16.1 (Appendix 1) for details 
• Note: Participants with known null (negative) mutations in both LDLR alleles are 
not eligible (see Section 5.2 exclusion criteria #1) 
4. Fasting LDL-C >130 mg/dL (3.4 mmol/L) at the screening visit, measured at the central 
laboratory 
5. 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  
6. 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 
7. 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 
8. Estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2 at screening  
9. 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. Documented evidence of a null (negative) mutation in both LDLR alleles 
2. Previous treatment (within 90 days of screening) with monoclonal antibodies directed 
towards PCSK9 
3. History of poor response to therapy with any monoclonal antibody directed towards 
PCSK9 (e.g. <15% reduction in LDL-C) 
4. Treatment with mipomersen or lomitapide (within 5 months of screening) 


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5. (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 
6. 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 
7. 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 
8. 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 
9. Heterozygous FH 
10. 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 


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• Persons directly involved in the conduct of the study 
11. Treatment with other investigational medicinal products or devices within 30 days or five 
half-lives, whichever is longer 
12. Planned use of other investigational products or devices during the course of the study 
13. Hypersensitivity to any of the ingredients of inclisiran 
14. Known history of alcohol and/or drug abuse 
15. Secondary hypercholesterolemia, e.g. hypothyroidism or nephrotic syndrome 
16. Major adverse cardiovascular events within 1 month prior to randomization 
17. Severe concomitant non-cardiovascular disease that carries the risk of reducing life 
expectancy to less than 2 years 
18. 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 
19. Poorly controlled diabetes mellitus (i.e. hemoglobin A1c (HbA1c) >10.0 %) 
20. 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. 
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 


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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. 
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. 


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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 HoFH 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. 
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. 


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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, 
niacin, colesevelam, bile acid 
absorption inhibitors, LDL-
apheresis) 
*For monoclonal antibodies 
directed towards PCSK9, 
mipomersen and lomitapide, 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 
Mipomersen, lomitapide 
Full Study Duration 
Discontinue study treatment 
Other investigational treatments 
Full Study Duration 
Discontinue study treatment 
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. 




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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 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: 


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• 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 
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 




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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 
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. 




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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. 
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. 




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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 
  


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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 
Physical Exam 
(abbreviated) 
  
S 
S 
S 
S 
S 
  
S 
S 
S 
S 
  
  
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 
  


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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 
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 
  
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. 


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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 
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) 
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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Laboratory tests 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. 
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 


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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. 
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). 


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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. 
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 


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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): 
• 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. 






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• 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. 
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, 


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and 
• Does not want any further visits or assessments 
and 
• Does not want any further study related contacts 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the 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 


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In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible and treated 
as a prematurely withdrawn participant. The investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the participant’s interests. The investigator or sponsor depending on local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial. 
9.2 
Study completion and post-study treatment 
Study completion is defined as when the last participant finishes their Study Completion visit 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision. 
All treated participants should have a safety follow-up call conducted 30 days after 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 HoFH 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. 


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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 
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 


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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: 
• 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 (HoFH) 
• 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). 


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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. 
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 


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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. 
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 


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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, 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) 


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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. 
It is anticipated that the DMC will review safety data 90 days after all 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. 


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11.2 
Database management and quality control 
Novartis personnel (or designated Contract Research Organization (CRO)) will review the data 
entered by investigational staff for completeness and accuracy. Electronic data queries stating 
the nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated investigator 
site staff are required to respond promptly to queries and to make any necessary changes to the 
data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical 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)). 


