Clinical trial NCT03851705
Conditions: Homozygous Familial Hypercholesterolemia
Keywords: HoFH
Sponsor: Novartis Pharmaceuticals
Start date: 2019-02-06; Completion date: 2021-09-09
Enrollment: 56 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study was a Phase III,A two-part (double-blind placebo-controlled/open-label) multicenter study to evaluate safety, tolerability, and efficacy of inclisiran in subjects with homozygous familial hypercholesterolemia (HoFH).

Detailed description:
This study had two sequential parts:

* Part 1: 6-month double-blind period in which subjects were randomized to receive either inclisiran or placebo
* Part 2: 18-month open-label follow-up period; placebo-treated subjects from Part 1 were transitioned to inclisiran at Day 180 and all subjects who participated in an open-label follow-up period of inclisiran only

Arms: arm 1: Participants who received a dose of 300 milligram (mg) inclisiran sodium for injection administered by SC injection on Day 1 and Day 90. arm 2: Participants who received a dose of placebos administered by SC injection on Day 1 and Day 90. arm 3: Participants who received a dose of 300 mg inclisiran sodium for injection administered by SC injection on Day 270, Day 450 and Day 630. In addition, participants who were assigned to the placebo arm in Part 1 will receive a dose of 300 mg inclisiran sodium administered by SC injection on Day 180 after completion of Part 1.
Interventions: intervention 1: Inclisiran Sodium for injection intervention 2: Placebo intervention 3: Placebos
Intervention descriptions: intervention 1: Inclisiran is a synthetic, chemically modified small interfering ribonucleic acid (siRNA) targeting proprotein convertase subtilisin kexin type 9 (PCSK9) messenger ribonucleic acid (mRNA) with a covalently attached triantennary N-acetylgalactosamine (GalNAc) ligand. intervention 2: Sterile normal saline (0.9% sodium chloride in water for injection) intervention 3: Sterile normal saline (0.9% sodium chloride in water for injection)

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development
KJX839/Inclisiran
Clinical Trial Protocol MDCO-PCS-17-02 (CKJX839A12302) / 
NCT03851705
A two-part (double-blind placebo-controlled/open-label) 
multicenter study to evaluate safety, tolerability, and 
efficacy of Inclisiran in subjects with homozygous 
familial hypercholesterolemia (HoFH)
ORION-5
Document type:
Amended Protocol Version
EUDRACT number:
2018-000893-31
Version number:
01 (Clean)
Clinical Trial Phase:
III
Release date:
08-Oct-2020 (content final)
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Amended Protocol Version 01 (Clean)
Protocol No. MDCO-PCS-17-02 (CKJX839A12302)
Protocol Synopsis
Name of Sponsor/Company: Novartis
Name of Finished Product: Inclisiran for Injection (also referred to as KJX839)
Name of Active Ingredient: inclisiran sodium
Title of Study: A two-part (double-blind placebo-controlled/open-label) multicenter study to evaluate 
safety, tolerability, and efficacy of inclisiran in subjects with homozygous familial hypercholesterolemia 
(HoFH).
Phase of Development: III
Study Centers: Multicenter study
Central Facilities: This list is maintained by the Sponsor
Number of Subjects: At least 45 subjects; subjects randomized 2:1 to inclisiran: placebo.
Principal Investigator: Prof. 
 South Africa:
Study Period: The estimated study period will be approximately 30 months from first subject enrolled in 
the study to last subject completed. This two-part study will include a 6-month double-blind placebo-
controlled period to assess the safety, tolerability, and efficacy followed by an 18-month open-label single 
arm follow-up period.
Objectives:
Primary
The primary objective is to evaluate the effect of inclisiran treatment on:

Low-density lipoprotein cholesterol (LDL-C) levels at Day 150
Secondary
The secondary objectives are to evaluate the effect of inclisiran on:

LDL-C levels over time

Proprotein convertase subtilisin/kexin type 9 (PCSK9) levels over time

Other lipids, lipoproteins, and apolipoproteins

Individual responsiveness of subjects to inclisiran including proportion of subjects achieving 
prespecified global lipid guidelines for their indication

Proportion of subjects with at least 30% LDL-C reduction from Day 1 over time
and to assess the

Safety and tolerability profile of inclisiran
 
 
 
Methodology:
Hypotheses: The primary hypothesis is that inclisiran, when used in combination with maximally 
tolerated statin therapy with or without ezetimibe, will be well-tolerated, will suppress PCSK9 synthesis 
assessed by the reduction in circulating PCSK9 >50% and will result in reduction of LDL-C, defined as 
mean percent change of >20% from Day 1 to Day 150 in subjects with HoFH.


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Amended Protocol Version 01 (Clean)
Protocol No. MDCO-PCS-17-02 (CKJX839A12302)
Study Design: This study will be a Phase III, two-part (double-blind placebo-controlled/open-label) 
multicenter study to evaluate safety, tolerability, and efficacy in subjects with HoFH. This study has two 
sequential parts:

Part 1: 6-month double-blind period in which subjects will be randomized to receive either inclisiran or 
placebo

Part 2: 18-month open-label follow-up period; placebo-treated subjects from Part 1 will be transitioned 
to inclisiran and all subjects will participate in an open-label follow-up period of inclisiran only
Informed consent will be obtained from subjects before the initiation of any study-specific procedures.
Subjects who meet study inclusion/exclusion criteria will be instructed to continue to follow a National 
Cholesterol Education Program Adult Treatment Panel III (or comparable) diet and be required to 
maintain their current lipid lowering drug therapy for the duration of the study.
In this study, at least 45 subjects will be enrolled and randomized 2:1 to receive either inclisiran 300 mg 
SC or placebo on Day 1. Inclisiran and placebo will both be administered by a health care provider. 
Subjects will be observed in the clinic for at least 30 minutes post injection before being discharged. A 
second dose of inclisiran or placebo will be given at Day 90. After completion of Part 1, the inclisiran-
treated subjects from Part 1 will receive a third dose of inclisiran administered on Day 270 and 
subsequent doses on Day 450 and Day 630. The placebo-treated subjects from Part 1 will be transitioned 
to inclisiran starting on Day 180 and the study will then transition to an open-label, single arm follow-up 
period of inclisiran only (Part 2). Placebo-treated subjects will receive their first dose of inclisiran on 
Day 180 and then subsequently receive a dose of inclisiran on Day 270, Day 450 and Day 630.
Subjects on a documented regimen of LDL or plasma apheresis will be allowed to continue their same 
regimen during the study using approximately the same frequency/timing as done at baseline. When 
apheresis is performed during a study visit (Dosing or Non-Dosing), blood samples for measurement of 
LDL-C, other lipids and laboratory assessments must be collected before the apheresis. When apheresis 
is performed during a Dosing Visit, dosing must occur just after completion of the apheresis. The next 
scheduled apheresis must not occur within 72 hours of injection of inclisiran. The subsequent study visit 
must occur at least 2 weeks after an apheresis was performed to ensure LDL-C levels measured during a 
study visit are not confounded by the apheresis (see Figure 3-2 for details).
Safety results including adverse events (AEs), serious adverse events (SAEs), electrocardiograms 
(ECGs), concomitant medications, and clinical laboratory parameters will be assessed at specified visits 
through to the end of study (EOS) visit. All AEs must be reported. Adverse events or abnormal test 
findings will be followed until the event (or its sequelae) or the abnormal test finding resolves, stabilizes at 
a level acceptable to the Sponsor/Investigator and/or returns to baseline values. Other safety related 
information that should be reported as AEs include injection site reactions, neurological and psychiatric 
events, potential anaphylactic/hypersensitivity reactions, new onset of diabetes, and worsening of 
glycemic control.
Samples to detect formation of ADA (including binding and neutralizing antibodies) will be collected on 
Day 1 (prior to the injection) and at Day 90, Day 330, and Day 720.
The primary endpoint will be measured at Day 150 after which placebo-treated subjects will be 
transitioned to inclisiran on Day 180. All subjects will be enrolled in a long-term open-label follow-up 
period through Day 720 (EOS).
Efficacy (pharmacodynamic) assessments will include measurement of the effects of inclisiran on levels 
of LDL-C, other lipoproteins including total cholesterol (TC), triglycerides, high density lipoprotein 
cholesterol (HDL-C), non-HDL-C, very low density lipoprotein cholesterol (VLDL-C), apolipoprotein A1 
(Apo-A1), apolipoprotein B (Apo-B), lipoprotein(a) [Lp(a)], and PCSK9. LDL-C is analyzed by beta-
quantification (BQ) on Day 1, Day 150 and Day 720, and calculated using the Friedewald method on all 
visit days.
The safety and tolerability data from the double blind and open label part of the study will be reviewed by 
an Independent Data Monitoring Committee IDMC) at pre-defined frequency. A recommendation will be 
made to continue, stop, or amend the study at any of these reviews.
 


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Amended Protocol Version 01 (Clean)
Protocol No. MDCO-PCS-17-02 (CKJX839A12302)
Diagnosis and Main Criteria for Selection:
Subjects may be included if they meet all of the following inclusion criteria:
1. Males and females, ≥18 years of age with a diagnosis of HoFH by genetic confirmation or a clinical 
diagnosis based on a history of an untreated LDL-C concentration >500 mg/dL (13 mmol/L) together with 
either xanthoma before 10 years of age or evidence of heterozygous familial hypercholesterolemia in 
both parents (see Appendix A)
2. Stable on a low-fat diet
3. Subjects on statins should be receiving a maximally tolerated dose. Maximum tolerated dose is 
defined as the maximum dose of statin that can be taken on a regular basis without intolerable adverse 
events. Intolerance to any dose of any statin must be documented as historical AEs attributed to the 
statin in question in the source documentation and on the Medical History page of the electronic case 
report form (eCRF) (see Appendix B)
4. Subjects not receiving statins must have documented evidence of intolerance to at least two different 
statins (see Appendix B)
5. Subjects on lipid-lower therapies (such as statin and/or ezetimibe) should be on a stable dose for ≥30 
days before screening with no planned medication or dose change during study participation
6. Fasting central laboratory LDL-C concentration ≥130 mg/dL (3.4 mmol/L)
7. Triglyceride concentration <400 mg/dL (4.5 mmol/L)
8. No current or planned renal dialysis or renal transplantation
9. Subjects on a documented regimen of LDL or plasma apheresis will be allowed to continue the 
apheresis during the study, if needed. The apheresis schedule should be maintained as deemed 
necessary and dosing should be scheduled to be done after apheresis. Administration of study drug 
should always occur at least 2 days following apheresis. Note: after implementation of protocol 
amendment 1, administration of study drug must either occur right after apheresis on the day of the study 
visit or at least 2 weeks following the last apheresis (see Figure 3-2).
10. Subjects must be willing and able to give written informed consent before initiation of any study-
related procedures. The subject should be willing to comply with all required study procedures
11. Willing to follow all study procedures including adherence to dietary guidelines, study visits, fasting 
blood draws, and compliance with study treatment regimens
Subjects will be excluded from the study if any of the following exclusion criteria apply prior to 
randomization:
1. Use of Mipomersen or Lomitapide therapy within 5 months of screening
2. Treatment (within 90 days of screening) with monoclonal antibodies directed towards PCSK9
3. New York Heart Association (NYHA) class IV heart failure or last known left ventricular ejection 
fraction <25%
4. Major adverse cardiovascular event within 3 months prior to randomization
5. Planned cardiac surgery or revascularization
6. Uncontrolled severe hypertension: systolic blood pressure >180 mmHg or diastolic blood 
pressure >110 mmHg prior to randomization despite anti-hypertensive therapy
7. Active liver disease defined as any known current infectious, neoplastic, or metabolic pathology of the 
liver or unexplained alanine aminotransferase (ALT), aspartate aminotransferase (AST), elevation >3x 
ULN, or total bilirubin >2x upper limit of normal (ULN) at screening confirmed by a repeat measurement at 
least 1 week apart
8. Severe concomitant noncardiovascular disease that carries the risk of reducing life expectancy to less
than the duration of the trial
9. History of malignancy that required surgery (excluding local and wide-local excision), radiation therapy 
and/or commencement of systemic therapy as treatment during the 3 years prior to randomization
10. Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use at 
least one acceptable effective method of contraception (eg, oral contraceptives, barrier methods, 
approved contraceptive implant, long- term injectable contraception, intrauterine device) for the entire 
duration of the study. Exemptions from this criterion:


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Amended Protocol Version 01 (Clean)
Protocol No. MDCO-PCS-17-02 (CKJX839A12302)
a.
Women >2 years postmenopausal (defined as 1 year or longer since their last menstrual period) 
AND more than 55 years of age
b.
Postmenopausal women (as defined above) and less than 55 years of age with a negative 
pregnancy test within 24 hours of enrolment
c.
Women who are surgically sterilized at least 3 months prior to enrolment
11. Known history of alcohol and/or drug abuse within 5 years
12. Any condition that according to the investigator could interfere with the conduct of the study, such as 
but not limited to:
a.
Subjects who are unable to communicate or to cooperate with the investigator.
b.
Unable to understand the protocol requirements, instructions and study-related restrictions, the 
nature, scope, and possible consequences of the study (including subjects whose cooperation is 
doubtful due to drug abuse or alcohol dependency)
c.
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)
d.
Have any medical or surgical condition, which in the opinion of the investigator would put the 
subject at increased risk from participating in the study
e.
Persons directly involved in the conduct of the study
13. 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 subject at significant risk (according to investigator’s 
[or delegate] judgment) if he/she participates in the clinical study
14. Any underlying known disease, or surgical, physical, or medical condition that, in the opinion of the 
Investigator (or delegate), might interfere with the interpretation of clinical study results
15. Treatment with other investigational medicinal products or devices within 30 days or 5 half-lives of the 
screening visit, whichever is longer
16. Previous participation in the study
17. Hypersensitivity to any of the ingredients of inclisiran
Test Product, Dose and Mode of Administration: Inclisiran sodium 300 mg (equivalent to 284 mg 
inclisiran) will be administered as a single SC injection (1.5 mL) on Day 1, Day 90, and then every 180 
days (Day 270, Day 450, and Day 630).
Duration of Treatment: The expected duration of the subjects’ participation in the study will be 
approximately 734 days which includes screening, investigational product administration, and the EOS 
period to Day 720.

Screening: Day -28 to -1

Randomization, initiation of investigational product: Day 1

Treatment Phase:

Dosing: Day 1 (inclisiran or placebo), Day 90 (inclisiran or placebo), Day 180 (placebo subjects 
switch to inclisiran), Day 270 (inclisiran), Day 450 (inclisiran), and Day 630 (inclisiran; final dose)

Additional clinic visits: Day 150, Day 180 (non-dosing visit for subjects randomized to the 
inclisiran arm), Day 330, Day 510, and Day 690

EOS visit: Day 720 (90 days after final dose)
Reference Therapy, Dose, and Mode of Administration: Placebo will be administered as a single SC 
injection (1.5 mL) on Day 1 and Day 90. On Day 180, placebo-treated subjects will transition to receive 
inclisiran.


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Amended Protocol Version 01 (Clean)
Protocol No. MDCO-PCS-17-02 (CKJX839A12302)
Criteria for Evaluation:
Efficacy:
The following endpoints will be examined:
Primary Endpoints:
Percent change in LDL-C from baseline to Day 150
Key Secondary Endpoint(s):

Absolute change in LDL-C from baseline to Day 150

Percentage change in Apo-B from baseline to Day 150.

Percentage change in non-HDL-C from baseline to Day 150.

Percentage change in total cholesterol from baseline to Day 150.

Proportion of subjects in each group with ≥30% LDL-C reduction from baseline at Day 150.
Other Secondary Endpoint(s):

Percentage change and absolute change in LDL-C from baseline to each assessment time up to Day 
720 (i.e., Days 90, 150, 180, 270, 330, 450, 510, 630, 690, and 720)

Percentage change and absolute change from baseline to Days 90, 150, 180, 330, 510, 690, and 720 
in PCSK9

Percentage change and absolute change from baseline to Days 150, 180, 330, 510, 690, and 720 in 
total cholesterol, Apo-B, and non-HDL-C for subjects receiving inclisiran

Individual responsiveness of subjects defined as the number of subjects reaching on treatment LDL-C 
levels of <25 mg/dL, <50 mg/dL, <70 mg/dL, and <100 mg/dL at Days 150, 180, 330, 510, 690, and 720 
including proportion of subjects in each group who attain global lipid targets for their indication

Proportion of subjects in each group with ≥ 20% or ≥30% LDL-C reduction from baseline at Days 150, 
180, 330, 510, 690, and 720

Absolute change and percentage change in other lipids, lipoproteins, apolipoproteins, and PCSK9 
from baseline at each subsequent visit to Day 720
 
 
 
 
Safety: AEs, SAEs, ECGs, vital signs, clinical laboratory values (hematology, glycated hemoglobin A1C 
[HbA1C], coagulation testing, chemistry, high sensitivity C-reactive protein (hsCRP), and urinalysis), 
formation and subsequent characterization of anti-drug antibodies (ADA), and results of neurological 
examinations will be collected at specified visits through to the EOS visit. Collection of AEs/SAEs will 
occur throughout the study at each study visit and all AEs must be reported. Adverse events or abnormal 
test findings will be followed until the event (or its sequelae) or the abnormal test finding resolves, 
stabilizes at a level acceptable to the Sponsor/Investigator and/or returns to baseline values. Other safety 
related information that should be reported as AEs include injection site reactions, neurological and 
psychiatric events, potential anaphylactic/hypersensitivity reactions, new onset of diabetes, and 
worsening of glycemic control.
Samples to detect formation of ADA (including binding and neutralizing antibodies) will be collected on 
Day 1 (prior to the injection) and at Day 90, Day 330, and Day 720.


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Protocol No. MDCO-PCS-17-02 (CKJX839A12302)
Statistical Methods:
Sample Size and Power:
The sample size calculation was performed with the hypothesis that the difference of mean percent 
change from baseline to Day 150 between inclisiran and placebo will be >20% (20% standard deviation) 
in subjects with HoFH when treated with inclisiran. The sample size of at least 45 subjects (randomized 
2:1 to inclisiran : placebo), with at least 30 subjects in the inclisiran arm, will provide >80% power to 
detect a 20% reduction of LDL-C levels from baseline in the inclisiran group compared to that in the 
placebo at one-sided significance level of 0.025 based on two-sample t-test.
Study Population:
Intent-to-Treat (ITT) population - All subjects randomized into the study will comprise the ITT population. 
Treatment classification will be based on the randomized treatment.
Safety Population – All subjects who received at least one dose of investigational product. Treatment 
classification will be based on the actual treatment received.
Modified Intent-to-Treat (mITT) Population – All randomized subjects who receive at least one dose of 
investigational product and have both the baseline and the 150 day follow-up LDL-C assessment will 
comprise the mITT population. Treatment classification will be based on the randomized treatment.
Unless specified otherwise, the ITT will be the primary analysis population for efficacy analysis and Safety 
population will be the primary population for safety analysis in this study. mITT population will be used to 
confirm the efficacy.
Statistical Analysis:
Statistical comparisons will only be performed for the Part 1 of the study. The statistical analysis for study 
Part 2 is descriptive.
Summary statistics for continuous variables will include the number of subjects, mean, median, standard 
deviation or standard error, minimum and maximum. For categorical variables, the frequency and 
percentage will be given.
The primary endpoint is the percent change from baseline in LDL-C following 150 days of treatment.
The primary analysis will be conducted using ANCOVA model based on the multiply imputed datasets 
(100 total) - Washout based approach. The ANCOVA model will include the fixed effect of treatment 
group (Inclisiran or placebo) and baseline LDL-C as a covariate. Treatment effects from these 100 
ANCOVA analyses will then be combined using Rubin’s method. The difference between treatment 
groups in mean change from baseline to Day 150 in LDL-C and corresponding two-sided 95% confidence 
interval will be provided. The p value for testing equal mean change from baseline to Day 150 in LDL-C 
will also be provided. For the key secondary endpoints, the efficacy analyses will be similar to the primary 
analysis of the primary efficacy endpoint, the ANCOVA model will be used on the multiply imputed 
datasets (100 total) - Washout based approach. Treatment effects from these 100 ANCOVA analyses will 
then be combined using Rubin’s method.
Additionally sensitivity analysis including MMRM on imputed data using PMM and without imputation will 
be performed for both primary and key secondary endpoints except for the endpoint of ≥30% LDL-C 
reduction from baseline to Day 150, which will be analyzed using the logistic regression model with 
treatment as the effect.
This study is sufficiently powered for the hypothesis testing in the primary and key secondary endpoints, 
all other endpoints are supportive hence no adjustment for multiplicity is planned.
Safety summaries will include the incidence of AEs, summaries of laboratory parameters, vital signs, and 
ECGs.


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Table of contents
Protocol Synopsis .................................................................................................2
Table of contents...................................................................................................8
List of tables........................................................................................................12
List of figures......................................................................................................12
List of abbreviations ...........................................................................................13
Amendment 1 (08-Oct-2020)..............................................................................16
1
Introduction.........................................................................................................26
1.1
Background.............................................................................................26
1.1.1
Disease Overview...................................................................26
1.1.2
PCSK9 Biology and Target Rationale....................................27
1.1.3
Mechanism of RNA Interference ...........................................28
1.2
Inclisiran, an siRNA Therapeutic for Hypercholesterolemia..................28
1.2.1
Nonclinical Studies.................................................................29
1.2.2
Clinical Studies.......................................................................30
1.3
Known and Potential Risks and Benefits................................................33
1.4
Study Rationale.......................................................................................33
1.4.1
Study Rationale ......................................................................33
1.4.2
Dose Rationale........................................................................34
1.5
Study Population.....................................................................................34
2
Study Objectives and Purpose ............................................................................34
2.1
Primary Objective ...................................................................................34
2.2
Secondary Objectives..............................................................................34
35
3
Study Design.......................................................................................................35
3.1
Type/Design of Study .............................................................................35
3.2
Schematic Diagram of Study Design......................................................36
3.3
Primary Endpoints...................................................................................37
3.4
Secondary Endpoints...............................................................................37
38
3.6
Measures to Minimize/Avoid Bias .........................................................38
3.6.1
Blinded Study.........................................................................38
4
Subject Population..............................................................................................38
4.1
Number of Subjects.................................................................................38


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4.2
Inclusion Criteria.....................................................................................39
4.3
Exclusion Criteria ...................................................................................40
4.4
Withdrawal Criteria.................................................................................41
4.4.1
Withdrawal from Study Medication.......................................42
4.5
Stopping Criteria.....................................................................................42
4.5.1
Individual Subject Dosing Stopping Criteria .........................42
5
Treatment of Subjects .........................................................................................43
5.1
Study Medications...................................................................................43
5.1.1
Inclisiran (also referred to as KJX839) ..................................43
5.1.2
Placebo ...................................................................................43
5.1.3
Packaging and Labeling .........................................................43
5.1.4
Storage....................................................................................44
5.1.5
Accountability ........................................................................44
5.1.6
Product Deficiencies (Complaints) Reporting........................44
5.2
Concomitant Medications .......................................................................45
5.2.1
Prohibited Concomitant Medications.....................................45
5.2.2
Permitted Concomitant Medications......................................45
5.3
Medical Management Guidelines ...........................................................46
5.3.1
Adverse events........................................................................46
5.3.2
Pregnancy ...............................................................................46
5.4
Restrictions..............................................................................................46
5.5
Blinding...................................................................................................46
5.5.1
Blinding of study medications................................................46
5.5.2
Method and Maintenance of Blinding....................................46
5.6
Unblinding ..............................................................................................47
5.6.1
In the Event of an Emergency: Unblinding a Code................47
6
Schedule and sequence of procedures ................................................................47
6.1
Schedule of Assessments ........................................................................48
6.2
General Conduct of the Study.................................................................52
6.3
Screening Period (Days -28 to -1)...........................................................52
6.4
Randomization (Day 1)...........................................................................53
6.5
Primary Efficacy Visit (Day 150)...........................................................53
6.6
Additional Dosing Visits (Days 90, 180, 270, 450, and 630).................54
6.7
Additional non dosing Clinic Visits (Days 330, 510 and 690)...............54


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6.7.1
Day 330 ..................................................................................55
6.7.2
Day 510 ..................................................................................55
6.7.3
Day 690 ..................................................................................55
6.8
End of Study (EOS) Visit (Day 720 - 90 days post last dose)................55
7
Protocol assessments...........................................................................................56
7.1
Assessment of Safety ..............................................................................56
7.1.1
Adverse Events.......................................................................56
7.1.2
Demographics and Medical History.......................................56
7.1.3
Vital Signs ..............................................................................56
7.1.4
Electrocardiograms.................................................................56
7.1.5
Physical Examination.............................................................56
7.1.6
Neurological Evaluation.........................................................56
7.1.7
Clinical Laboratory Assessments ...........................................57
7.1.8
Stored samples........................................................................58
7.2
Assessment of Efficacy...........................................................................59
7.2.1
Change from Day 1 in LDL-C................................................59
7.2.2
Change from Day 1 in Lipids/Lipoproteins............................59
7.3
Assessment of Pharmacodynamics .........................................................59
60
8
Adverse Events ...................................................................................................60
8.1
Definitions...............................................................................................60
8.1.1
Adverse Event ........................................................................60
8.1.2
Serious Adverse Event ...........................................................60
8.1.3
Special Situations ...................................................................61
8.2
Collection and Assessment of Adverse Events.......................................61
8.2.1
Pre-existing Conditions ..........................................................61
8.2.2
Adverse Event Severity..........................................................61
8.2.3
Relationship to Investigational Product..................................61
8.3
Requirements For Additional Safety Data Collection ............................62
8.3.1
Special Situations ...................................................................62
8.3.2
Other safety related information.............................................62
8.4
Procedure for Adverse Event Reporting.................................................63
8.4.1
Serious Adverse Events (SAEs).............................................63
8.4.2
Nonserious AEs......................................................................63


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8.4.3
Special situations....................................................................63
8.5
Expectedness...........................................................................................64
8.5.1
Expectedness Determination ..................................................64
8.6
Study Stopping Criteria...........................................................................64
8.6.1
Independent Data Monitoring Committee (IDMC) Stopping 
Rules.......................................................................................64
8.6.2
Sponsor Discontinuation Stopping Criteria............................64
9
Data Collection ...................................................................................................64
10 Statistical Plan.....................................................................................................65
10.1
Sample Size.............................................................................................65
10.2
Randomization ........................................................................................65
10.3
General Statistical Considerations and Definitions ................................66
10.3.1
General Statistical Methods....................................................66
10.3.2
Analysis Population................................................................66
10.3.3
Analysis Windows and Baseline ............................................66
10.3.4
Missing Data Handling...........................................................66
10.4
Statistical Analyses .................................................................................67
10.4.1
Demographic and Background Characteristics ......................67
10.4.2
Investigational Product and Concomitant Medications..........67
10.4.3
Efficacy Analysis....................................................................67
10.4.4
Safety Analysis.......................................................................69
10.5
Interim Analysis......................................................................................70
10.5.1
Interim Safety Review............................................................70
11 Records Retention...............................................................................................70
12 Quality Control and Quality Assurance..............................................................71
12.1
Monitoring ..............................................................................................71
12.2
Auditing ..................................................................................................71
12.3
Protocol Deviations.................................................................................71
13 Ethics and Responsibility....................................................................................72
13.1
Informed Consent....................................................................................72
13.2
Institutional Review Board/Ethics Committee .......................................72
14 Confidentiality ....................................................................................................73
15 Investigator Agreement (for Original Protocol) .................................................73
16 References...........................................................................................................75


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Amended Protocol Version 01 (Clean)
Protocol No. MDCO-PCS-17-02 (CKJX839A12302)
Appendix A: Simon Broome diagnostic criteria for Familial 
Hypercholesterolemia .............................................................................79
Appendix B: Requirements for background lipid lowering treatment ...............80
Appendix C: Recommended Neurological Examination....................................82
Appendix D: Sampson Criteria for Diagnosing Anaphylaxis ............................86
List of tables
Table 1-1
Renal Function Categories by Estimated CrCl Ranges..........32
Table 5-1
Investigational Product...........................................................43
Table 6-1
Schedule of Assessments........................................................49
List of figures
Figure 3-1
Schematic Diagram of Study Design .....................................36
Figure 3-2
Timing of blood sample collection, apheresis and dosing .....37


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Amended Protocol Version 01 (Clean)
Protocol No. MDCO-PCS-17-02 (CKJX839A12302)
List of abbreviations
ADA
anti-drug antibodies
AE
adverse event
ALP
alkaline phosphatase 
ALT
alanine aminotransferase 
ANCOVA
Analysis of Covariance
Apo-A1
apolipoprotein A1
Apo-B
apolipoprotein B
aPTT
activated partial thromboplastin
ASGPR
asialoglycoprotein receptor
AST
aspartate aminotransferase
AUC
area under the curve
β-HCG
Beta human chorionic gonadotropin
BQ
Beta-quantification
BUN
total protein urea (blood urea nitrogen)
CFR
Code of Federal Regulations
CHD
coronary heart disease
CI
confidence interval
CK
creatine kinase
Cmax
maximum plasma concentration
CPK
creatine phosphokinase
CrCl
creatinine clearance
CV
Cardiovascular
CVD
cerebrovascular disease 
dL
deciliter(s)
DMC
Data Monitoring Committee
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
electronic case report form 
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
EOS
end of study
EU
European Union
FDA
Food and Drug Administration
FUP
follow-up
GalNAc
N-acetylgalactosamine
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
GPV
Global Pharmacovigilance
HbA1C
glycated hemoglobin A1C


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Amended Protocol Version 01 (Clean)
Protocol No. MDCO-PCS-17-02 (CKJX839A12302)
HDL-C
high density lipoprotein cholesterol
HoFH
homozygous familial hypercholesterolemia
HR
heart rate
hsCRP
high sensitivity C-reactive protein 
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals 
IDMC
Independent Data Monitoring Committee
IFN-γ
interferon-gamma
IL6
interleukin 6 
INR
International normalized ratio 
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
intent-to-treat
IV
Intravenous
L
Liter(s)
LDL
low density lipoprotein 
LDL-C
low density lipoprotein cholesterol
LDLR
low density lipoprotein receptor
Lp(a)
lipoprotein(a)
MCH
mean cell hemoglobin 
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MDCO
The Medicines Company
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
MI
myocardial infarction
mITT
Modified intent-to-treat
mL
milliliter(s)
mmHg
millimeters of mercury
mmol
Millimole
MMRM
mixed-effect models for repeated measures
mRNA
messenger ribonucleic acid
NYHA
New York Heart Association
PCS
potentially clinical significant
PCSK9
proprotein convertase subtilisin/kexin type 9
PD
pharmacodynamic
PEF
peak expiratory flow
PK
pharmacokinetic
PMM
Pattern-Mixture Model


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Amended Protocol Version 01 (Clean)
Protocol No. MDCO-PCS-17-02 (CKJX839A12302)
PT
prothrombin time
RISC
RNA-induced silencing complex
RNA
ribonucleic acid
RNAi
ribonucleic acid interference
SAE
serious adverse event
SAP
Statistical Analysis Plan
SC
Subcutaneous
SD
standard deviation
siRNA
small interfering ribonucleic acid
SUSAR
suspected unexpected serious adverse reaction
t1/2
terminal half-life
TBIL
total bilirubin
TC
total cholesterol
TEAE
treatment emergent adverse event
TNF-α
tumor necrosis factor-alpha 
TTR
target transthyretin
ULN
upper limit of normal
US
United States
VLDL-C
very low density lipoprotein cholesterol
WHO
World Health Organization


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Page 16 of 86
Amended Protocol Version 01 (Clean)
Protocol No. MDCO-PCS-17-02 (CKJX839A12302)
Amendment 1 (08-Oct-2020)
Amendment rationale
The first subject for this trial was randomized in Feb 2019 and enrollment was completed 
in Sep 2019 (with 56 subjects enrolled). Part 1 (double-blind phase) of the trial was 
completed on 02-Mar-2020, when the last subject completed the Day 180 visit and 
treatment allocation was unblinded. At time of this amendment, 51 subjects are still on 
study treatment.
This amendment is written to address the change in sponsorship from The Medicines 
Company to Novartis after acquisition of The Medicines Company by Novartis in January 
2020. Administrative changes were made to the title page, the footer and headers and 
throughout the protocol to reflect the change in sponsorship and adding the Novartis study 
and IMP numbers. Additional other changes are made to improve study conduct and 
interpretation of results, incorporate Novartis processes, language and change in sponsor 
contacts, allow for some flexibility during the COVID-19 pandemic and to remove the 
option for subjects to receive study treatment beyond Day 720 because other alternative 
treatments are available.
Finally, the main statistical analysis model of the primary endpoint was updated as per 
FDA agreement. The key secondary endpoints have been aligned with the Statistical 
Analysis Plan (SAP) submitted to FDA on 09-Mar-2020.
Changes to the protocol
The following table specifies each major protocol amendment change section-by-section 
in the order written in the protocol.
Section
Original protocol
Amendment
Rationale for change
Title page
MDCO Title page 
including MDCO contact 
information
Novartis protocol title 
page
To reflect change in 
sponsorship, add Novartis 
protocol number and IMP code, 
remove MDCO personnel 
Procedures in case of 
an Emergency
MDCO template to 
provide emergency 
contacts in protocol
Removed
Emergency Contact information 
will be shared with sites outside 
of the protocol
Protocol Synopsis
Synopsis of original 
protocol
Synopsis of protocol 
amendment
Updated to reflect all changes 
made to original protocol; 
addition of principal investigators 
Prof. 
 and Prof. 
 of 
the trial
List of Abbreviations For original protocol
For protocol amendmentUpdated to include additional 
abbreviations introduced with 
protocol amendment
Amendment 1
n/a
Added
Section to provide amendment 
rationale, protocol changes and 
impact on IRB/IEC added


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Amended Protocol Version 01 (Clean)
Protocol No. MDCO-PCS-17-02 (CKJX839A12302)
Section
Original protocol
Amendment
Rationale for change
Throughout protocol
Inclisiran, MDCO
Updated:
Inclisiran sodium 300mg 
(equivalent to 284 mg 
inclisiran);
Inclisiran Novartis IMP 
name KJX839
Novartis trial numbers; 
change in sponsor
To reflect change in 
sponsorship, (change MDCO to 
Novartis and/or Sponsor), to add 
Novartis protocol numbers and 
IMP code, and to clarify amount 
of inclisiran sodium vs inclisiran 
administered
Section 1.2.1
Last sentence: Additional 
nonclinical studies are 
ongoing or planned.
Removed
Updated to reflect that there are 
no ongoing or planned 
nonclinical studies at this time. 
The results from all completed 
nonclinical studies are available 
in the latest Investigator 
Brochure.
Section 1.2.2.1
Last sentence: Additional 
clinical pharmacology 
studies are ongoing or 
planned.
Removed
Updated to reflect that there are 
no ongoing or planned clinical 
pharmacology studies at this 
time. The results from all 
completed clinical pharmacology 
studies are available in latest 
Investigator Brochure.
Section 1.2.2.2.3
Study ORION-2 
Updated study results, 
and added MDCO and 
Novartis protocol 
numbers
ORION-2 has been completed; 
updated study results to reflect 
this status
Section 1.2.2.2.4
Study ORION-7 
Updated study results, 
and added MDCO and 
Novartis protocol 
numbers
ORION-7 has been completed; 
updated study results to reflect 
this status
Section 1.3 Known 
potential risks and 
benefits
referred to IB version 10
Referred to current 
version of IB;
Ensures that investigators 
reviews information from most 
current version of Investigator’s 
Brochure
Section 2.2 Secondary 
objectives
• Proportion of subjects 
with at least 20% LDL-C 
reduction from Day 1 over 
time
• Proportion of subjects 
with at least 30% LDL-C 
reduction from Day 1 
over time
To align with secondary 
endpoints as described in the 
Statistical Analysis Plan (SAP) 
submitted to FDA on 9-Mar-
2020.