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


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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 
 at screening and the baseline/Randomization 
visit (Day 1) will be summarized by treatment group. New or changed lipid-modifying therapy 
 after baseline will be summarized by treatment group and part. 
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 primary endpoint 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 analysis will summarize change from baseline using summary statistics to 
characterize change from baseline in LDL-C by treatment group and the difference between 
treatment groups at the Day 330 time point. No formal hypothesis testing is planned.  
12.4.3 
Handling of remaining intercurrent events of primary estimand 
No remaining intercurrent events are expected. 
12.4.4 
Handling of missing values not related to intercurrent event 
The primary endpoint will not have missing data imputed. Only data from the Day 330 visit 
time point and baseline data needed to evaluate change from baseline in LDL-C will be included 
in the primary analysis. 
12.4.5 
Sensitivity analyses for primary endpoint/estimand 
No sensitivity analyses are planned. 
12.4.6 
Supplementary analysis 
Supplementary analyses of LDL-C percent change from baseline to Day 330 may be performed 
in select subgroups.  
Details of any supplementary analyses that will be performed, including subgroups included in 
this analysis, will be specified in the SAP. 
12.4.7 
Supportive analyses 
A linear mixed-effects model for repeated measures (MMRM) analysis will be used as a 
covariate-adjusted analysis of the difference in percent change from baseline to Day 330 in 
LDL-C. The MMRM will include fixed effects for treatment, visits, interaction between 


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treatment and visits, and baseline LDL-C. The Restricted Maximum Likelihood (REML) 
estimation approach will be used with covariance structure set as "Unstructured". Two-sided 
95% confidence intervals for the difference between treatment groups will be provided. Full 
details of the supportive analysis will be provided in the SAP. 
12.5 
Analysis of secondary endpoints/estimands 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) 
Secondary efficacy endpoints include: 
• Time-adjusted percent change in LDL-C from baseline after Day 90 and up to Day 330 
(Year 1) 
• Percent change and absolute change in LDL-C from baseline to each assessment time up 
to Day 720 (Year 2) 
• Percent change and absolute change in Apo B from baseline to each assessment time up to 
Day 720 (Year 2) 
• Percent change and absolute change in Lp(a) from baseline to each assessment time up to 
Day 720 (Year 2) 
• Percent change and absolute change in non-HDL-C from baseline to each assessment time 
up to Day 720 (Year 2) 
• Percent change and absolute change in total cholesterol from baseline to each assessment 
time up to Day 720 (Year 2) 
• Percent change and absolute change in triglycerides from baseline to each assessment time 
up to Day 720 (Year 2) 
• Percent change and absolute change in HDL-C from baseline to each assessment time up 
to Day 720 (Year 2) 
• Percent change and absolute change in VLDL-C from baseline to each assessment time up 
to Day 720 (Year 2) 
• Percent change and absolute change in Apo A1 from baseline to each assessment time up 
to Day 720 (Year 2) 
• Percent change and absolute change in PCSK9 from baseline to each assessment time up 
to Day 720 (Year 2) 
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. 


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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. 
• 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. 






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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 
References are available upon request 
Baigent C, Keech A, Kearney PM, et al (2005) Efficacy and safety of cholesterol-lowering 
treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials 
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Barkas F, Liberopoulos EN, Kostapanos MS, et al (2015) Lipid target achievement among 
patients with very high and high cardiovascular risk in a lipid clinic. Angiology; 66(4):346-
53. 
Bertolini S, Pisciotta L, Rabacchi C, et al (2013) Spectrum of mutations and phenotypic 
expression in patients with autosomal dominant hypercholesterolemia identified in Italy. 
Atherosclerosis; 227: 342–348. 
Blom DJ, Harada-Shiba M, Rubba P, et al (2020) Efficacy and safety of Alirocumab in adults 
with Homozygous Familial Hypercholesterolemia: The ODYSSEY HoFH Trial. J Am Coll 
Cardiol; 76(2):131-42. 
Casula M, Tragni E, Catapano AL (2012) Adherence to lipid-lowering treatment: the patient 
perspective. Patient Prefer Adherence; 6:805-14. 
Clinical Trials Facilitation and Coordination Group CTFG (2020). Recommendations related 
to contraception and pregnancy testing in clinical trials. Version 1.1. (Online): 
https:www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2020_09_HMA_CTFG_Contraception_guidance_Vers
ion_1.1_updated.pdf (Accessed 15-Feb-2023). 
Cuchel M, Bruckert E, Ginsberg HN (2014) Homozygous familial hypercholesterolaemia: 
new insights and guidance for clinicians to improve detection and clinical management. A 
position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European 
Atherosclerosis Society. Eur Heart J; 35:2146-57. 
Davidson MH, Maki KC, Pearson TA, et al (2005) Results of the National Cholesterol 
Education (NCEP) Program Evaluation ProjecT Utilizing Novel E-Technology (NEPTUNE) 
II survey and implications for treatment under the recent NCEP Writing Group 
recommendations. Am J Cardiol; 96:556-63. 
Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in 
Children and Adolescents; National Heart, Lung, and Blood Institute (2011) Expert Panel on 
Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and 
Adolescents: Summary Report. Pediatrics; 128 Supp 5:S213-S256. 
Ference BA, Ginsberg HN, Graham I, et al (2017) Low-density lipoproteins cause 
atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical 
studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. 
Eur Heart J; 38(32):2459-72. 
Fitzgerald K, White S, Borodovsky A, et al (2017) A Highly Durable RNAi Therapeutic 
Inhibitor of PCSK9. N Engl J Med; 376(1):41-51. 