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Page 18 of 86
Amended Protocol Version 01 (Clean)
Protocol No. MDCO-PCS-17-02 (CKJX839A12302)
Section
Original protocol
Amendment
Rationale for change
Section 3.1 
Type/Design of Study;
Section 3.2 
The apheresis schedule 
should be maintained as
deemed necessary and 
dosing and subsequent 
assessments for LDL-C 
and other lipids should be 
scheduled to be done 
after apheresis, using the 
same frequency/timing as 
done at baseline. For 
example, if baseline LDL-
C was drawn 2 days after 
apheresis, subsequent 
measurement of LDL-C 
and other lipids should be 
taken 2 days after a 
subsequent apheresis. 
Administration of study 
drug should always occur 
at least 2 days following 
apheresis.
Removed and replaced 
by:
The apheresis schedule 
should be maintained as 
deemed necessary, 
using approximately the 
same frequency/timing 
as done at baseline.
When apheresis is 
performed during a 
study visit (Dosing or 
Non-Dosing), blood 
samples for 
measurement of LDL-C, 
other lipids and 
laboratory assessments 
must be collected before 
the apheresis. When 
apheresis is performed 
during a Dosing Visit, 
dosing should occur just 
after completion of the 
apheresis. The next 
scheduled apheresis 
must not occur within 72 
hours of injection of 
inclisiran. The 
subsequent study visit 
must occur at least 2 
weeks after an 
apheresis was 
performed to ensure 
LDL-C levels measured 
during a study visit are 
not confounded by the 
apheresis (see Figure 3-
2 for details).
Figure 3-2 – added to 
Section 3.2
To ensure that LDL-C 
measurements are not 
confounded by apheresis, 
specific time windows and new 
timing between sample 
collection, apheresis and study 
drug administration were 
introduced.
Section 3.1 
Type/Design of Study
Subjects who have 
completed the study to 
Day 720 will be given the 
opportunity to enroll into 
an open-label extension 
trial.
removed
As other alternative treatment 
options are available and there is 
no need to provide patients with 
additional open-label inclisiran.


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Page 19 of 86
Amended Protocol Version 01 (Clean)
Protocol No. MDCO-PCS-17-02 (CKJX839A12302)
Section
Original protocol
Amendment
Rationale for change
Section 3.4
Secondary Endpoints
Added additional 
secondary endpoints:
• Percentage change in 
Apo-B from baseline to 
Day 150.
•Percentage change in 
non-HDL-C from 
baseline to Day 150.
•Percentage change in 
total cholesterol from 
baseline to Day 150.
•Proportion of subjects 
in each group with ≥30% 
LDL-C reduction from 
baseline at Day 150.
To align with the Statistical 
Analysis Plan (SAP) submitted to 
FDA on 9-Mar-2020.
Section 4.2
Inclusion Criteria
Inclusion 9
Note: After 
implementation of 
protocol amendment 1, 
administration of study 
drug must either occur 
right after apheresis on 
the same day of the 
study visit or at least 2 
weeks following the last 
apheresis (see Figure 3-
2).
Added additional clarification on
proposed new timing of 
apheresis after implementation 
of the protocol amendment to 
ensure that apheresis is not 
impacting drug levels and/or 
LDL-C measurements.
Section 4.4 
Withdrawal Criteria
It is imperative to obtain 
complete follow-up data 
for all subjects whether or 
not they receive their 
assigned treatment or 
have discontinued 
investigational product.
All subjects 
discontinuing 
participation in this trial 
should be encouraged 
to complete the EOS 
except for those 
subjects who specifically 
withdrew consent
Section updated to indicate that 
EOS visit should be encouraged 
for all patients discontinuing 
participation from trial.


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Page 20 of 86
Amended Protocol Version 01 (Clean)
Protocol No. MDCO-PCS-17-02 (CKJX839A12302)
Section
Original protocol
Amendment
Rationale for change
Section 4.4.1 
Withdrawal from 
Study Medication
The Independent Data 
Monitoring Committee 
(IDMC) will be notified.
n/a
Removed. Reasons for 
withdrawals will be presented to 
the IDMC at the regular 
meetings.
It is imperative to obtain 
complete follow-up data 
(through Day 720 
procedures) for all 
randomized subjects 
whether or not they 
receive their assigned 
treatment or have 
discontinued 
investigational product.
n/a
Removed to indicate that EOS 
should be performed within 90 
days from last dose (as indicated 
in Assessment Schedule) and no 
additional follow-up data need to 
be collected.
Section 5.1.6 Product 
Complaints
Change of section title 
to Product Deficiencies 
(Complaints) Reporting
Updated section to remove 
MDCO contact information
Section 5.2.1
Prohibited 
Concomitant 
Medications
The following 
medications/treatments 
are not permitted to be 
added during the study:
Background lipid-
lowering treatment 
should remain stable 
throughout the study 
duration. As a result, the 
following 
medications/treatments 
are not permitted to be 
added or changed 
during the study:
Clarification that background 
lipid-lowering treatment should 
remain stable throughout the 
study duration not to confound 
study results.
Section 5.2.2
Permitted 
Concomitant 
Medication
Lipid-lower medications; 
subjects already on a 
stable (≥30 days before 
screening)
lipid-lower medications 
(such as statins and/or 
ezetimibe) should remain 
on the dose that they 
have received during 
participation in the 
original protocol unless 
clinically indicated
Lipid-lowering 
medications; subjects 
already on a stable (≥30 
days before screening) 
lipid-lowering 
medications (such as 
statins and/or ezetimibe) 
should remain on the 
dose that they have 
received at time of study 
entry
Clarification and correction of 
typos, Removal of ‘unless 
clinically indicated’ as changes in 
the background medication can 
confound the efficacy endpoint of
the study.
Section 5.3.2
Pregnancy
Follow-up evaluation of 
fetus and newborn 
should also be 
performed up to 12 
months after birth.
Added to adhere to Novartis 
reporting guidelines


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Page 21 of 86
Amended Protocol Version 01 (Clean)
Protocol No. MDCO-PCS-17-02 (CKJX839A12302)
Section
Original protocol
Amendment
Rationale for change
Section 6.1
Schedule of 
Assessments
Added:
If the COVID-19 
pandemic limits or 
prevents on-site study 
visits, alternative 
methods of providing 
continuing care may be 
implemented. Phone 
calls or virtual contacts 
(e.g. teleconsult) can 
replace on-site study 
visits, for the duration of 
the pandemic until it is 
safe for the participant 
to visit the site again. 
Given the long lasting 
efficacy and infrequent 
dosing regimen of 
inclisiran, it is possible 
to introduce a more 
variable dosing 
schedule of +/- 2 
months during this 
pandemic, which still 
allows subjects to 
receive inclisiran. If the 
two-month window is 
utilized for the next 
dose, the subsequent 
dose may be 
administered up to a 
maximum of 8 months’ 
time from the next dose 
(if the next dose is given 
early) or within a 
minimum of 4 months’ 
time (if the next dose is 
given late).
If a dose is not given 
within this two-month 
window, then the subject 
should be considered to 
have had a missed dose 
and should return as per 
the schedule in the 
protocol for the 
subsequent dose.
Schedule of 
assessments also 
updated.
Added COVID-19 related 
language regarding allowing for 
a more flexible visit and dosing 
schedule of +/- 2 months during 
COVID-19 pandemic.


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Page 22 of 86
Amended Protocol Version 01 (Clean)
Protocol No. MDCO-PCS-17-02 (CKJX839A12302)
Section
Original protocol
Amendment
Rationale for change
Section 6.3 Screening 
period (Days -28 to -1)
The following procedures 
will be performed within 
14 days prior to 
randomization
Demographics and 
medical history
 
 
The following 
procedures will be 
performed within 28 
days prior to 
randomization
Demographics and 
medical history including
disease history (prior 
history related to the 
disease and prior use of 
disease related 
medication, e.g. 
monoclonal antibodies 
to PCSK9)
 
 
 
Correction of typo to clarify 
screening period is 28 days as 
per administrative memo issued 
on 6-Mar-2019.
Additional clarification to 
information collected for disease 
history
 
sample in this study. 
These data are needed to allow 
for better interpretation of study 
results.
Section 6.4 
Randomization
If a local reaction around 
the injection site occurs 
that requires the patient 
to be seen between visits 
or if a reaction is 
noticeable on a 
subsequent visit, 
photographs of the 
injection site should be 
obtained at first 
presentation and at each 
of the follow-up visits until 
the injection site reaction 
resolves, if possible.
If a local reaction around 
the injection site occurs 
that requires the subject 
to be seen between 
visits or if a reaction is 
noticeable on a 
subsequent visit, 
photographs of the 
injection site may be 
obtained if deemed 
necessary.
As we have now accumulated 
more safety data on type and 
extent of injection site reactions, 
the determination as to if and 
when to take photographs is left 
to the investigator.
Section 6.6
Additional Dosing 
Visits
Added:
Note: For subjects 
randomized to the 
inclisiran arm this will be 
a non-dosing visit but 
the same assessments 
as described below will 
be performed.
Added clarification that Day 180 
is only a dosing visit for subjects 
randomized to the placebo 
group. For subjects randomized 
to the inclisiran group this is a 
non-dosing visit, all assessments 
except for dosing are performed 
as described in this section.
Section 6.7
Additional Non-
Dosing Visits
Note: for subjects 
randomized to the 
inclisiran group the Non-
dosing visit on Day 180 
is described in Section 
6.6.
To add clarification that subjects 
randomized to the inclisiran 
group, will have a non-dosing 
visit on Day 180 with the same 
assessments described in 
Section 6.6 (except for study 
drug administration)


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Page 23 of 86
Amended Protocol Version 01 (Clean)
Protocol No. MDCO-PCS-17-02 (CKJX839A12302)
Section
Original protocol
Amendment
Rationale for change
Section 7.1.7 Clinical 
samples &
Section 7.1.7.7. Lipids
Added:
If an apheresis is 
performed on a visit day, 
blood samples must be 
collected prior to the 
apheresis, and prior to 
the administration of 
study drug (on dosing 
visits).
Added clarification that samples 
should be collected prior to start 
of apheresis to not confound 
LDL-C measurements
Section 7.2.1 Change 
from Day 1 in LDL-C
At baseline, Day 150, 
and Day 720 LDL-C will 
be analyzed BQ; at other 
visits, samples will be 
stored for measurement 
via calculated LDL-C.
Reworded: For all study 
visits LDL-C will be 
calculated (using the 
Friedewald method), in 
addition at baseline 
(Day 1), Day 150 and 
Day 720 LDL-C will be 
analyzed by BQ.
To clarify that results for LDL-C 
using beta-quantification (BQ) 
will be available for 3 study 
visits, and calculated LDL-C 
results will be available for all 
visits during which a blood 
sample is collected. 
Section 8.4.3.2 
Pregnancy
Added:
The pregnancy should 
be followed up to 
determine outcome, 
including spontaneous 
or voluntary termination, 
details of the birth, and 
the presence or 
absence of any birth 
defects, congenital 
abnormalities, or 
maternal and/or 
newborn complications. 
Newborns should be 
followed for 12 months.
Added to further describe the 
pregnancy and newborn follow-
up.
Section 8.6.1
Similar review will be 
performed by the Safety 
Review Committee (SRC) 
during the open label part 
of the study.
Removed
Safety Review Committee and 
Data Monitoring Committee have 
been merged to one 
Independent Data Monitoring 
Committee, which will review the 
double-blind and open-label part 
of the study
Section 10.4.3
Efficacy Analysis
Primary analysis using 
MMRM
Primary analysis using 
ANCOVA
Missing data imputation 
by Wash-out model.
Main statistical analysis model of 
the primary endpoint was 
updated as per FDA agreement.


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Amended Protocol Version 01 (Clean)
Protocol No. MDCO-PCS-17-02 (CKJX839A12302)
Section
Original protocol
Amendment
Rationale for change
Section 10.5.1
Interim Safety Review
Following Day 180 the 
unblinded data will be 
reviewed by the Safety 
Review Committee (SRC)
Following Day 180 the 
unblinded data will be 
reviewed by the IDMC.
Safety Review Committee and 
Data Monitoring Committee have 
been merged to one 
Independent Data Monitoring 
Committee, which will review the 
double-blind and open-label part 
of the study
Section 12.3
Protocol Deviations
The following Protocol 
Deviations will require 
additional information in 
the eCRF explaining why 
the deviation occurred 
and what will be done to 
prevent it from re-
occurring:
Removed first two 
paragraphs.
Reworded third 
paragraph: Deviations 
from the protocol 
identified during the 
conduct of the trial will 
be recorded in the e-
CRF, as applicable, and 
will be reviewed 
periodically. These 
include, but are not 
limited to the following:
Added sentence at the 
end of the section: 
Additional protocol 
deviations and 
associated actions 
depending on the nature 
and impact of the 
protocol deviation will be 
defined and periodically 
reviewed by standard 
automated and/or 
manual checks by the 
clinical team or 
monitors.
Updated to align with Novartis 
process of recording protocol 
deviations and actions involved.
Reworded third paragraph and 
added last paragraph to allow for 
recording and periodic review of 
all deviations observed during 
study conduct in the eCRF, as 
applicable, including those listed 
in the original protocol.
Additional minor changes to correct typos and provide clarifications were only 
incorporated directly into the protocol and are not specifically listed in the above summary 
of changes.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities as appropriate.
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation.


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Amended Protocol Version 01 (Clean)
Protocol No. MDCO-PCS-17-02 (CKJX839A12302)
The changes herein affect the Informed Consent. Sites are required to update and submit 
for approval a revised Informed Consent that takes into account the changes described in 
this protocol amendment.


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Amended Protocol Version 01 (Clean)
Protocol No. MDCO-PCS-17-02 (CKJX839A12302)
1
Introduction
Inclisiran (also referred to as KJX839) is a novel synthetic ribonucleic acid (RNA) 
interference (RNAi) therapeutic for injection (subcutaneous [SC] use) and used for the 
treatment of hypercholesterolemia. This protocol describes a study to evaluate the effect of 
inclisiran treatment on low density lipoprotein cholesterol (LDL-C) levels at Day 150 in 
subjects with homozygous familial hypercholesterolemia (HoFH). This study is sponsored 
by Novartis and will be conducted in compliance with Good Clinical Practices (GCP) 
including the Declaration of Helsinki and all applicable regulatory requirements.
1.1
Background
1.1.1
Disease Overview
Despite advances in treatment, cardiovascular disease (CVD) is the leading cause of death 
worldwide, resulting in over 17 million deaths annually (WHO 2016). Eighty percent of 
all CVD deaths are due to coronary heart disease (CHD) or strokes. Elevated low-density 
lipoprotein associated 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).
Approximately 100 million 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 (Decision Resources 
Group 2015). Yet residual risk for cardiovascular (CV) events remains and statins are 
associated with well-known limitations. First, not all patients reach LDL-C levels 
associated with optimal protection against clinical events (Davidson et al 2005; Foley et al 
2003; CTT Collaborators et al 2008; Foody et al 2010; Baigent et al 2005). Second, not all 
patients tolerate statins or are able to take statins at sufficiently intensive doses. And third, 
observational studies have demonstrated that >50% of patients do not adhere to statin 
therapy for more than 6 months (Mann et al 2010; Poluzzi et al 2008).
There is an unmet need for additional treatment options beyond currently available 
treatments for lowering of the LDL-C level to reduce cardiovascular risk.
Despite statins alone or in combination with other lipid lowering medications, current 
therapies for the management of elevated LDL-C remain insufficient in some patients 
(Fitzgerald et al 2017; Barkas et al 2015; Jameson et al 2014; Jones et al 2012). This is 
particularly true in patients with pre-existing CHD and/or diabetes or a history of familial 
hypercholesterolemia (Appendix A), who are at the highest risk and require the most 
intensive management (Davidson et al 2005).
Proprotein convertase subtilisin/kexin type 9 (PCSK9), a member of the serine protease 
family, plays a key role in controlling the levels of low-density lipoprotein receptors 
(LDLR) on the surface of hepatocytes (Khorova 2017). PCSK9 is expressed and secreted 


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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. 
Loss of function mutations in PCSK9 have been found to lead to increased LDLR in liver, 
reduced serum LDL-C, and a lower risk for CHD (Berge et al 2006; Cohen et al 2006; 
Kotowski et al 2006; Zhao et al 2006) with no apparent negative health consequences. 
(Zhao et al 2006; Hooper et al 2007; Horton et al 2009).
Recently developed and approved PCSK9-blocking monoclonal antibodies reduce 
circulating PCSK9 levels and lower LDL-C levels. Results from the first completed large 
CV outcomes trial (FOURIER) were reported in March 2017. Repatha® (evolocumab) 
significantly reduced the risk of cardiovascular events. The study in approximately 27,000
patients with clinically evident atherosclerotic cardiovascular disease met its primary 
composite endpoint (cardiovascular death, nonfatal MI, nonfatal stroke, hospitalization for 
unstable angina or coronary revascularization) and the key secondary composite endpoint 
(cardiovascular death, nonfatal MI or nonfatal stroke) (Sabatine et al 2015).
The data from PCSK9 blocking antibodies such as Repatha® (evolocumab) and Praluent®
(arilocumab) are very encouraging. However, these products are dosed SC every 2 to 4 
weeks necessitating up to 26 injections per year (Hooper et al 2005; Navarese et al 2015; 
Zhang et al 2015). In contrast, one injection of inclisiran is anticipated to be given three 
times in the first year and every 6 months thereafter.
1.1.2
PCSK9 Biology and Target Rationale
PCSK9 is a member of the subtilisin serine protease family. Proprotein convertase 
subtilisin kexin type 9 is predominantly expressed by the liver and is critical for the down 
regulation of hepatocyte LDLR expression (Mousavi et al 2009). LDL-C levels in plasma 
are markedly elevated in humans with gain of function mutations in PCSK9, classifying 
them as having severe familial hypercholesterolemia (Abifadel et al 2003). Data from 
genetic association studies have identified loss of function alleles in human PCSK9 that 
result in lower PCSK9 protein levels and lower LDL-C levels (Zhao et al 2006; Hooper et 
al 2007; Horton et al 2009). In one published study, heterozygous individuals (carrying a 
single copy of a loss of function PCSK9 mutation) had significantly lower LDL-C with 
median levels of approximately 70 mg/dL (1.81 mmol/L) (Cohen et al 2006). Over a 
15-year period of retrospective data analysis, this sustained lowering in LDL-C levels 
translated to an 88% lower risk of risk for CHD. Follow-up publications describe two adult 
individuals that are compound heterozygous for loss of function alleles of PCSK9. These 
individuals lack detectable plasma PCSK9 protein, have LDL-C levels ≤20 mg/dL, and yet 
are otherwise healthy (Zhao et al 2006; Hooper et al 2007). Additionally, recent human 
clinical trials with PCSK9 blocking antibodies have shown significant lowering of LDL-C 
in healthy volunteers and across a range of high cardiovascular (CV)-risk populations and 
with elevated LDL-C both with and without statins (Banerjee et al 2012; Dias et al 2012; 
Milazzo et al 2012; Raal et al 2012; Roth et al 2012; Stein et al 2012; Sullivan et al 2012; 


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Hooper et al 2013). Two monoclonal agents to inhibit PCSK9 are currently approved in 
Europe and North America. Recent cardiovascular outcomes trials have further confirmed 
that PCSK9 is a validated drug target whose inhibition results in LDL-C lowering and 
significant outcomes benefit without otherwise negatively impacting overall health (Ridker 
et al 2017; Sabatine et al 2017).
1.1.3
Mechanism of RNA Interference
Ribonucleic acid interference (RNAi) is a naturally occurring cellular mechanism for 
regulating gene expression that is mediated by small interfering RNAs (siRNAs). Typically, 
synthetic siRNAs are 19-base to 25-base pair double-stranded oligonucleotides in a 
staggered duplex with a two- to four-nucleotide overhang at one or both of the 3’ ends. 
Such siRNAs can be designed to target an endogenous messenger RNA (mRNA) transcript 
of a given gene. When introduced into cells, the guide (or antisense) strand of the siRNA 
loads into an enzyme complex called the RNA-Induced Silencing Complex (RISC). This 
enzyme complex subsequently binds to its complementary mRNA sequence, mediating 
cleavage of the target mRNA and the suppression of the target protein encoded by the 
mRNA (Elbashir et al 2001).
Since unmodified siRNAs are rapidly eliminated and do not achieve significant tissue 
distribution upon systemic administration (Soutschek et al 2004), various formulations are 
currently used to target their distribution to tissues, and to facilitate uptake of siRNAs into 
the relevant cell type. One approach that has been used successfully in vivo, in animal 
models (including in rodents and nonhuman primates) and humans employs intravenous 
delivery of siRNA in lipid nanoparticle formulations (Soutschek et al 2004; Morrissey et 
al 2005; Geisbert et al 2006; Judge et al 2006; Zimmermann et al 2006; Coelho et al 2013; 
Tabernero et al 2013). Another approach for liver-specific gene silencing is subcutaneously 
administered siRNA conjugated to a N-acetylgalactosamine (GalNAc) carbohydrate ligand 
(Ashwell and Morell 1974). Conjugation of a triantennary GalNAc ligand to an siRNA 
enables hepatocyte binding and subsequent cellular uptake via the asialoglycoprotein 
receptor (ASGPR), resulting in engagement of the RNAi pathway and down regulation of 
hepatic proteins. Single and multiple doses of subcutaneously administered siRNA-
GalNAc conjugates have been used to target transthyretin (TTR) mRNA for the treatment 
of TTR-mediated amyloidosis. ALN-TTRCSC has been found to be generally safe and 
well tolerated in Phase I and Phase II clinical trials in over 40 healthy volunteers and 
18 subjects with familial amyloidotic cardiomyopathy and senile systemic amyloidosis 
(ALN-TTRSC-001; EudraCT 2012-004203-12 and ALN-TTRSC-002; EudraCT 2013 
002856 33).
1.2
Inclisiran, an siRNA Therapeutic for Hypercholesterolemia
Inclisiran sodium is a chemically synthesized small interfering RNA (siRNA) 
double-stranded oligonucleotide, covalently linked to a ligand containing three GalNAc 
residues.


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Inclisiran is a long-acting, subcutaneously delivered, synthetic siRNA directed against 
PCSK9 that is conjugated to triantennary GalNAc carbohydrates. These carbohydrates 
bind to abundant liver-expressed ASGPR, leading to inclisiran uptake specifically into 
hepatocytes.
When introduced into the hepatocyte, inclisiran engages the natural pathway of RNAi by 
binding intracellularly to the RISC, enabling it to cleave messenger RNA (mRNA) 
molecules encoding PCSK9 specifically. The cleaved PCSK9 mRNA is degraded and thus 
unavailable for protein translation, which results in decreased levels of the PCSK9 protein. 
A single siRNA-bound RISC is catalytic and cleaves many transcripts and the duration of 
action is anticipated to be longer than other mechanisms.
1.2.1
Nonclinical Studies
Inclisiran was specifically designed with molecular and biochemical characteristics to 
minimize untoward side effects which are reflected by the absence of dose limiting 
toxicities in preclinical models. For example, GalNAc ligands were added to the RNA 
strands in order to target inclisiran to receptors on hepatocytes, thereby greatly reducing 
uptake by heterologous tissue. This is highlighted by tissue distribution studies in rats 
showing that compared to liver, inclisiran exposure in other tissues was 36- to 1076-fold 
lower than liver. In addition, once inclisiran is inside the cell, there is a low likelihood of 
off-target binding because inclisiran is sequestered within RISC and guided to its 
complementary PCSK9 mRNA sequence which is highly conserved across diverse ethnic 
and geographical populations. The specificity of the active antisense strand of inclisiran 
was determined by performing a comprehensive search against the human transcriptome 
using an exhaustive “brute-force” algorithm implemented in the python script 
‘BruteForce.py’. The search revealed 20 possible off-target transcripts, two of which are 
not normally expressed in liver cells. The other 18 transcripts were subsequently assayed 
in an in vitro study to experimentally assess their response to inclisiran. The 18 gene 
transcripts were transfected into liver cells along with inclisiran and expression analysis 
indicated a ≥45-fold difference between the “on target” suppression of PCSK9 and the 
suppression of any of the “off-target” transcripts.
Inclisiran was well tolerated in all studies. The most common findings were related to the 
expected pharmacological effects of inclisiran on lipid profiles and histopathological 
findings of vacuolation in hepatocytes of rats and lymph node macrophages of monkeys 
and the presence of basophilic granules in hepatocytes of monkeys and kidneys of rats. 
These microscopic findings are not considered adverse because they are not associated with 
changes in clinical pathology parameters. Liver function enzymes were only minimally to 
mildly increased, and were reversible following treatment-free periods, and there were no 
changes in urinalysis or urine chemistry parameters.


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1.2.2
Clinical Studies
1.2.2.1
Clinical pharmacology
Inclisiran is inactive in plasma and acts directly in the hepatocytes leading to inhibition of 
PCSK9 protein synthesis. After SC administration of inclisiran, peak plasma 
concentrations were observed by 4 hours and became undetectable in plasma in 24 to 
48 hours with a fast elimination half-life (t1/2) of 7.3 hours and dose-proportional increase 
in exposure parameters of maximum plasma concentration (Cmax) and area under the curve 
(AUC). There was no accumulation of inclisiran plasma concentrations following multiple 
weekly, biweekly or monthly dosing. Mean fraction excreted unchanged in the urine was 
around 25%. In vitro studies using hepatic P450 metabolic enzymes showed that inclisiran 
neither inhibited nor induced common hepatic metabolic pathways.
In ORION-7 (CKJX839A12103) (Section 1.2.2.2.4), a single 300 mg SC dose of inclisiran 
sodium was observed to increase Cmax and AUC up to approximately two-fold in subjects 
with mild and moderate renal impairment, and increased Cmax up to four-fold and AUC up 
to three-fold in subjects with severe renal impairment compared to subjects with normal 
renal function. However, by 48 hours plasma levels of inclisiran were below the level of 
quantification in all groups.
Despite the differences observed in pharmacokinetic (PK) parameters over the first 48 
hours following injection of inclisiran, there were generally no relevant differences 
between the groups with respect to PCSK9 reduction and LDL-C reduction. In addition, 
there was no difference in the overall safety profile between subjects with normal renal 
function and those with mild, moderate, or severe renal impairment.
This finding is consistent with that observed in the previous Phase I (ALN-PCSSC-001, 
CKJX839A12101) study (Section 1.2.2.2.1) where doses above 300 mg led to a dose 
related increase in PK parameters. A single 500 mg dose increased AUC 2-3 fold and Cmax
4-5 fold compared to a single 300 mg dose, which is similar to the increase observed in 
subjects with severe renal impairment compared to those with normal renal function in this 
study. In both the Phase I (ALN-PCSSC-001, CKJX839A12101) and Phase II (ORION-1, 
CKJX839A12201) studies single doses above 300 mg did not lead to greater reductions in 
PCSK9 or LDL-C levels over time or differences in the safety profile.
These data support the administration of inclisiran to subjects with mild, moderate, or 
severe renal impairment in future and ongoing clinical studies with inclisiran.
1.2.2.2
Clinical
Results are presented from 4 clinical trials:
1.2.2.2.1 Study ALN-PCSSC-001 (CKJX839A12101)
ALN-PCSSC-001 (CKJX839A12101, completed) was a Phase I study in which single (25 
mg, 100 mg, 300 mg, 500 mg and 800 mg) and multiple (125 mg once weekly (four doses), 


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250 mg every 2 weeks (two doses), 300 mg every 4 weeks (two doses) and 500 mg every 
four weeks (two doses) doses of inclisiran sodium were evaluated. Subjects in this study 
were followed until their LDL-C levels returned to ≥80% of the baseline value or until 180
days after the last dose was given, whichever occurred first. At cumulative doses of 100 
mg or greater, the majority of subjects reached 180 days of follow-up after the last dose, 
confirming the extended duration of action of inclisiran. No further follow-up occurred 
beyond this time point in this Phase I study. All adverse events (AEs) were mild or 
moderate (Grade 1 or 2) in severity with no differences relative to placebo other than skin 
reactions which were infrequent, mild and reversible following inclisiran.
The Phase I study demonstrated that the 300 mg dose of inclisiran sodium administered as 
a single or multiple dose is the lowest dose to achieve near-maximal reductions in PCSK9 
and LDL-C levels. Two 300 mg doses of inclisiran sodium given 30 days apart achieved 
an additional 10% LDL-C reduction compared to a single 300 mg dose. PK parameters of 
inclisiran demonstrated a short plasma half-life (t1/2 = ~6 hours) and did not correlate with 
the observed pharmacodynamic (PD) effects of inclisiran.
1.2.2.2.2 Study ORION-1 (MDCO-PCS-15-01, CKJX839A12201)
ORION-1 (MDCO-PCS-15-01, CKJX839A12201; completed) was a Phase II placebo 
controlled, dose-finding trial performed in 501 subjects with atherosclerotic cardiovascular 
disease which showed dose-dependent PD effects of inclisiran. The 300 mg dose provided 
near maximal PCSK9 and LDL-C reductions. The 500 mg dose did not provide a 
meaningful further increase in PD effect.
The loading dose regimen of 300 mg given on Day 1 and on Day 90 led to reduced mean 
PCSK9 and LDL-C levels by 69% and 53%, respectively, at Day 180. This regimen also 
produced a time-adjusted average LDL-C reduction of 51% for the 6-month period 
following the second (Day 90) loading dose. Return of LDL-C from nadir levels was 
observed at a linear rate of 2 to 3% per month. At Day 270 (6 months after the second 300 
mg dose), LDL-C reduction was similar to that observed on Day 90. There were no 
clinically significant safety observations other than mild-moderate, short-lived skin 
reactions at injection site in approximately 5% of subjects. Local injection site reactions 
were not dose-related.
1.2.2.2.3 Study ORION-2 (MDCO-PCS-16-02, CKJX839A12202)
ORION-2 (MDCO-PCS-16-02, CKJX839A12202; completed) was a Phase II, open label, 
single arm, multicenter pilot study in subjects with homozygous familial 
hypercholesterolemia. Four subjects were randomized and received open-label inclisiran 
sodium 300 mg SC on Day 1. The subsequent dosing interval was determined by PCSK9 
level at Day 60 or 90 or rate of change of PCSK9 between Days 60 and 90. Three subjects 
received a second injection because mean serum PCSK9 levels were not suppressed by >70% 
at Day 60 or 90, as compared to baseline.


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Inclisiran treatment resulted in robust and durable reductions in PCSK9 levels in all four 
subjects treated at a dose of 300 mg SC. Three of the four subjects also had significantly 
reduced levels of LDL-C. One subject had a significant reduction in PCSK9 but not a 
concomitant reduction in LDL-C. The mean percentage LDL-C reduction from baseline 
was 12.3% and 21.0% at Day 90 and Day 180, respectively. The maximum reductions in 
LDL-C were at Day 120 for two subjects and at Day 150 for a third subject. Therefore, the 
second dose achieved a greater reduction in LDL-C than after the first dose.
The mean percentage PCSK9 reduction from baseline was 59.0% and 62.9% at Day 90 and 
Day 180, respectively. Decreases in other lipids, lipoproteins, and apolipoproteins were 
commensurate with the decreases in LDL-C.
No safety observations were noted and inclisiran was generally well tolerated. Three of the 
four subjects reported adverse events. There were no deaths and one SAE (unstable angina, 
which was not considered related to study drug). No subjects withdrew due to an adverse 
event and no adverse events at the injection site were reported.
A number of notable elevations chemistry parameters were observed. One subject with an 
elevated total bilirubin (>1x ULN) at screening experienced a single elevation of total 
bilirubin >2x ULN on Day 120. There were no ALT or AST elevations >3 x ULN or CK 
elevations >5x ULN. None of the subjects developed anti-drug antibodies.
The results from this pilot study support the 300mg dose and dose regimen for the ongoing 
Phase III ORION-5 study in HoFH.
1.2.2.2.4 Study ORION-7 (MDCO-PCS-16-03, CKJX839A12103)
ORION-7 (MDCO-PCS-16-03, CKJX839A12103; completed) was a Phase I, single-dose, 
open-label trial to evaluate the safety, PK, and PD of a single dose of inclisiran sodium 300 
mg SC injection. Subjects were classified into one of four renal function groups (normal, 
mild, moderate, and severe), as defined by creatinine clearance (CrCl) which was 
calculated using the Cockcroft and Gault estimation from a spot serum creatinine level 
(Table 1-1).
Table 1-1
Renal Function Categories by Estimated CrCl Ranges
Group
Description
Estimated CrCl (mL/min)
1
Normal renal function
≥ 90 
2
Mild renal impairment
60 to 89
3
Moderate renal impairment
30 to 59
4
Severe renal impairment
15 to 29
CrCl=creatinine clearance
The subjects in the normal renal function group (Group 1) were dosed following 
completion of dosing of the subjects in the three renal impairment groups. These subjects 
were matched for age (+/- 10 years), body weight (+/- 20%), and proportional race and 


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gender in order to ensure that the normal renal function group was comparable to the renal 
impairment groups for average demographics.
Thirty-one subjects were randomized into the study, eight subjects in each of the normal 
renal function and the mild and moderate renal impairment groups and seven in the severe 
renal impairment group. All subjects completed the study (EOS visit, Day 60), and 
additional follow-up visit (Day 120 or Day 180).
At Day 60, PCSK9 levels were reduced by 68.1%, 74.2%, 79.7%, and 67.9% in the normal, 
mild, moderate, and severe renal impairment groups respectively. There were no observed 
differences in PCSK9 reduction in subjects with normal renal function compared with 
those with mild, moderate, or severe renal impairment. At Day 60, LDL-C was reduced by 
57.6%, 35.1%, 53.1%, and 49.2%, in the normal renal function group and the mild, 
moderate, and severe renal impairment groups respectively. Mean LDL-C reduction was 
less in the mild renal impairment group compared to the other three groups. Overall, LDL-
C reduction was generally similar between groups with no impact of renal function on 
LDL-C response.
A single injection of 300 mg inclisiran sodium was generally well tolerated in all study 
groups with no clinically significant safety findings. There was no difference in the overall 
safety profile between subjects with normal renal function and those with mild, moderate, 
or severe renal impairment.
1.3
Known and Potential Risks and Benefits
Subjects taking part in this clinical study will receive guideline recommended standard of 
care as background therapy (including maximally-tolerated statin therapy and/or other 
LDL-C lowering therapies) when administered inclisiran or placebo. Reduction of LDL-C 
has been associated with reduced CV risk both by epidemiology and in controlled clinical 
trials. Local reaction at injection site is the only event known to be attributed to inclisiran 
treatment. The safety profile of inclisiran observed to date is considered acceptable for this 
clinical trial.
An expanded risk-benefit summary is provided in the current version of the Investigator’s 
Brochure (IB).
1.4
Study Rationale
1.4.1
Study Rationale
The overall safety data from inclisiran nonclinical studies and clinical data from the Phase I 
and Phase II study (ORION-1, CKJX839A12201), and the results from multiple PCSK9 
antibody studies demonstrated that potent lowering of PCSK9 is well tolerated in human 
subjects and support the dose and dosing schedule proposed in this Phase III study.