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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 
prespecified secondary analysis of the FOURIER trial. Lancet; 390:1962-71. 
Go AS, Mozaffarian D, Roger VL, et al (2014) Heart disease and stroke statistics-2014 
update: a report from the American Heart Association. Circulation; 129:e28-e292. 
Grundy SM, Cleeman JI, Bairey Merz CN, et al (2004) Implications of recent clinical trials 
for the National Cholesterol Education Program Adult Treatment Panel III guidelines. 
Circulation; 110:227-39.  
Howie SRC (2011) Blood sample volumes in child health research: review of safe limits. Bull 
World Health Organ; 89:46-53. 
ICH Harmonized Guideline Addendum to ICH E11 (2017) Clinical investigation of medicinal 
products in the pediatric population E11 (R1). (Internet) Available from: 
database.ich.org/sites/default/files/E11_R1_Addendum.pdf (Accessed 10 Jun 2020). 
Jameson K, Zhang Q, Zhao C, et al (2014) Total and low-density lipoprotein cholesterol in 
high-risk patients treated with atorvastatin monotherapy in the United Kingdom: analysis of a 
primary-care database. Curr Med Res Opin; 30(4):655-65. 
Jones PH, Nair R, Thakker KM (2012) Prevalence of dyslipidemia and lipid goal attainment 
in statin treated participants from 3 data sources: a retrospective analysis. J Am Heart Assoc.; 
1(6):e001800. 
Khvorova A (2017) Oligonucleotide Therapeutics - A New Class of Cholesterol-Lowering 
Drugs. N Engl J Med; 376(1):4-7. 
Kolansky DM, Cuchel M, Clark BJ, et al (2008) Longitudinal evaluation and assessment of 
cardiovascular disease in patients with homozygous familial hypercholesterolemia. Am J 
Cardiol; 102:1438-43. 
Lakoski SG, Lagace TA, Cohen JC, et al (2009) Genetic and metabolic determinants of 
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 
Food and Drug Administration Amendments Act of 2007. JAMA Pediatr; 167(10):926-32. 
Moorjani S, Roy M, Torres A, et al (1993) Mutations of low-density-lipoprotein-receptor 
gene, variation in plasma cholesterol, and expression of coronary heart disease in homozygous 
familial hypercholesterolaemia. Lancet; 341:1303-6. 
Mousavi SA, Berge KE, and Leren TP (2009) The unique role of proprotein convertase 
subtilisin/kexin 9 in cholesterol homeostasis. J Intern Med; 266(6):507-19. 
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Diagnosis, and Management. Cardiol Ther; 4(1):25-38. 
Nordestgaard BG, Chapman MJ, Humphries SE, et al (2013) Familial hypercholesterolaemia 
is underdiagnosed and undertreated in the general population: guidance for clinicians to 
prevent coronary heart disease : Consensus Statement of the European Atherosclerosis 
Society. Eur Heart J; 34(45):3478-90. 