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In addition, a pilot study (ORION-2, CKJX83912202) in which a 300 mg dose of inclisiran 
sodium was administered to subjects with HoFH resulted in robust and prolonged 
reductions in PCSK9 and LDL-C levels in plasma.
This study is being conducted in subjects with a genetic or clinical diagnosis of HoFH;
Orphan designation for this disease has been received from the US Food and Drug 
Administration (FDA).
1.4.2
Dose Rationale
Previous studies have shown that a 300 mg dose of inclisiran sodium is well tolerated and 
provides maximum efficacy (ie, doses higher than 300 mg did not provide additional 
efficacy in LDL-C lowering). In this study, the 300 mg dose of inclisiran sodium will be 
administered on Days 1, 90, 270 and 450 to subjects with HoFH. Modelling and simulation 
has demonstrated that this regimen will allow for the necessary robust and sustained 
reduction in PCSK9 (and LDL-C) and has the potential to tackle the lack of adherence 
generally seen in the chronic management of subjects with hypercholesterolemia. The 300 
mg dose of inclisiran sodium will be used for the entire duration of this study for subjects 
receiving inclisiran.
In addition, a pilot study (ORION-2, CKJX839A12202) in which a 300 mg dose of 
inclisiran sodium was administered to subjects with HoFH resulted in robust and prolonged 
reductions in PCSK9 and LDL-C levels in plasma.
1.5
Study Population
This study will include male and female subjects ≥18 years of age with a genetic or clinical 
diagnosis of HoFH.
2
Study Objectives and Purpose
2.1
Primary Objective
The primary objective is to evaluate the effect of inclisiran treatment on:

Low-density lipoprotein cholesterol (LDL-C) levels at Day 150
2.2
Secondary Objectives
The secondary objectives of this study are to evaluate the effect of inclisiran on:

LDL-C levels over time

Proprotein convertase subtilisin/kexin type 9 (PCSK9) levels over time

Other lipids, lipoproteins, and apolipoproteins

Individual responsiveness of subjects to inclisiran including proportion of subjects 
achieving prespecified global lipid guidelines for their indication


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
Proportion of subjects with at least 30% LDL-C reduction from Day 1 over time
And to assess the:

Safety and tolerability profile of inclisiran
3
Study Design
3.1
Type/Design of Study
This study will be a Phase III two-part (double-blind placebo-controlled/open-label) 
multicenter study in subjects with HoFH and elevated LDL-C despite maximum tolerated 
dose of LDL-C lowering therapies to evaluate the safety, tolerability, and efficacy of 
subcutaneous inclisiran injection(s). This study has two sequential parts:

Part 1: 6-month double-blind period in which subjects will be randomized to receive 
either inclisiran or placebo

Part 2: 18-month open-label follow-up period; placebo-treated subjects from Part 1 
will be transitioned to inclisiran and all subjects will participate in an open-label 
follow-up period of inclisiran only
Informed consent will be obtained from subjects before the initiation of any study-specific 
procedures. Subjects who meet study inclusion/exclusion criteria will be instructed to 
continue to follow a National Cholesterol Education Program Adult Treatment Panel III 
(or comparable) diet and be required to maintain their current lipid lowering drug therapy
for the duration of the study.
In this study, at least 45 subjects will be enrolled and randomized 2:1 to receive either 
inclisiran sodium 300 mg SC or placebo on Day 1. Inclisiran and placebo will both be 
administered by a health care provider. Subjects will be observed in the clinic for at least 
30 minutes post injection before being discharged. A second dose of inclisiran or placebo 
will be given at Day 90.


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After completion of Part 1, the inclisiran-treated subjects from Part 1 will receive a third 
dose of inclisiran administered on Day 270 and subsequent doses on Day 450 and Day 630. 
The placebo-treated subjects from Part 1 will be transitioned to inclisiran on Day 180, the 
start of the open-label, single arm follow-up period of inclisiran only (Part 2). Placebo-
treated subjects will receive their first dose of inclisiran on Day 180 and then subsequently 
receive a dose of inclisiran on Day 270, Day 450, and Day 630.
Subjects on a documented regimen of LDL or plasma apheresis will be allowed to continue 
their same regimen during the study using approximately the same frequency/timing as 
done at baseline. When apheresis is performed on a study visit (Dosing or Non-Dosing), 
blood samples for measurement of LDL-C, other lipids and laboratory assessments must 
be collected before the apheresis. When apheresis is performed on a Dosing Visit, dosing 
must occur just after completion of the apheresis. The next scheduled apheresis must not 
occur within 72 hours of injection of inclisiran. The subsequent study visit must occur at 
least 2 weeks after an apheresis was performed to ensure LDL-C levels measured during a 
study visit are not confounded by the apheresis (see Figure 3-2 for details).
3.2
Schematic Diagram of Study Design
Figure 3-1
Schematic Diagram of Study Design
FUP=follow-up; V=visit


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Figure 3-2
Timing of blood sample collection, apheresis and dosing
3.3
Primary Endpoints
The primary endpoint of this study is:

Percent change in LDL-C from baseline to Day 150 (Part 1 of study)
3.4
Secondary Endpoints
The key secondary endpoints of this study are:

Absolute change in LDL-C from baseline to Day 150

Percentage change in Apo-B from baseline to Day 150.

Percentage change in non-HDL-C from baseline to Day 150.

Percentage change in total cholesterol from baseline to Day 150.

Proportion of subjects in each group with ≥30% LDL-C reduction from baseline at 
Day 150.
The other secondary endpoints of this study are:

Percentage change and absolute change in LDL-C from baseline to each assessment 
time up to Day 720 (ie, Days 90, 150, 180, 270, 330, 450, 510, 630, 690, and 720)

Percentage change and absolute change from baseline to Days 90, 150, 180, 330, 510, 
690, and 720 in PCSK9

Percentage change and absolute change from baseline to Days 150, 180, 330, 510, 
690, and 720 in total cholesterol, Apo-B, and non-HDL-C for subjects receiving 
inclisiran

Individual responsiveness of subjects defined as the number of subjects reaching on 
treatment LDL-C levels of <25 mg/dL, <50 mg/dL, <70 mg/dL, and <100 mg/dL at 
Days 150, 180, 330, 510, 690, and 720 including proportion of subjects in each group 
who attain global lipid targets for their indication

Proportion of subjects in each group with greater or equal to 30% LDL-C reduction 
from baseline at Days 150, 180, 330, 510, 690, and 720


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
Absolute change and percentage change in other lipids, lipoproteins, apolipoproteins, 
and PCSK9 from baseline at each subsequent visit to Day 720

Safety and tolerability profile of inclisiran as measured by AEs, SAEs, vital signs, 
clinical laboratory values, ECG measurements and formation and subsequent 
characterization of anti-drug antibodies (ADA)
3.6
Measures to Minimize/Avoid Bias
3.6.1
Blinded Study
Part 1 of this study will employ double-blind technique with a placebo control. 
Randomization via automated interactive response technology (IRT) will be used to assign 
subject to blinded investigational product kits. In addition, investigational product will be 
dispensed and administered in a blinded syringe. Blinding will minimize bias based on 
subject selection, baseline characteristics, clinical endpoint and AE reporting. Specifics on 
how the blind for the investigational product is maintained are provided in Section 5.5.
4
Subject Population
This will be a multicenter, international study in subjects with HoFH and elevated LDL-C 
despite maximum tolerated dose of LDL-C lowering therapies.
4.1
Number of Subjects
At least 45 subjects will be randomized 2:1 to inclisiran or placebo.


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4.2
Inclusion Criteria
Subjects may be included in the study if they meet all of the following criteria:
1. Males and females, ≥18 years of age with a diagnosis of HoFH by genetic 
confirmation or a clinical diagnosis based on a history of an untreated LDL-C 
concentration >500 mg/dL (13 mmol/L) together with either xanthoma before 
10 years of age or evidence of heterozygous familial hypercholesterolemia in both 
parents (see Appendix°A).
2. Stable on a low-fat diet
3. Subjects on statins should be receiving a maximally tolerated dose. Maximum 
tolerated dose is defined as the maximum dose of statin that can be taken on a regular 
basis without intolerable adverse events. Intolerance to any dose of any statin must be 
documented as historical AEs attributed to the statin in question in the source 
documentation and on the Medical History page of the electronic case report form 
(eCRF) (see Appendix B)
4. Subjects not receiving statins must have documented evidence of intolerance to at 
least two different statins (see Appendix B)
5. Subjects on lipid-lower therapies (such as statin and/or ezetimibe) should be on a 
stable dose for ≥30 days before screening with no planned medication or dose change 
during study participation
6. Fasting central laboratory LDL-C concentration ≥130 mg/dL (3.4 mmol/L)
7. Triglyceride concentration <400 mg/dL (4.5 mmol/L)
8. No current or planned renal dialysis or renal transplantation
9. Subjects on a documented regimen of LDL or plasma apheresis will be allowed to 
continue the apheresis during the study, if needed. The apheresis schedule should be 
maintained as deemed necessary and dosing should be scheduled to be done after 
apheresis. Administration of study drug should always occur at least 2 days following 
apheresis. Note: after implementation of protocol amendment 1, administration of 
study drug must occur right after apheresis on the same day of the study visit or at 
least 2 weeks following the last apheresis (see Figure 3-2).
10. Subjects must be willing and able to give written informed consent before initiation 
of any study-related procedures. The subject should be willing to comply with all 
required study procedures
11. Willing to follow all study procedures including adherence to dietary guidelines, 
study visits, fasting blood draws, and compliance with study treatment regimens


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4.3
Exclusion Criteria
Subjects will be excluded from the study if any of the following exclusion criteria apply 
prior to randomization:
1. Use of Mipomersen or Lomitapide therapy within 5 months of screening
2. Treatment (within 90 days of screening) with monoclonal antibodies directed towards 
PCSK9
3. New York Heart Association (NYHA) class IV heart failure or last known left 
ventricular ejection fraction <25%
4. Major adverse cardiovascular event within 3 months prior to randomization
5. Planned cardiac surgery or revascularization
6. Uncontrolled severe hypertension: systolic blood pressure >180 mmHg or diastolic 
blood pressure >110 mmHg prior to randomization despite anti-hypertensive therapy
7. Active liver disease defined as any known current infectious, neoplastic, or metabolic 
pathology of the liver or unexplained alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), elevation >3x ULN, or total bilirubin >2x upper limit of 
normal (ULN) at screening confirmed by a repeat measurement at least 1 week apart
8. Severe concomitant noncardiovascular disease that carries the risk of reducing life 
expectancy to less than the duration of the trial
9. History of malignancy that required surgery (excluding local and wide-local 
excision), radiation therapy and/or commencement of systemic therapy as treatment 
during the 3 years prior to randomization
10. Females who are pregnant or nursing, or who are of childbearing potential and 
unwilling to use at least one acceptable effective method of contraception (eg, oral 
contraceptives, barrier methods, approved contraceptive implant, long- term 
injectable contraception, intrauterine device) for the entire duration of the study. 
Exemptions from this criterion:
a. Women >2 years postmenopausal (defined as 1 year or longer since their last 
menstrual period) AND more than 55 years of age
b. Postmenopausal women (as defined above) and less than 55 years of age with a 
negative pregnancy test within 24 hours of enrolment
c. Women who are surgically sterilized at least 3 months prior to enrolment
11. Known history of alcohol and/or drug abuse within 5 years
12. Any condition that according to the investigator could interfere with the conduct of 
the study, such as but not limited to:
a. Subjects who are unable to communicate or to cooperate with the investigator.
b. Unable to understand the protocol requirements, instructions and study-related 
restrictions, the nature, scope, and possible consequences of the study (including 
subjects whose cooperation is doubtful due to drug abuse or alcohol dependency)


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c. 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)
d. Have any medical or surgical condition, which in the opinion of the investigator 
would put the subject at increased risk from participating in the study
e. Persons directly involved in the conduct of the study
13. 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 subject at 
significant risk (according to investigator’s [or delegate] judgment) if he/she 
participates in the clinical study
14. Any underlying known disease, or surgical, physical, or medical condition that, in the 
opinion of the Investigator (or delegate), might interfere with the interpretation of 
clinical study results
15. Treatment with other investigational medicinal products or devices within 30 days or 
5 half-lives of the screening visit, whichever is longer
16. Previous participation in the study
17. Hypersensitivity to any of the ingredients of inclisiran
Subjects excluded for any of the above reasons may not be re-screened for participation at 
any time even if the exclusion characteristic has changed.
4.4
Withdrawal Criteria
All subjects have the right to withdraw from the study at any point during treatment without 
prejudice. The investigator can discontinue any subject at any time if medically necessary. 
It will be documented whether or not each subject completed the clinical study. If study 
treatment or observations were discontinued, the reason will be recorded and the Sponsor 
should be notified promptly. The reasons a subject may discontinue their participation in 
the study could be from one of the following:

AE

Death

Subject withdrew consent

Physician decision

Lost to follow-up

Initiation of protocol-prohibited lipid-lowering therapy (eg, an approved PCSK9 
inhibitor)
The applicable reason above will be recorded in the eCRF. All data collected up until the 
time of subject withdrawal is to be entered into the eCRF. All subjects discontinuing 
participation in this trial should be encouraged to complete the EOS visit except for those 
subjects who specifically withdrew consent.


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Participating study sites will be trained on the importance of completing study follow-up 
procedures, and collecting the documentation required for missing data values. Any 
withdrawn subjects will not be replaced in this study.
4.4.1
Withdrawal from Study Medication
In the event a subject withdraws or is withdrawn from the study medication (eg, receives 
first injection and not second injection), the investigator will inform the Medical Monitor 
and the Sponsor immediately. If there is a medical reason for withdrawal, the subject will 
remain under the supervision of the investigator for protocol-specified safety follow up 
procedures.
4.5
Stopping Criteria
4.5.1
Individual Subject Dosing Stopping Criteria
During the study subjects will have clinic visits at regular intervals. Dosing with study 
medication (inclisiran and/or matching placebo) should be temporarily discontinued or 
stopped in subjects with:
1. Intolerable adverse events, or if the Investigator believes that continuing dosing will 
be detrimental to the subject’s mental or physical health. This includes severe or 
serious reactions at the injection site and any anaphylactic type reactions.
2. Unexplained increases in transaminases (ALT or AST) or total bilirubin as follows:
a. ALT or AST >8xULN
b. ALT or AST >5xULN for more than 2 weeks
c. ALT or AST >3xULN and (total bilirubin >2xULN or INR >1.5)
d. ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
The investigator should evaluate to see if other causes for the laboratory abnormalities are 
immediately apparent, such as obstructive gall bladder or bile duct disease, viral or 
alcoholic hepatitis, malignancy involving the liver, congestive hepatopathy, other 
hepatotoxins or heritable disorders.
3. Unexplained creatine kinase (CK) values >5 x ULN confirmed by repeat test when 
the CK elevation is associated with muscle pain, muscle tenderness and/or muscle 
weakness, or new onset renal dysfunction.
In the case that study medication is permanently discontinued the subject will be asked to 
complete the remainder of the scheduled visits without receiving study medication 
(inclisiran or placebo).
All trial subjects should be followed until all abnormalities return to normal or to the 
baseline state.


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5
Treatment of Subjects
5.1
Study Medications
5.1.1
Inclisiran (also referred to as KJX839)
Investigational product (inclisiran) information is described in Table 5-1.
Table 5-1
Investigational Product
Product Name:
Inclisiran for injection
Active ingredient
Inclisiran sodium
Dosage Form:
Solution for Injection
Unit Dose
Inclisiran sodium 300 mg/1.5 mL (equivalent to 284 mg inclisiran)
Route of 
Administration
SC use
Physical Description
Clear, colorless to pale yellow solution essentially free of 
particulates
Manufacturer
 
Investigational product preparation: The procedure for preparing investigational 
product is provided in the Pharmacy Manual.
Investigational product administration: Subjects will be administered a single SC 
injection of 300 mg Inclisiran for Injection at predefined time points as described in the 
Schedule of Assessments (Table 6-1). Investigational product injection will be 
administered by qualified clinical study site staff under the supervision of the investigator 
or designee. The site of injection is the abdomen, alternating sides for each injection. Do 
not inject into areas of active skin disease or injury such as sunburns, skin rashes, 
inflammation, tattoos or skin infections.
5.1.2
Placebo
For Part 1, placebo will be supplied by the Sponsor to clinical study site as sterile normal 
saline (0.9% sodium chloride in water for injection) for SC injection. The placebo will be 
blinded and look identical to the inclisiran investigational product. Placebo will be 
administered as a single SC injection in an amount matched to the doses within the active 
inclisiran arm (Table 5-1).
5.1.3
Packaging and Labeling
Investigational product (Inclisiran for Injection and matching placebo) will be provided by 
the sponsor in a blinded fashion. All inclisiran and placebo investigational product will 
look identical to each other. Medication labels will comply with regulatory requirements. 


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The storage conditions for each medication provided will be described on the medication 
label.
All inclisiran and placebo investigational product will have a yellow shroud to maintain 
the blind.
5.1.4
Storage
Investigational product will be stored at controlled room temperature (20°C to 25°C [68°F 
to 77°F], with allowable excursions between 15°C and 30°C [59°F to 86°F]) as specified 
in the Pharmacy Manual. Access should be strictly limited to the investigator, pharmacists, 
and their designees. No special procedures are required for the safe handling of Inclisiran 
for Injection.
5.1.5
Accountability
The investigator or designee must maintain an inventory record of investigational product 
(inclisiran/placebo) received and all administered to assure the regulatory authorities and 
the Sponsor that the new investigational product will not be dispensed to any person who 
is not a subject under the terms and conditions set forth in this protocol. Investigational 
product accountability forms and/or specific instructions can be found in the Pharmacy 
Manual.
The investigational product supplied for use in this study is to be prescribed only by the 
Principal Investigator or designated sub-investigators and may not be used for any purpose 
other than that outlined in this protocol.
During the study, all used investigational product containers will be kept until the monitor 
has reviewed the accountability records.
All unused investigational product will be destroyed on site (or returned to the packaging 
and labeling facility for destruction) once the investigational product has been inventoried 
and the monitor has reviewed the accountability records. In the event that investigational 
product needs to be returned for any other reason, the site will receive a written request 
listing the investigational product lot number(s) to be returned and the reason for the return 
request.
5.1.6
Product Deficiencies (Complaints) Reporting
Sites are required to report any product deficiencies (complaints) observed to the Sponsor 
immediately but no later than 24 hours from the time of awareness.
Product Deficiencies reporting: deficiencies related to the identity, durability, reliability, 
quality, safety, effectiveness or performance of a product, after it is released for distribution 
(European Union [EU] DIR 2001/83/EC). (Derived from Ref United States [US] 21 CFR 
211.198).


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Product Technical Complaint: is defined as any verbal or written expression of
dissatisfaction with a Novartis product after it is released for distribution, in its identity, 
quality, stability, durability, usability, reliability, safety, effectiveness or performance
Examples include:

An indication that there is an unexpected physical change in the drug product such as 
discoloration, change in shape of the drug product, presence of particulates or any 
other physical change that might indicate contamination, a manufacturing defect or 
any other event that might indicate a compromise in product quality.

An indication that the content does not meet its labeled volume, count, etc.

An indication that there is an unexpected physical change in any part of the container 
(this includes the vial/container, any part of the seal, the cap or the label).

An indication that the product is mislabeled.

An indication that there is an unexpected physical change of the product or container 
once the product is diluted or reconstituted (the container includes the unit dose, bag, 
intravenous line, syringe or any other item that is in contact with the product).

An indication that the product is falsified, tampered with, or adulterated.
5.2
Concomitant Medications
5.2.1
Prohibited Concomitant Medications
Background lipid-lowering treatment should remain stable throughout the study duration. 
As a result, the following medications/treatments are not permitted to be added or changed 
during the study:

Additional medications prescribed to lower LDL-C after study entry (eg, statins, 
ezetimibe, lomitapide, mipomersen, niacin, colesevelam, bile acid absorption 
inhibitors)

Monoclonal antibodies directed towards PCSK9

Any medication taken for the purpose of lipid lowering, including over-the-counter or 
herbal therapies.
5.2.2
Permitted Concomitant Medications
The following medications/treatments are permitted during the study:

Hormone replacement therapy

Lipid-lowering medications; subjects already on a stable (≥30 days before screening) 
lipid-lowering medications (such as statins and/or ezetimibe) should remain on the 
dose that they have received at time of study entry

Prescription medications prescribed to treat preexisting medical conditions such as 
diabetes and hypertension


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
Prescription or nonprescription medications, when necessary to treat an AE, and at 
the discretion of the investigator
5.3
Medical Management Guidelines
5.3.1
Adverse events
Adverse events or abnormal test findings must be followed until the event (or its sequelae) 
or the abnormal test finding resolves, stabilizes at a level acceptable to the 
Sponsor/Investigator and/or returns to baseline values.
5.3.2
Pregnancy
Pregnant women are excluded from the study. If a subject becomes pregnant during the 
course of the study, the investigational product administration must be discontinued and 
the pregnancy should be followed through to outcome. Follow-up evaluation of fetus and 
newborn should also be performed up to 12 months after birth. Reporting of pregnancy and 
any associated AEs are specified in Section 8.4.3.2.
5.4
Restrictions
Subjects will have to comply with the following restrictions during the study:

Fasted for at least 8 hours for all visits for fasting lipids and glucose blood samples

Blood donation will not be allowed at any time during the study

Must refrain from unaccustomed strenuous physical exercise for 48 hours before the 
screening and any study visit until the follow-up has been completed
5.5
Blinding
5.5.1
Blinding of study medications
Part 1 of this study will be conducted under a double-blind placebo-control. Study 
medication will be blinded prior to distribution to the site. Each unit dose of investigational 
product will contain a yellow shroud to maintain the blind.
Randomization via an automated IRT will be used to assign subjects to blinded 
investigational product. The clinical study site pharmacist will maintain the double blind 
according to site-specific procedures and the Pharmacy Manual. It should be noted that 
inclisiran may be visually distinguishable from placebo; therefore, blinded syringes will be 
provided to all study sites and used to maintain the blind.
5.5.2
Method and Maintenance of Blinding
Investigational product will be blinded prior to distribution to sites. All unit doses of 
investigational product (inclisiran/placebo) will contain a yellow shroud to maintain the 
blind.


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5.6
Unblinding
The unblinding of investigational product during the study can only be performed via the 
IRT. The Principal Investigators/designee will have authorization to unblind a subject via 
the IRT.
During Part 1 of the study, in the event of a suspected unexpected serious adverse reaction 
(SUSAR), The Medicines Company Global Pharmacovigilance (MDCO GPV) 
Department may be required to unblind a subject to meet reporting requirements per 
country specific regulations. In this case, a designated member will have authorization to 
unblind via the IRT.
5.6.1
In the Event of an Emergency: Unblinding a Code
In Part 1, unblinding by request of an Investigator should occur only in the event of an 
emergency or AE for which it is necessary to know the investigational product to determine 
an appropriate course of therapy for the subject. If the Investigator must identify the 
treatment assignment to an individual subject, an Investigator or qualified designee should 
request the medication information from the IRT. The documentation received from the 
IRT indicating the code break must be retained with the subject's source documents in a 
secure manner so as not to unblind the treatment assignment to other site or Sponsor 
personnel. The Investigator is also advised not to reveal the study treatment assignment to 
other site or Sponsor personnel.
6
Schedule and sequence of procedures
The Schedule of Assessments (Table 6-1) summarizes the study assessments by time point. 
This study consists of four periods: Screening, Randomization, Treatment, and End of 
Study.

Screening period (Days -28 to -1): occurs prior to randomization and consists of 
confirming eligibility and collecting baseline assessments.

Randomization (Day 1): occurs on the day of initial administration of investigational 
product (inclisiran or placebo).

Treatment period (Day 1 through Day 690): occurs from the start of investigational 
product administration through the final clinic visit.

Dosing: Day 1 (inclisiran or placebo), Day 90 (inclisiran or placebo), Day 180 
(inclisiran for placebo subjects switching to inclisiran), Day 270 (inclisiran), Day 
450 (inclisiran), and Day 630 (inclisiran; final dose)

Additional clinic visits: Day 150, Day 180 (non-dosing visit for subjects 
randomized to the inclisiran arm), Day 330, Day 510, and Day 690

End of study (EOS) visit: Day 720 (90 days after final dose)


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The expected duration of a subject’s participation in this study is approximately 734 days 
which includes screening, investigational product administration, and the EOS period to 
Day 720.
6.1
Schedule of Assessments
The schedule of assessments is provided in (Table 6-1).
If the COVID-19 pandemic limits or prevents on-site study visits, alternative methods of 
providing continuing care may be implemented. Phone calls or virtual contacts (e.g. 
teleconsult) can replace on-site study visits, for the duration of the pandemic until it is safe 
for the participant to visit the site again. Given the long lasting efficacy and infrequent 
dosing regimen of inclisiran, it is possible to introduce a more variable dosing schedule of 
+/- 2 months during this pandemic, which still allows subjects to receive inclisiran. If the 
two-month window is utilized for the next dose, the subsequent dose may be administered 
up to a maximum of 8 months’ time from the next dose (if the next dose is given early) or 
within a minimum of 4 months’ time (if the next dose is given late).
If a dose is not given within this two-month window, then the subject should be considered 
to have had a missed dose and should return as per the schedule in the protocol for the 
subsequent dose.


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Table 6-1
Schedule of Assessments
Visit
Screening
Randomization 
and Treatment
Treatment
EOS13
Day -28 to 
-1
V1
(baseline)
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
(90 days 
post last 
dose)
Timelines
Day 1
Day 
90
Day 
150
Day 
180
Day 
270
Day 
330
Day 
450
Day 
510
Day 
630
Day 
690
Day 720
Visit windows (+/-weeks)
1
3
3
3*
3*
3*
3*
3*
3*
3*
3*
Informed Consent
X
Medical history and prior 
meds
X
Assessment of eligibility1
X
X
β-HCG pregnancy test 2
X
X
X
X
X
X
X
X
X
X
X
Study drug administration
(inclisiran)
X
X
X
X
X
Study drug administration
(placebo; switch to
inclisiran at Day 180)
X
X
X
X
X
X
Physical examination 3
X
X
Neurological examination4
X
X
X
X
Weight/Height/Waist 
circumference 5
X
X
X
X
X
Vital signs6
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
Fasted lipid 
profile/biomarkers7
X
X
X
X
X
X
X
X
X
X
X
X


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Visit
Screening
Randomization 
and Treatment
Treatment
EOS13
Day -28 to 
-1
V1
(baseline)
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
(90 days 
post last 
dose)
Timelines
Day 1
Day 
90
Day 
150
Day 
180
Day 
270
Day 
330
Day 
450
Day 
510
Day 
630
Day 
690
Day 720
Full serum chemistry 8
X
X
Limited serum chemistry9
X
X
X
X
X
X
X
X
X
X
Hematology and 
coagulation10
X
X
X
X
Urinalysis (local) 11
X
X
X
ADA assessment
X
X
X
X
X
Previous/concomitant 
meds
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
β-HCG=beta-human chorionic gonadotrophic hormone; ADA=anti-drug antibodies; BP=blood pressure; CPK=creatine phosphokinase; CV=cardiovascular; 
ECG=electrocardiogram; eGFR=estimated glomerular filtration rate; EOS=end of study; HbA1C=glycated hemoglobin A1C; HDL-C=high density lipoprotein 
cholesterol; HR=heart rate; LDL-C=low density lipoprotein cholesterol; SC=subcutaneous; V=visit
*: The visit window is extended to +/- 2 months during the COVID-19 pandemic, to allow on-site visits (rather than remote visits) to occur as much as possible
1. Assessment of laboratory eligibility criteria will be based on central laboratory values obtained within timeframes defined in the inclusion and exclusion 
criteria.
2. Only in women of childbearing potential (performed locally, prior to any dosing, using central laboratory kit supplies; urine pregnancy test).
3. Physical examination is the responsibility of the principal investigator or medically qualified designee.
4. Full neurological examination will be performed as described in Appendix°C.
5. Height will be measured at baseline only and used to calculate body mass index.


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Visit
Screening
Randomization 
and Treatment
Treatment
EOS13
Day -28 to 
-1
V1
(baseline)
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
(90 days 
post last 
dose)
Timelines
Day 1
Day 
90
Day 
150
Day 
180
Day 
270
Day 
330
Day 
450
Day 
510
Day 
630
Day 
690
Day 720
6. On dosing days, vital signs will be measured prior to injection. When available, an automated BP device is recommended for collection of BP and the result 
recorded to the nearest mmHg. The subject should be sitting at rest for at least 5 minutes prior to these assessments. One assessment for each vital sign (HR, 
BP) is required per applicable visit
7. See Section 7.2 for details of specific tests to be analyzed
8. See Section 7.1.7.3 for details of specific tests to be analyzed
9. See Section 7.1.7.3 for details of specific tests to be analyzed
10. See Section 7.1.7.1 and Section 7.1.7.2 for details of specific tests to be analyzed
11. Performed locally using the central laboratory kit supplies
13. For subjects prematurely and permanently discontinued from study treatment, EOS visit will be scheduled as soon as possible. If decision to discontinue is 
made at a specific visit, this visit will become the EOS visit and EOS visit procedures should be followed.


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6.2
General Conduct of the Study
Written informed consent will be obtained for this study by the principal investigator or sub-
investigator from all subjects before the performance of any protocol-specific procedure.
Please see the Schedule of Assessments (Table 6-1)
for a detailed schedule and 
Section 7 for details of all tests required in each panel.
6.3
Screening Period (Days -28 to -1)
All screening laboratory tests will be collected and shipped to the Central Laboratory, with the 
exception of urinalysis and pregnancy test, which will be done in-house at the participating 
institution’s laboratory using the testing materials provided by the Central Laboratory. The results 
of all screening laboratory tests should be reviewed prior to enrollment. If results do not confirm 
subject eligibility or suggest any contraindication to treatment with inclisiran, and/or other required 
ancillary medication(s), the subject must not be enrolled.
The following procedures will be performed within 28 days prior to randomization:

Informed consent

Assessment of inclusion and exclusion criteria

Demographics and medical history including disease history (prior history related to the 
disease and prior use of disease related medication, e.g. monoclonal antibodies to PCSK9)

Pregnancy test (performed locally, using central laboratory supplies) (women of childbearing 
potential only)

Physical examination (including height, weight, and waist circumference)

Vital signs (blood pressure and heart rate) (Section 7.1.3)

12-lead ECG

Fasting lipid profile/biomarkers (Section 7.2)

Central clinical laboratory (limited serum chemistry, hematology and coagulation)
(Section 7.1.7)

Urinalysis (performed locally, using central laboratory supplies)

Previous and concomitant medications
 
Central laboratory blood draws should be performed after all other screening tests have been 
confirmed. Results must be available before the start of investigational product injection on Day 1 
to confirm subjects meet eligibility criteria (Section 4.2 and Section 4.3). Please refer to
Section 7.1.7 and Section 7.2 for details of laboratory tests performed during the screening period.


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6.4
Randomization (Day 1)
Randomization should only occur once subject eligibility is confirmed and will be conducted via 
an automated IRT to assign subjects to investigational product. All treatment groups will be studied 
concurrently. At least 45 subjects are planned to be randomized 2:1 (inclisiran: placebo) for 
inclusion in the study.
The following procedures will be performed prior to the injection:

Assessment of inclusion and exclusion criteria

Pregnancy test (performed locally, prior to any dosing, using central laboratory supplies) 
(women of childbearing potential only)

Randomization

Neurological examination (Appendix°C)

Vital signs: blood pressure and heart rate (Section 7.1.3)

Fasting lipid profile/biomarkers (Section 7.2)

Central clinical laboratory (full serum chemistry, hematology and coagulation) 
(Section 7.1.7)

Urinalysis (performed locally, using central laboratory supplies)

Assessment of ADA (Section 7.1.7.8)
The following procedures will be performed after the injection:

Concomitant medications

AE/SAE reporting
Investigational product (inclisiran or placebo) administration will occur at this visit for all subjects 
as per Section 5.1.1 and the Pharmacy Manual.
Subjects must be observed in the clinic for at least 30 minutes after injection.
Should a subject develop signs or symptoms of anaphylaxis when investigational product 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 logically possible).
If a local reaction around the injection site occurs that requires the subject to be seen between visits 
or if a reaction is noticeable on a subsequent visit, photographs of the injection site may be obtained 
if deemed necessary. Photographs should be submitted to the study inbox.
Detailed instructions for investigational product administration are found in the Pharmacy Manual.
6.5
Primary Efficacy Visit (Day 150)
The following assessments will be completed during this visit:

Pregnancy test (performed locally, prior to any dosing, using central laboratory supplies, if 
applicable) (women of childbearing potential only)

Weight and waist circumference

Fasting lipid profile/biomarkers (Section 7.2)


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
Assessment of ADA (Section 7.1.7.8)

Vital signs: blood pressure and heart rate (Section 7.1.3)

Central clinical laboratory (limited serum chemistry, hematology, and coagulation) 
(Section 7.1.7)

Neurological examination (Appendix°C)

Concomitant medications

AE/SAE reporting
6.6
Additional Dosing Visits (Days 90, 180, 270, 450, and 630)
Subjects will return on Day 90 for a second investigational product injection. Subsequent inclisiran 
injections will be administered to all subjects on Day 270, Day 450 and Day 630. In addition, on 
Day 180 subjects originally randomized to the placebo group will be switched to inclisiran and 
receive their first dose of inclisiran on Day 180.
Note: For subjects randomized to the inclisiran arm, Day 180 will be a non-dosing visit but the 
same assessments as described below will be performed except for investigational product 
administration.
The following assessments will be completed during these visits prior to investigational product 
administration:

Pregnancy test (performed locally, prior to any dosing, using central laboratory supplies, if 
applicable) (women of childbearing potential only)

Vital signs: blood pressure and heart rate (Section 7.1.3)

Fasting lipid profile/biomarkers (Section 7.2)

Assessment of ADA (Day 90 only) (Section 7.1.7.8)

Central clinical laboratory (limited serum chemistry) (Section 7.1.7)

Concomitant medication

AE/SAE reporting
Administration of the investigational product is identical to Day 1 and is per Section 5.1.1 and the 
Pharmacy Manual.
Subjects must be observed in the clinic for at least 30 minutes after injection.
Should a subject develop signs or symptoms of anaphylaxis on days when investigational product 
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 logically possible).
6.7
Additional non dosing Clinic Visits (Days 330, 510 and 690)
Subjects will return to the clinic for dosing follow-up visits on Days 330, 510, and 690. Note: for 
subjects randomized to the inclisiran group the Non-dosing visit on Day 180 is described in 
Section 6.6. The following assessments will be completed during these visits:


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6.7.1
Day 330

Pregnancy test (performed locally, using central laboratory supplies, if applicable) (women 
of childbearing potential only)

Weight and waist circumference

Fasting lipid profile/biomarkers (Section 7.2)

Assessment of ADA (Section 7.1.7.8)

Central clinical laboratory (limited serum chemistry) (Section 7.1.7)

Neurological examination (Appendix°C)

Concomitant medications

AE/SAE reporting
6.7.2
Day 510

Fasting lipid profile/biomarkers (Section 7.2)

Central clinical laboratory (limited serum chemistry) (Section 7.1.7)

Concomitant medications

AE/SAE reporting
6.7.3
Day 690

Pregnancy test (performed locally, using central laboratory supplies, if applicable) (women 
of childbearing potential only)

Fasting lipid profile/biomarkers (Section 7.2)

Central clinical laboratory (limited serum chemistry) (Section 7.1.7)

Concomitant medications

AE/SAE reporting
6.8
End of Study (EOS) Visit (Day 720 - 90 days post last dose)
A subject’s participation in the study is complete when the final visit, 90 days after the last dose 
of investigational product, has occurred. The following assessments will be completed during this 
visit:

Pregnancy test (performed locally, using central laboratory supplies, if applicable) (women 
of childbearing potential only)

Physical examination (including weight and waist circumference)

Neurological examination (Appendix°C)

Vital signs: blood pressure and heart rate (Section 7.1.3)

12-lead ECG

Fasting lipid profile/biomarkers (Section 7.2)

Assessment of ADA (Section 7.1.7.8)

Central clinical laboratory (full serum chemistry, hematology and coagulation) 
(Section 7.1.7)


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
Urinalysis (performed locally, using central laboratory supplies)

Concomitant medication

AE/SAE reporting

All ongoing AEs or abnormal test findings will be followed until the event (or its 
sequelae) or the abnormal test finding resolved, stabilized at a level acceptable to the 
Sponsor/Investigator and/or returned to baseline values (Section 8.4.1)
7
Protocol assessments
7.1
Assessment of Safety
7.1.1
Adverse Events
Subjects will be carefully monitored for adverse events by the investigator during the designated 
study period (see Section 8 for details).
7.1.2
Demographics and Medical History
Baseline demographic information will be collected during screening, and will include age, sex, 
and race/ethnicity.
Relevant medical history includes all ongoing medical or surgical issues and any statin intolerance 
documentation. Remote medical and surgical history >5 years from the time of screening should 
only be included if considered relevant to the study.
7.1.3
Vital Signs
Vital signs include heart rate and blood pressure. When available, an automated blood pressure
device is recommended for collection of blood pressure and the result recorded to the nearest 
mmHg. The subject should be sitting at rest for at least 5 minutes prior to these assessments. One 
assessment for each vital sign (heart rate, blood pressure) is required per applicable visit.
7.1.4
Electrocardiograms
Twelve lead ECGs will be collected at the time points in the Schedule of Assessments 
(Table 6-1) only, unless clinically indicated.
7.1.5
Physical Examination
The physical examination should include a focused examination, which may include general, 
respiratory, cardiovascular, abdominal, and extremities evaluations, and recording of weight, waist 
circumference, and height (baseline only).
7.1.6
Neurological Evaluation
A full neurological examination (Appendix°C) will be performed as per the Schedule of 
Assessment (Table 6-1).