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Raal FJ, Kallend D, Ray KK, et al (2020) Inclisiran for the Treatment of Heterozygous 
Familial Hypercholesterolemia. N Engl J Med; 382(16):1520-30. 
Ray KK, Stoekenbroek RM, Kallend D, et al (2019) Effect of 1 or 2 Doses of Inclisiran on 
Low-Density Lipoprotein Cholesterol Levels: One-Year Follow-up of the ORION-1 
Randomized Clinical Trial. JAMA Cardiol; 4(11):1067-75. 
Ray KK, Wright RS, Kallend D, et al (2020) Two Phase 3 Trials of Inclisiran in Patients with 
Elevated LDL Cholesterol. N Engl J Med; 382(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 
management of anaphylaxis: summary report. J Allergy Clin Immunol; 115(3):584-91. 
Sampson HA, Munoz-Furlong A, Campbell RL, et al (2006) Second symposium on the 
definition and management of anaphylaxis: summary report – Second National Institute of 
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Clin Immunol; 117(2):391-7. 
Santos RD, Gidding SS, Hegele RA, et al (2016) Defining Severe Familial 
Hypercholesterolaemia and the Implications for Clinical Management: A Consensus 
Statement From the International Atherosclerosis Society Severe Familial 
Hypercholesterolemia Panel. Lancet Diabetes Endocrinol; 4:850-61. 
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Stone NJ, Robinson JG, Lichtenstein AH, et al (2014) 2013 ACC/AHA Guideline on the 
Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. A 
Report of the American College of Cardiology/American Heart Association Task Force on 
Practice Guidelines. Circulation; 129 Supp 2:S1-S45. 
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Hypercholesterolemia patients with identical mutations variably express the LDLR (Low-
Density Lipoprotein Receptor): Implications for the efficacy of Evolocumab. Arterioscler 
Thromb Vasc Biol; 38(3):592-8. 
Varghese MJ (2014) Familial hypercholesterolemia: A review. Ann Pediatr Card; 7(2):107-
17. 
WHO (2017) World Health Organization Cardiovascular diseases. (Internet) Available from: 
who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds) (Accessed 03 Jun 2020). 
Wiegman A, Gidding SS, Watts GF, et al (2015) Familial hypercholesterolaemia in children 
and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J; 
36:2425-37. 
Wilemon KA, Patel J, Aguilar-Salinas C, et al (2020) Reducing the Clinical and Public Health 
Burden of Familial Hypercholesterolemia: A Global Call to Action. JAMA Cardiol; 5(2):217-
29. 


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Youngblom E, Pariani M, and Knowles JW (2016) Familial Hypercholesterolemia. Initial 
posting: January 2, 2014; last update: December 8, 2016. In: Pagon RA, Adam MP, Ardinger 
HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, 
Seattle; 1993-2016. Available from: ncbi.nlm.nih.gov/books/NBK174884/ (Accessed 27 Jan 
2020). 


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16 
Appendices 
16.1 
Appendix 1: Diagnostic criteria for HoFH 
Participants with a genetic diagnosis of HoFH by the following genotype criteria are 
eligible: 
• Documented homozygous or compound heterozygous mutations in both LDLR alleles 
• Note: Participants with known null (negative) mutations in both LDLR alleles, i.e. 
double null (negative), are not eligible (see Section 5.2 exclusion criteria) 
• Presence of homozygous or compound heterozygous mutations in Apo B, PCSK9, or low 
density lipoprotein receptor adaptor protein 1 (LDLRAP1) 
• Presence of double heterozygous mutations (i.e. mutations in different genes) in the LDLR, 
Apo B, PCSK9, or LDLRAP1 alleles (e.g. LDLR/PCSK9) 


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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  
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 
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 


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ALT or AST 
Total bilirubin 
Liver 
Symptoms 
Action 
ALT or AST increase with bilirubin increase: 
• Study drug can be restarted 
only if another etiology is 
identiﬁed and liver enzymes 
return to baseline 
  
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) 
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 


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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  


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


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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 Homozygous 
Familial Hypercholesterolemia and Elevated LDL-cholesterol 
(ORION-13)
NCT Number: 
 NCT04659863 
Document Date: 
Statistical Analysis Plan (Amendment 4): 20-Nov-2024


Appendix 16.1.9
Documentation of statistical methods
 
History of changes
Version
Summary of changes
1.0
Original version
1
Statistical methods
The most recent version of Statistical Analysis Plan (SAP) is included below. 
 
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Clinical Development
KJX839/inclisiran
CKJX839C12302 / NCT04659863
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 homozygous familial 
hypercholesterolemia and elevated LDL-cholesterol (ORION-13)
Statistical Analysis Plan (SAP)
Author:
Trial statistician
Document type:
SAP Documentation
Document status:
Amendment 4
Release date:
20-Nov-2024
Number of pages:
36
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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Date
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title impacted 
(Current)
 
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Date
Time 
point
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update
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title impacted 
(Current)
20-Nov-
2024 
Amendment 
4
Prior 
to final 
DB 
lock
Reason for 
update
Outcome for update
Section 
impacted 
 
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Date
Time 
point
Reason for 
update
Outcome for update
Section and 
title impacted 
(Current)
 
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Table of contents
Table of contents..................................................................................................................7
List of tables.........................................................................................................................9
List of figures.......................................................................................................................9
List of abbreviations ..........................................................................................................10
1
Introduction........................................................................................................................12
1.1
Study design...........................................................................................................12
1.2
Study objectives and endpoints..............................................................................13
2
Statistical methods .............................................................................................................14
2.1
Data analysis general information..........................................................................14
2.1.1
General definitions ................................................................................15
2.2
Analysis sets...........................................................................................................17
2.2.1
Subgroup of interest ..............................................................................17
2.3
Disposition, demographics and other baseline characteristics...............................18
2.3.1
Disposition.............................................................................................18
2.3.2
Demographics and other baseline characteristics..................................18
2.3.3
Medical history/current medical condition............................................18
2.4
Treatments (study treatment, prior and concomitant therapies) ............................18
2.4.1
Study treatment......................................................................................19
2.4.2
Prior, concomitant and post therapies ...................................................19
2.5
Analysis of the primary objective..........................................................................20
2.5.1
Primary endpoint ...................................................................................20
2.5.2
Statistical hypothesis, model, and method of analysis ..........................20
2.5.3
Handling of remaining intercurrent events of primary estimands.........21
2.5.4
Handling of missing values not related to intercurrent event................21
2.5.5
Sensitivity analyses for primary endpoint/estimand..............................21
2.5.6
Supplementary analysis.........................................................................21
2.6
Analysis of the secondary objectives.....................................................................21
2.6.1
Secondary endpoints..............................................................................21
2.6.2
Statistical hypothesis, model, and method of analysis ..........................22
2.6.3
Sensitivity analyses for secondary endpoint/estimand..........................22
2.6.4
Supplementary analysis.........................................................................22
2.7
Safety analyses.......................................................................................................22
2.7.1
Adverse events (AEs)............................................................................22
2.7.2
Deaths....................................................................................................25
2.7.3
Laboratory data......................................................................................25
 
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2.7.4
Diabetes assessment ..............................................................................26
2.7.5
Vital signs..............................................................................................29
2.7.6
Immunogenicity.....................................................................................29
2.7.7
Other safety evaluation..........................................................................30
30
2.9
Biomarkers.............................................................................................................30
30
2.11
Interim analysis......................................................................................................31
3
Sample size calculation......................................................................................................31
4
Change to protocol specified analyses...............................................................................31
5
Appendix............................................................................................................................32
5.1
Imputation rules .....................................................................................................32
5.1.1
Study drug .............................................................................................32
5.1.2
AE date imputation................................................................................32
5.1.3
Concomitant medication date imputation..............................................32
5.2
AEs coding/grading................................................................................................32
5.3
Analyses to be performed in Part 1 analysis (ANA1) and Part 2 analysis 
(ANA2) ..................................................................................................................32
5.4
Search criteria for other safety topics ....................................................................33
5.5
Laboratory parameters derivations.........................................................................33
5.6
Vital signs – definition of clinically notable values...............................................35
5.7
Statistical models ...................................................................................................35
5.8
Rule of exclusion criteria of analysis sets..............................................................35
6
Reference ...........................................................................................................................36
 