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7.1.7
Clinical Laboratory Assessments
Specimens will be obtained at the time points in the Schedule of Assessments (Table 6-1). If an 
apheresis is performed on a visit day, blood samples must be collected prior to the apheresis, and 
prior to the administration of study drug (on dosing visits).
Subjects will be in a fasted state for all clinical laboratory assessments. Screening laboratory tests 
will be performed by the Central Laboratory, with the exception of urinalysis and pregnancy test, 
which will be done in-house at the participating institution’s laboratory using testing materials 
supplied by the Central Laboratory. Results from these screening tests related to eligibility must 
be available before the start of investigational product injection on Day 1 to confirm subjects meet 
eligibility criteria. Details regarding the processing, shipping, and analysis of samples will be 
provided in the Laboratory Manual. Note: Efficacy laboratory assessments (eg, LDL-C and 
PCSK9) are described in Section 7.2.
7.1.7.1
Hematology
Blood draws for hematology will include:

Hemoglobin, hematocrit, erythrocytes, reticulocytes, mean cell hemoglobin (MCH), mean 
corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), platelet 
count, white blood cell count with differential.
7.1.7.2
Coagulation
Blood draws for coagulation will include:

Prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin 
(aPTT).
7.1.7.3
Chemistry
Blood draws for chemistry will be performed per
the Schedule of Assessments 
(Table 6-1). Analysis will vary based on visit day as follows:

Full serum chemistry - Baseline (Day 1) and EOS (Day 720)
AST, ALT, alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), total bilirubin 
(TBIL), direct and indirect bilirubin, creatine phosphokinase (CPK), lactate, bicarbonate, uric 
acid, creatinine, urea (BUN), estimated glomerular filtration rate (eGFR), sodium, potassium, 
calcium, inorganic phosphate, chloride, albumin, total protein, glucose (fasting), glycated 
hemoglobin A1C (HbA1C), and tryptase (as required).

Limited serum chemistry - Screening, Days 90, 150, 180, 270, 330, 450, 510, 630, and 
690
ONLY: AST, ALT, ALP, GGT, TBIL, CPK, creatinine, eGFR, fasting glucose, HbA1C (not 
at Day 150, 330, or 510), and tryptase (as required).
7.1.7.4
Inflammatory markers (IL6, IFN-γ, and TNF-α, hsCRP)
High sensitivity C-reactive protein (hsCRP) testing is performed routinely for safety throughout 
the study and is part of the central laboratory draws.


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Tryptase and other inflammatory markers such as interleukin 6 (IL6), interferon-gamma (IFN-γ) 
and tumor necrosis factor-alpha (TNF-α) may be performed from centrally stored sample aliquots 
at a later date, as required. Should a subject 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 logically possible).
7.1.7.5
Urinalysis
Urinalysis will be performed at the time points defined in the Schedule of Assessments 
(Table 6-1) and evaluated by dipstick analyses at the investigational site (a standardized dipstick 
test will be supplied by the Central Laboratory). Urinalysis will be performed from a sample of 
mid-stream urine. In case of abnormal results, microscopy and other assessments will be performed 
at the local laboratory and the abnormality recorded as an AE.
The following parameters will be assessed:

Nitrite, protein, glucose, ketone, urobilinogen, bilirubin, red blood cells/erythrocytes, white 
blood cells/leukocytes, pH, urine sediment (microscopic examination will be only performed 
in the event of abnormalities).
7.1.7.6
Urine Pregnancy
Urine pregnancy testing will be performed locally at the visits specified in the Schedule of 
Assessments (Table 6-1), using the supplies provided by the Central Laboratory.
7.1.7.7
Lipids / Lipoproteins
Lipids and lipoproteins assessments are described in Section 7.2.
If an apheresis is performed on a visit day, blood samples must be collected prior to the apheresis, 
and, prior to the administration of the study drug (on dosing visits).
7.1.7.8
Anti-drug Antibodies
A serum sample for detection of formation of anti-drug antibodies will be collected at the time 
points in the Schedule of Assessments (Table 6-1). Collection will be prior to investigational 
product administration (injection) and then as per the Schedule of Assessments.
7.1.8
Stored samples
 
 
 
Biological samples for 
biomarker research will be retained on behalf of the Sponsor for a maximum of 1 year following 
the last subject's last visit in the study. Details regarding the collection, processing, storage, and 
shipping will be in the Study Laboratory Manual.


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7.2
Assessment of Efficacy
Subjects will be in a fasted state for all efficacy laboratory 
assessments of 
lipids/lipoproteins/biomarkers. Specimens will be obtained at the time points in the Schedule of 
Assessments (Table 6-1). Parameters to be assessed will include:

Total cholesterol (TC), triglycerides, LDL-C, HDL-C, non-HDL-C, VLDL-C, Apo-A1, Apo-
B, lipoprotein (a) [Lp(a)], hsCRP, and PCSK9.
7.2.1
Change from Day 1 in LDL-C
The primary efficacy endpoint is the percent change in LDL-C from baseline to Day 150.
In addition, this study will assess:

Absolute change in LDL-C (beta quantification [BQ]) from baseline to Day 150

Percentage change and absolute change in LDL-C from baseline to each assessment time up 
to Day 720 (ie, Days 90, 150, 180, 270, 330, 450, 510, 630, 690, and 720)

Individual responsiveness defined as the number of subjects reaching on treatment LDL-C 
levels of <25 mg/dL, <50 mg/dL, 70 mg/dL, and <100 mg/dL at Days 150, 330, 510, 690, 
and 720

Proportion of subjects in each group with greater or equal to 30% LDL-C reduction from 
baseline at Days 150, 180, 330, 510, 690, and 720
Blood samples for determination of LDL-C concentrations will be collected at the time points in 
the Schedule of Assessments (Table 6-1). For all study visits, LDL-C will be calculated (using the 
Friedewald method), in addition at baseline (Day 1), Day 150 and Day 720 LDL-C will be analyzed 
by BQ. Details regarding the collection, processing, shipping, and storage of the samples will be 
provided in a Laboratory Manual.
7.2.2
Change from Day 1 in Lipids/Lipoproteins
Secondary efficacy assessments will include the measure the effects of inclisiran on levels of lipids 
and lipoproteins including total cholesterol, triglycerides, LDL-C, HDL-C, non-HDL-C, VLDL-
C, Apo-A1, Apo-B, Lp(a), hsCRP, and PCSK9.
 
Plasma samples will be analyzed using a validated enzyme linked immunosorbent assay to 
determine PCSK9 protein concentration. Full details of the analytical methods used will be 
described in a separate bioanalytical report.
7.3
Assessment of Pharmacodynamics
Assessment of lipids/lipoproteins as discussed in Section 7.2 will cover pharmacodynamics.


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8
Adverse Events
8.1
Definitions
8.1.1
Adverse Event
Any untoward medical occurrence in a patient or clinical trial subject administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment. An adverse 
event can therefore be any unfavorable and unintended sign (eg, an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.
8.1.2
Serious Adverse Event
Any untoward medical occurrence that at any dose:

Results in death,

Is life-threatening, ie, the subject was, in the opinion of the investigator, at immediate risk of 
death from the event as it occurred (it does not include an event that, had it occurred in a 
more severe form, might have caused death),

Results in a significant, persistent or permanent change, impairment, damage or disruption in 
the subject's body function/structure, physical activities and/or quality of life,

Requires in-subject hospitalization or prolongs hospitalization,

Is a congenital anomaly/birth defect, or

Is another medically significant event where medical and scientific judgement 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 patient or might require intervention to prevent one 
of the other outcomes listed above. 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. Any suspected 
transmission via a medicinal product of an infectious agent is also considered a serious 
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A distinction should be drawn between serious and severe AEs. Severity is an estimate or measure 
of the intensity of an AE, while the criteria for serious AEs are indications of adverse subject 
outcomes for regulatory reporting purposes. A severe AE need not necessarily be considered 
serious and a serious AE need not be considered severe. For example, nausea that persists for 
several hours may be considered severe nausea, but not an SAE. On the other hand, a MI that may 
be considered minor could be an SAE if it prolonged hospitalization.
8.1.3
Special Situations
Information that is not necessarily considered an adverse event but which can possibly contribute 
to the overall knowledge concerning the safety of the investigational product.
Examples include, but are not limited to, reports of pregnancy/lactation exposures with or without 
any AEs related to the parent or child; medication errors - actual and potential; accidental exposure; 
suspected transmission via an investigational product of an infectious agent; drug interaction.
8.2
Collection and Assessment of Adverse Events
8.2.1
Pre-existing Conditions
Planned hospital admissions and/or surgical operations for an illness or disease that existed at 
baseline and did not aggravate during the study should not be reported as AEs.
8.2.2
Adverse Event Severity
The severity of AEs will be assessed by the Investigator using the 3-point scale below:
1 = Mild: Discomfort noticed, but no disruption to daily activity.
2 = Moderate: Discomfort sufficient to reduce or affect normal daily activity.
3 = Severe: Inability to work or perform normal daily activity.
8.2.3
Relationship to Investigational Product
The relationship between the AE and the investigational product will be assessed by using a binary 
assessment. The investigator should determine whether there is a ‘Reasonable possibility’ or ‘No 
reasonable possibility’ that the investigational product caused the event based on the definitions 
below.
Reasonable possibility - There is a reasonable possibility that the administration of the 
investigational product caused the AE. There is evidence to suggest a causal relationship between 
the investigational product and the AE.
No reasonable possibility - There is no reasonable possibility that the administration of the 
investigational product caused the AE. There is no temporal relationship between the 
investigational product and event onset, or an alternative etiology has been established.


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8.3
Requirements For Additional Safety Data Collection
8.3.1
Special Situations
Special Situations designated for this study include:

Medication errors that fall into the following categories

wrong investigational product

wrong dose (including overdose, underdose, change in dosing regimen, strength, form 
concentration, amount)

wrong route of administration

wrong subject (ie, not administered to the intended subject)

accidental exposure

Pregnancy/lactation exposures with or without any AEs related to the parent or child

Suspected transmission via a medicinal product of an infectious agent

Drug interactions
8.3.2
Other safety related information
Injection-site reactions including individual signs or symptoms at the injection site following 
investigational product administration should be recorded on specifically designed eCRF pages. 
Photographs of injection-site reactions, if they were obtained during the study visits, should be 
forwarded to study inbox.
Other safety related information that should be reported as adverse events in accordance with the 
process described in Section 8.4 include:

Abnormal neurological examination, eg, peripheral sensory and motor evaluation, an 
assessment of gait, pain, position, strength and reflexes (Appendix°C).

Potential anaphylactic reactions assessed by Sampson criteria (Appendix°D). If Sampson 
criteria are positive, confirm by elevation of tryptase in blood plasma measured within 
30 minutes of symptoms.

Hyperglycemia-related AEs:

Report ‘New onset of diabetes’ in subjects with no medical history of diabetes when:

HbA1C becomes ≥6.5% and/or

Two consecutive values of fasting plasma glucose that are ≥126 mg/dL

If a new concomitant medication for control of plasma glucose is added, further 
information to assess for a diagnosis of new onset diabetes will be collected.

Report ‘Worsening of the glycemic control’ or ‘diabetic complications’ in subjects with 
a medical history of disease (HbA1C ≥6.5% at baseline) when:

HbA1C increases from baseline > 0.5% and/or

New concomitant medication or increase in dose of current antidiabetic therapy is 
initiated to improve the control of plasma glucose level.


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8.4
Procedure for Adverse Event Reporting
8.4.1
Serious Adverse Events (SAEs)
All SAEs that occur during the designated study period from randomization through EOS must be 
reported using study specific SAE Report Form within 24 hours of awareness of the event. Each 
SAE must also be recorded on the source documents and on the appropriate page of the eCRF.
The Investigator should provide any follow-up information for the event to the Sponsor on an 
updated SAE Report Form as soon as it becomes available. The Sponsor will contact the 
Investigator, if necessary, to clarify any of the event information or request additional information.
If the Investigator is notified of a SAE that occurs post-study period, that he or she wishes to report 
to the Sponsor (eg, an event suspected to be causally related to investigational product), the event 
should be reported through the process described above.
Where appropriate, if required by local regulations or procedures, the Investigator should report 
these events to the Institutional Review Board (IRB)/Ethics Committee (EC) and/or national 
regulatory authority in addition to the Sponsor.
8.4.2
Nonserious AEs
All nonserious AEs that occur during the designated study period from randomization through 
EOS must be assessed and recorded on the source documents and eCRF, regardless of causal 
relationship to the investigational product.
8.4.3
Special situations
8.4.3.1
Medication Errors
Medication errors (e.g, wrong dose concentration, wrong treatment, wrong regimen, wrong 
injection site), with or without an associated AE, will be reported as a protocol deviation 
(Section 12.3). Medication errors and an associated SAE will be recorded in the eCRF and also 
reported to the Sponsor as described in Section 8.4.1. Medication errors and an associated non-
serious AE will be recorded in the eCRF as described in Section 8.4.2.
8.4.3.2
Pregnancy
Occurrences of pregnancy/lactation exposure in a study subject from the time of Day 1 through 
EOS must be reported to the Sponsor within 24 hours using the Pregnancy Exposure Report Form.
In cases where a pregnancy/lactation exposure occurs with a SAE, the SAE Report Form should 
be used to report the SAE and the Pregnancy Exposure Report Form should be used to report the 
pregnancy/lactation exposure.
When a pregnancy occurs without any concurrent SAE, the Pregnancy Exposure Report Form 
must be submitted alone.
The pregnancy should be followed up to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 


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abnormalities, or maternal and/or newborn complications. Newborns should be followed for 12 
months.
8.5
Expectedness
8.5.1
Expectedness Determination
Novartis Safety Department will be responsible for determining whether an AE is expected or 
unexpected for the purpose of SUSAR reporting. An AE will be considered unexpected if the 
nature, severity, or frequency of the event is not consistent with the safety information previously 
described for the investigational product in the current/approved version of the Inclisiran
Investigator’s Brochure.
8.6
Study Stopping Criteria
8.6.1
Independent Data Monitoring Committee (IDMC) Stopping Rules
The IDMC will use all available evidence and its collective judgment to make a recommendation 
to continue, stop, or amend the study at any of its reviews during the double blind and open label 
part of the study. Any statistical considerations are not a substitute for the committee’s medical, 
scientific, or statistical expertise. Details will be provided in the IDMC charter.
8.6.2
Sponsor Discontinuation Stopping Criteria
The Sponsor will review data on an ongoing basis and may, on discussion with the IDMC terminate 
the study for any clinically significant drug related safety signal (eg. serious hypersensitivity 
reactions or drug induced liver injury, etc).
Premature termination of a study may also occur because of a regulatory authority decision, change 
in opinion of the IRB/EC, drug safety problems, or at the discretion of the Sponsor. In addition, 
the Sponsor retains the right to discontinue development of inclisiran at any time.
If a study is prematurely terminated or discontinued, the Sponsor will promptly notify the 
investigator. After notification, the investigator must contact all participating subjects and the 
hospital pharmacy (if applicable) within 30 days of the notification. Final study visits should occur 
within 30 days of subject contact. As directed by the Sponsor, all study materials must be collected 
and all eCRFs completed to the greatest extent possible.
The Sponsor will inform the health authorities and the IRBs/EC that the study has been stopped 
and the reasons for doing so, within the locally applicable timelines.
9
Data Collection
An electronic data capture (EDC) system which is 21 CFR Part 11 compliant will be used for this 
study. All users will be trained on the technical features of the EDC as well as the content of the 
eCRF by qualified personnel prior to gaining access to the EDC. A UserID/Password will be 
granted after training. This ID is not to be shared amongst the study staff. All users must have a 
unique account to enter or review data. The eCRF should be filled out by the site 3 days after each 