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List of tables
Table 1-1
Objectives and related endpoints...........................................................13
Table 2-1
Visit mapping ........................................................................................16
Table 5-1
Clinical notable criteria for selected laboratory tests ............................34
Table 5-2
Notable liver function test values..........................................................34
Table 5-3
Clinical notable criteria for vital signs ..................................................35
List of figures
Figure 1-1
Study design ..........................................................................................13
 
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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
HoFH
Homozygous Familial Hypercholesterolemia 
ISR
Injection site reaction
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 analysis set
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SCR
Screened set
SD
Standard deviation
SOC
System Organ Class
 
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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 CKJX839C12302 (ORION-13). The purpose of this Phase 3 study is to evaluate safety, 
tolerability, and efficacy of inclisiran in adolescents (aged 12 to <18 years) with homozygous 
familial hypercholesterolemia HoFH and elevated LDL-C (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 HoFH 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-13 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 HoFH 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 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.
Approximately 12 participants 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). 
Information regarding sample size calculation is provided in Section 3.
 
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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, 
 
objectives.
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 evaluate 
the effect of inclisiran compared to 
placebo on reducing LDL-C [percent 
change] at Day 330 (Year 1) in 
adolescents (aged 12 to <18 years) 
with HoFH 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)
•
Evaluate the effect of inclisiran 
compared to placebo on 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)
•
Evaluate the effect of inclisiran 
compared to placebo (for Year 1) and 
•
Percent change and absolute change in LDL-C, 
Apo B, lipoprotein (a) [Lp(a)], non-high density 
 
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Objective(s)
Endpoint(s)
long-term (up to Day 720), on 
lowering LDL-C, other lipoprotein and 
lipid parameters, and PCSK9 over 
time
lipoprotein cholesterol (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 of 
inclisiran compared to placebo (for 
Year 1) and long-term (up to Day 
720), in adolescents (aged 12 to <18 
years) with HoFH
•
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)
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 screening visit up to the day 360 visit 
date prior to dosing day/date. Part 1 data will be presented by two separate groups (inclisiran 
 
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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 are defined as 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 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 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 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. 
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.
 
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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.
LDL-C to be used in analysis
The endpoints involving LDL-C will use the beta quantification (ultracentrifugation) LDL-C 
for all subjects. In cases where beta quantification (ultracentrifugation) LDL-C values are 
missing and calculated LDL-C is available, the calculated LDL-C will be used for analysis 
purposes.
VLDL-C
The endpoints involving VLDL-C will use the beta quantification (ultracentrifugation) VLDL-
C for all subjects. In cases where beta quantification (ultracentrifugation) VLDL-C values are 
missing and calculated VLDL-C is available, the calculated VLDL-C will be used for analysis 
purposes.
Discontinuation visit mapping
For patients who discontinued 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:
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 
 
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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 
Day 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, 
 efficacy 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. 
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 in study Part 
2 and received at least one dose of study treatment 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
No sub-group analysis will be performed.
 
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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 Part1 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 HoFH 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 SBP, DBP, 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.
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 and preferred term, 
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.
 
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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 
the 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 for treatment 
discontinuation. Listing will also be provided.
2.4.2
Prior, concomitant and post therapies
Prior (pre- baseline, defined as any medication that was stopped ≥1 day before first dose date 
of study medication) medication will be summarized by treatment and concomitant (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) medications 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
•
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.
 
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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 evaluate the effect of inclisiran compared to placebo on reducing 
LDL-C [percent change] at Day 330 (Year 1) in adolescents (aged 12 to <18 years) with HoFH 
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 HoFH 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 HoFH, if they occur, as would be 
the case in clinical practice. 
The primary estimand is described by the following attributes:
•
Population: Adolescents with the HoFH 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.
•
Endpoint: Percentage change in LDL-C from baseline to Day 330 (Year 1)
•
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 
HoFH. The type and dose of the concomitant lipid-lowering therapy for HoFH 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].
•
The summary measure: difference between treatments in mean percentage change at 
Day 330.
2.5.2
Statistical hypothesis, model, and method of analysis
The primary analysis will summarize change from baseline using summary statistics to 
characterize change from baseline in LDL-C by treatment group and the difference between 
treatment groups along with 95% CI at the Day 330 time point. No formal hypothesis testing is 
 
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planned. The individual patients' data on the percentage change in LDL-C from baseline at Day 
330 will be listed and depicted by waterfall plots. 
2.5.3
Handling of remaining intercurrent events of primary estimands
No remaining intercurrent events are expected.
2.5.4
Handling of missing values not related to intercurrent event
The primary endpoint will not have missing data imputed. Only data from the Day 330 visit 
time point and baseline data needed to evaluate change from baseline in LDL-C will be included 
in the primary analysis.
2.5.5
Sensitivity analyses for primary endpoint/estimand
Since the sample size is small, in case of sparse data, median percentage change from baseline 
to Day 330 in LDL-C will be considered.
2.5.6
Supplementary analysis
A linear mixed-effects model for repeated measures (MMRM) analysis will be used as a 
covariate-adjusted analysis of the difference in percent change from baseline to Day 330 in 
LDL-C. 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, and baseline LDL-C 
as covariates. 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. Two-sided 95% 
confidence intervals for the difference between treatment groups will be provided.
The above supplementary analysis was planned but will not be performed due to the small 
sample size in the placebo group.
 
 Summary statistics by treatment groups and treatment difference 
along with 95% CI will be provided.
2.6
Analysis of the secondary objectives
2.6.1
Secondary endpoints
Secondary efficacy endpoints include:
•
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.
•
Percent change and absolute change in LDL-C，Apo B,  Lp(a),  non-HDL-C,  total 
cholesterol,  triglycerides,  HDL-C,  VLDL-C,  Apo A1, and PCSK9 from baseline to each 
assessment time up to Day 720 (Year 2)
 
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2.6.2
Statistical hypothesis, model, and method of analysis
Descriptive summaries by treatment group will be presented for all secondary endpoints. 
Additionally, mean treatment difference and associated 95% CI will be provided for time-
adjusted percentage change in LDL-C from baseline after Day 90 and up to Day 330, for 
absolute change in LDL-C at Day 330 and for percentage change in Apo B, Lp(a), non-HCL-
C, total cholesterol and PCSK9 at Day 330. No formal hypothesis testing will be performed. 
Summaries of LDL-C by treatment, visit and subject will be additionally presented. Listings 
will be provided. 
2.6.3
Sensitivity analyses for secondary endpoint/estimand
Since the sample size is small, in case of sparse data, median percentage change from baseline 
to Day 330 will be considered.
2.6.4
Supplementary analysis
 
 Summary statistics by treatment groups and treatment 
difference will be provided for time-adjusted percentage change in LDL-C from baseline after 
Day 90 and up to Day 330 and for percentage change in Apo B, non-HCL-C, total cholesterol 
and PCSK9 at Day 330 and Day 720. 
2.7
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 adverse events (AEs) that started on or after the first dose of double-blind 
treatment or adverse events (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 by visit/time point summary.
2.7.1
Adverse events (AEs)
The number (and percentage) of participants with TEAEs will be summarized by Part in the 
following ways:
•
Overall summary.
 
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•
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  >=15% 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.
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 database 
lock) and on TEAEs and SAEs suspected to be related to study treatment will be provided by 
system organ class and preferred term for 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.
 
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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 participants 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.
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 within 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. Listings 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 AEs of other safety topics, refer to Appendix 5.4.
For detailed analysis of new onset diabetes and worsening of glycemic control, please see 
Section 2.7.4. Any immune-related events will be identified in the SOC of immune system 
disorders.
 
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The percentage of participants with abnormal ECG findings reported as AEs will be 
summarized by treatment group and Part.
2.7.2
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.
2.7.3
Laboratory data
Laboratory data consist of hematology, biochemistry, sexual hormones, urinalysis 
measurements and ADA (see Section 2.7.6 ). 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 are applied) will be used to compare baseline to the worst 
on-treatment value by treatment group and Part. All data collected 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 subjects were 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 visits. 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.
 
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2.7.4
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
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% 
 
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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. 
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% 
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%
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% 
 
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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:
•
No medical history of diabetes.
•
HbA1c < 5.7% AND fasting plasma glucose < 100 mg/dL at baseline.
 
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•
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. 
2.7.5
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.
2.7.6
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.
In addition, further ADA details will be assessed and will be listed in a separate ADA report. If 
applicable, additional analyses may be conducted.
 
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2.7.7
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 assessment 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, missing menarche data will be 
imputed to yes if the previous assessment was yes for menarche.
  
 
 
 
 
 
 
 
 
 
 
2.9
Biomarkers
Analyses of PCSK9 and lipids/lipoproteins are discussed in Section 2.6. No additional 
biomarkers will be evaluated in this study.
 
 
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2.11
Interim analysis
Interim 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 for this study was selected based on feasibility. 
4
Change to protocol specified analyses
No change from protocol specified analysis was made.
 
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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.
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
Overall: 
Part 1 & Part 2 combined 
Disposition
ANA1
ANA2
Protocol 
Deviations
ANA1
ANA2
Demography and 
baseline 
characteristics 
ANA1
Medical History
ANA1
Prior therapies 
(Including lipid 
modifying 
therapy 
ANA1
Concomitant 
therapies**
ANA1
ANA2
SAF for 
ANA1;
 
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(Including lipid 
modifying 
therapy 
OAS for 
ANA2.
CM will be 
counted in 
both parts 
when 
starting from 
part 1 and 
continuing 
to part 2
Doses, Duration 
on study, 
Exposure
ANA1
ANA2
For exposure
Efficacy (Primary 
endpoint & 
secondary 
endpoints)
ANA1
Efficacy 
(secondary 
endpoints)
ANA1
ANA2
For some selected efficacy 
parameters
AEs**
ANA1
ANA2
SAF for 
ANA1；
OAS for 
ANA2.
Diabetes 
assessment 
ANA1
ANA2
SAF for 
ANA1；
OAS for 
ANA2.
Lab and Vital 
signs 
ANA1
ANA2
SAF for 
ANA1；
OAS for 
ANA2.
5.4
Search criteria for other safety topics
The most recent eCRS available during database lock will be used.
5.5
Laboratory parameters derivations
The following table shows the criteria for clinically notable laboratory values. Not all 
parameters have notable criteria defined:
 
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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%
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
 
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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
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. 
5.6
Vital signs – definition of clinically notable values
The following table show the clinical notable criteria for vital signs.
Table 5-3
Clinical notable criteria for vital signs 
Age
SBP [mmHg]
DBP [mmHg]
HR [min-1]
≥12 years
< 90, > 145
< 55, > 90
< 45, > 95
5.7
Statistical models
No additional details to be discussed.
5.8
Rule of exclusion criteria of analysis sets 
The protocol deviations (PD) and other criteria leading to complete exclusion from analyses 
sets will be included in this section and will be finalized before study DBL.
 
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Reference
Cuchel M, Raal FJ, Hegele RA, et al (2023) 2023 Update on European Atherosclerosis 
Society Consensus Statement on Homozygous Familial Hypercholesterolaemia: new 
treatments and clinical guidance. Eur Heart J; 44: 2277-2291.
 
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Clinical Study Report Appendix 16.1.9, v1.0
Study No. CKJX839C12302