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visit. It is not expected that the eCRF will serve as source for any data collected in this study. If 
there is a reason for a site to do so, it must be approved by Sponsor and documented in the site 
files.
Prior to the database being locked, the investigator or designee will review, approve and sign/date 
each completed eCRF. This signature serves as attestation of the Investigator’s responsibility for 
ensuring that all data entered into the eCRF are complete, accurate and authentic. After the end of 
the study, a copy of the data will be provided to the site. This copy will contain the final data, an 
audit trail of activity on the data, and any queries and answers that were posted for data clarification. 
For this study, the EOS will be defined as the last visit of the last subject.
10
Statistical Plan
This study will be a Phase III, two-part (double-blind placebo-controlled/open-label) multicenter 
study to evaluate safety, tolerability, and efficacy in subjects with HoFH. This study has two 
sequential parts:

Part 1: 6-month double-blind period in which subjects will be randomized to receive either 
inclisiran or placebo

Part 2: 18-month open-label follow-up period; placebo-treated subjects from Part 1 will be 
transitioned to inclisiran and all subjects will participate in an open-label follow-up period of 
inclisiran only
The study will be a multicenter, international study. A separate Statistical Analysis Plan (SAP) 
document will provide more detailed specifications in data analysis and presentation.
10.1
Sample Size
The sample size calculation was performed with the hypothesis that the difference of mean percent 
change from baseline to Day 150 between inclisiran and placebo will be >20% (20% standard 
deviation) in subjects with HoFH when treated with inclisiran. The sample size of at least 45 
subjects (randomized 2:1 to inclisiran : placebo), with at least 30 subjects in the inclisiran arm, 
will provide >80% power to detect a 20% reduction of LDL-C levels from baseline in the inclisiran 
group compared to that in the placebo at one-sided significance level of 0.025 based on two-sample 
t-test.
10.2
Randomization
Randomization should only occur once subject eligibility is confirmed and will be conducted via 
an automated interactive response technology (IRT) to assign subjects to blinded investigational 
product at 2:1 ratio to inclisiran versus placebo. Each subject will receive SC injections of blinded 
inclisiran or placebo on Day 1 and Day 90. The inclisiran-treated subjects will receive a third dose 
of inclisiran administered on Day 270 and subsequent doses on Day 450 and Day 630. The 
placebo-treated subjects from Part 1 will transition to an open-label, single arm follow-up period 
of inclisiran only; placebo-treated subjects will receive their first dose of inclisiran on Day 180 
and then subsequently receive a dose of inclisiran on Day 270, Day 450, and Day 630.


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10.3
General Statistical Considerations and Definitions
10.3.1
General Statistical Methods
All study-collected data will be summarized by treatment group using descriptive statistics, graphs, 
and/or raw data listings. Descriptive statistics for continuous variables will include number of 
subjects (n), mean, standard deviation (SD), median, quartiles (Q1 and Q3), minimum (min) and 
maximum (max) values. Analysis of categorical variables will include frequency and percentage.
10.3.2
Analysis Population
The following populations will be used for data analyses and/or presentation.
10.3.2.1 Intent-to-Treat (ITT) Population
All subjects randomized into the study will comprise the ITT population. Treatment classification 
will be based on the randomized treatment. The ITT population will be used as the primary 
population for efficacy.
10.3.2.2 Modified Intent-to-Treat (mITT) Population
All randomized subjects who receive at least one dose of investigational product and have both 
the baseline and the 150 day follow-up LDL-C assessment will comprise the mITT population. 
Treatment classification will be based on the randomized treatment. This population will be used 
to confirm the efficacy.
10.3.2.3 Safety Population
All subjects who received at least one dose of investigational product. Treatment classification 
will be based on the actual treatment received. This will be primary population for the safety 
analyses.
10.3.3
Analysis Windows and Baseline
The observational period for the study includes the screening period (Day -28 to Day -1), the 
treatment period (Day 1 to Day 690), and the EOS visit (Day 720±3 weeks). Any event occurring 
beyond the defined observational period, even if collected on the eCRF, will not be included in the 
planned statistical analysis. However, all data, including that reported after the defined 
observational period, will be included in the subject data listings.
Unless otherwise specified, for evaluations that are collected at multiple occasions prior to 
initiation of investigational product administration, the latest evaluation will be considered the 
"Baseline" evaluation for analysis.
10.3.4
Missing Data Handling
The sponsor will diligently follow up each subject from the beginning till end of study (Day 720±3 
weeks), and make every effort to keep each subject visit within protocol specified window on all
efficacy assessments of lipids/lipoproteins/biomarkers to keep missing data to the minimum 


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regardless of whether the subject is on study treatment, use ancillary therapies, experience an 
adverse event, or adhere to the protocol.
However, if a missing value indeed occurs for any efficacy parameter up to Day 180, it’s going to 
be imputed using appropriate imputation method. The method of the imputation will be consistent 
with that in the other Phase III studies and the details will be in the SAP.
For all missing values after Day 180 on all efficacy parameters, for all other parameters other than 
efficacy, missing data will not be imputed and will be excluded from the associated analysis.
10.4
Statistical Analyses
10.4.1
Demographic and Background Characteristics
Subject demographics and baseline characteristics (including medical history) will be summarized 
by treatment group using the ITT or safety populations.
10.4.2
Investigational Product and Concomitant Medications
Summaries of investigational product and each prior (pre-baseline) medication and concomitant 
(baseline or later) medication will be provided by treatment. Separate summaries will be provided 
for prior medication use. Medications will be coded using the World Health Organization (WHO) 
drug dictionary. Subjects will be counted only once within each period by medication.
10.4.3
Efficacy Analysis
This study is sufficiently powered to show the effect in the primary and key secondary endpoints, 
all other secondary 
 endpoints are supportive hence statistical testing on all other 
secondary 
 endpoints will be performed only if the null hypothesis on primary and 
the key secondary endpoints are rejected. No adjustment for multiplicity is planned among the 
other secondary
 endpoints.
The ITT population will be the primary population for the efficacy analysis. Efficacy analysis may 
also be performed for the mITT population as supportive analysis.
10.4.3.1 Primary Efficacy Endpoints
The primary efficacy endpoint is percent change from baseline to Day 150 in LDL-C.
The primary analysis will be conducted using ANCOVA model based on the multiply imputed 
datasets (100 total). The ANCOVA model will include the fixed effect of treatment group 
(Inclisiran or placebo) and baseline LDL-C as a covariate. Treatment effects from these 100 
ANCOVA analyses will then be combined using Rubin’s method. The difference between 
treatment groups in mean change from baseline to Day 150 in LDL-C and corresponding two-
sided 95% confidence interval will be provided. The p-value for testing equal mean change from 
baseline to Day 150 in LDL-C will also be provided.
The missing data imputation for primary analysis will be the Washout-model-based approach. The 
washout model can be thought of as a modified control-based Pattern-Mixture Model (PMM) that 


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will be used to explore the possibility of data missing not at random (MNAR) for subjects who 
discontinued the study early.
Sensitivity analysis for the primary efficacy endpoint will use Wilcoxon rank-sum test, a 
nonparametric analysis method, as well as the two-sample t-test.
Also, we will perform sensitivity analyses to explore the dropout pattern and its possible impact 
on treatment comparisons in order to support the robustness of the conclusion drawn from the 
primary analysis using data up to Day 180. Pattern-Mixture Model (PMM) will be used to check 
the robustness when data missing not at random (MNAR) for subjects who discontinued study 
treatment. A control-based pattern-mixture model will be utilized. Multiple imputation will be 
used to account for uncertainty in the imputation process and results from a Mixed-effects Model 
for Repeated Measures (MMRM) on the imputed datasets will be combined using Rubin’s method. 
Furthermore, a tipping point analysis will be performed to search for the tipping point that reverses 
the study conclusion. In addition, an analysis based on a Mixed-effects Model for Repeated 
Measures (MMRM) without multiple imputation will be performed.
The primary analysis and sensitivity analyses will be performed on both ITT and mITT populations.
Details of the sensitivity analysis specified above will be in the SAP.
10.4.3.2 Secondary Efficacy Endpoints
For the first four key secondary endpoints, the following efficacy analyses will be performed on 
the ITT and mITT populations:

Similar to the primary analysis of the primary efficacy endpoint, the ANCOVA model will 
be used on the multiply imputed datasets (100 total) – Washout based approach. Treatment 
effects from these 100 ANCOVA analyses will then be combined using Rubin’s method.

MMRM model will be used on the multiply imputed datasets (100 total) – PPM based 
imputation. Treatment effects from these 100 ANCOVA analyses will then be combined 
using Rubin’s method

Analysis based on a Mixed-effects Model for Repeated Measures (MMRM) without multiple 
imputation will be performed.
For the key secondary endpoint of ≥ 30% LDL-C reduction from baseline to Day 150, a logistic 
regression model with treatment as the effect will be used, and the odds ratio and its 95% 
confidence interval will be provided. The multiply imputed datasets created from both the washout 
model and the control-based PMM will be utilized in this analysis.
For the other secondary endpoints specified in Section 3.4, generally descriptive and graphical 
summaries by treatment group will be presented for the ITT population. The two-sided 95% 
confidence interval may be provided for continuous variables based on the MMRM model. Odds 
ratio and 95% confidence interval may be provided for binary variables. Nominal p-values may be 
provided when applicable.Details of the analyses for the secondary endpoints are specified in the 
SAP.


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10.4.4
Safety Analysis
The safety objectives of this study are to evaluate the safety and tolerability profile of inclisiran.
10.4.4.1 Adverse Events
The Medical Dictionary for Regulatory Activities (MedDRA) dictionary will be used for coding 
AEs. An AE (classified by preferred term) occurring during the investigational product treatment 
period will be counted as a treatment emergent AE (TEAE) either if it is not present at baseline or 
if it is present at baseline but increased in severity during the treatment period.
The number (percentage) of subjects reporting TEAEs for each preferred term will be tabulated by 
system-organ class, by system-organ class and severity, and by system-organ class and relationship 
to investigational product. If more than one event occurred with the same preferred term for the 
same subject, the subject will be counted only once for that preferred term using the most severe 
or related occurrence for the summary by severity, or relationship to investigational product, 
respectively.
10.4.4.2 Laboratory Tests
Laboratory values will be summarized by treatment group, including changes and percent changes 
from baseline at each time point. Analyses will also be performed for each laboratory parameter 
by treatment group for incidence rates of potentially clinical significant (PCS) values for subjects 
without PCS value at baseline.
Numerical values of laboratory parameters from different local laboratories with different units 
and normal ranges will be converted to the conventional units and normalized to a standard set of 
reference/normal ranges. The normalization process will be performed and separated by each of 
the laboratory parameters. A shift analysis by normal range will be done which counts the number 
of patients with a low, normal or high value at baseline and a low, normal or high value post 
baseline.
10.4.4.3 Vital Signs
Change and percent change from baseline in vital signs will be summarized descriptively at each 
scheduled time point by treatment group.
10.4.4.4 Neurological Examinations
The percentage of subjects with a treatment-emergent abnormal neurological examination and the 
specific abnormality reported will be summarized by treatment group.
10.4.4.5 Pharmacodynamic Parameters
Pharmacodynamic biomarker samples will be collected and stored for up to 1 year following the 
completion of the last subject for research purposes to identify and/or verify biomarkers that are 
predictive of response to inclisiran treatment (in terms of efficacy, safety and tolerability).


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10.5
Interim Analysis
No formal interim analysis will be performed in this study.
10.5.1
Interim Safety Review
The Independent Data Monitoring Committee (IDMC) will review safety data 90 days after the 
first 20 subjects receive the first injection of inclisiran or placebo. Thereafter the IDMC will review 
safety data every 3 months until all patients have reached Day 180 unless requested otherwise by 
the IDMC. A recommendation will be made to continue, stop or amend the study at any of these 
reviews. Following Day 180 the unblinded data will be reviewed by the IDMC.
11
Records Retention
The US FDA regulations require all investigators participating in clinical study drug studies to 
maintain detailed clinical data for one of the following periods:

At least two years following the date on which a New Drug Application is approved by the 
FDA, or

Two years after the Sponsor notifies the investigator that no further application is to be filed 
with the FDA.
Similarly, current EU Directives / Regulations and International Conference on Harmonisation 
(ICH) guidelines collectively require that essential clinical study documents (including case report 
forms) other than patient’s medical files must be retained for the following time period:

for at least 15 years after completion or discontinuation of the study,

or for at least two years after the granting of the last marketing authorization in the European 
Community and when there are no pending or contemplated marketing applications in the 
European Community,

or for at least two years after formal discontinuation of clinical development of the 
investigational product.
Subject's medical files should be retained in accordance with applicable legislation and in 
accordance with the maximum period of time permitted by the hospital, institution or private 
practice. The documents can be retained for a longer period, however, if required by the applicable 
regulatory requirements or by agreement with the sponsor.
To comply with these requirements, the investigator will not dispose of any records relevant to 
this study without either (1) written permission from the Sponsor or (2) providing an opportunity 
for the Sponsor to collect such records. The investigator shall take responsibility for maintaining 
adequate and accurate hard copy source documents of all observations and data generated during 
this study, including the hard copy or discs received from the sponsor of the final data. Such 
documentation is subject to inspection by the Sponsor or its agents, the FDA and/or other 
regulatory agencies.


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Quality Control and Quality Assurance
12.1
Monitoring
The Sponsor has ethical, legal and scientific obligations to carefully follow this study in 
accordance with established research principles and applicable regulations. The investigator, as 
part of his responsibilities, is expected to cooperate with the Sponsor in ensuring that the study 
adheres to the protocol and GCP requirements.
As part of a concerted effort to fulfill these obligations, the Sponsor's monitor will visit the center(s) 
during the study in accordance with the Monitoring Plan set forth for this study. The investigator 
will permit the Sponsor to monitor the study as frequently as is deemed necessary and provide 
access to medical records/source documents to ensure that data are being recorded adequately, that 
data are verifiable and that protocol adherence is satisfactory.
12.2
Auditing
The Sponsor may conduct audits at the study center(s). Audits will include, but not be limited to, 
investigational product supply, presence of required documents, the informed consent process, and 
comparison of eCRFs with source documents. The investigator agrees to permit audits conducted 
at a reasonable time in a reasonable manner.
Regulatory authorities worldwide may also inspect the investigator during or after the study. The 
investigator should contact the Sponsor immediately if this occurs, and must permit regulatory 
authority inspections.
12.3
Protocol Deviations
Deviations from the protocol identified during the conduct of the trial will be recorded in the eCRF. 
These include but are not limited to the following:

Inclusion criteria violation

Exclusion criteria violation

Laboratory assessments not drawn at Day 1, Day 150, 510 or Day 720 (EOS) visits

Mis-Dosing for any reason other than subject safety or withdrawal (defined as missing dose 
or a dose delayed by more than 30 days)*

Subject taking any prohibited concomitant medication

Change in baseline statin or other lipid-lowering therapy dose

SAEs not reported to the Sponsor within 24 hours

Informed Consent not signed prior to study entry
*If the mis-dosing was unintended, ie, a medication error, the error should be reported as per 
instructions in Section 8.4.3.1, Medication Errors.
Additional protocol deviations and associated actions depending on the nature and impact of the 
protocol deviation will be defined and periodically reviewed by standard automated and/or manual 
checks by the clinical team or monitors.


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13
Ethics and Responsibility
This study will be conducted in compliance with the protocol, the Sponsor’s standard operating 
procedures and/or guidelines, the US FDA regulations, the ICH GCP guidelines, the Declaration 
of Helsinki and other local regulations, as applicable.
13.1
Informed Consent
Written informed consent will be obtained from all subjects (or their guardian or legally authorized 
representative), and whenever possible, or as per IRB or EC guidelines before any study-related 
procedures (including any pre-treatment procedures) are performed. The investigator(s) has both 
ethical and legal responsibility to ensure that each subject (and their guardian or legally authorized 
representative) being considered for inclusion in this study is given a full explanation of the 
protocol. This shall be documented on a written informed consent form, which shall be approved 
by the same IRB or EC responsible for approval of this protocol. Each informed consent form shall 
include the elements required by ICH, Part E6, Section 4.8 and any applicable local regulations. 
The investigator agrees to obtain approval from the Sponsor of any written informed consent form 
used in the study, preferably prior to submission to the IRB or EC.
Once the appropriate essential information has been provided to the subject and fully explained by 
the investigators (or a qualified designee) and it is felt that the subject understands the implications 
of participating, the subject and the investigator (or designee) shall sign the IRB- or EC-approved 
written informed consent form. The subject shall be given a copy of the signed informed consent 
form, and the original shall be filed appropriately, according to the institution. A second copy may 
be filed in the subject's medical record, if allowed by the institution.
13.2
Institutional Review Board/Ethics Committee
This protocol, the written informed consent form and any materials presented to subjects shall be 
submitted to the IRB or EC identified with this responsibility. Notification in writing of approval 
must come from the IRB or EC chairman or secretary, to the investigator, either as a letter or as a 
copy of the appropriate section of the IRB or EC meeting minutes where this protocol and 
associated informed consent form were discussed. The investigator will not participate in the 
decision. If the investigator is an IRB or EC member, the written approval must indicate such 
nonparticipation in the voting session. The investigator will submit status reports to the IRB or EC 
as required by the governing body. The IRB or EC must be notified by the investigator in writing 
of the interruption and/or completion of the study; the investigator must promptly report to the 
IRB or EC all changes in research (protocol amendments) and will not make such changes without 
IRB or EC approval, except where necessary to eliminate apparent immediate hazards to human 
subjects. In cases where it is necessary to eliminate immediate hazards to subjects, the IRB or EC 
must then be notified of the change as per local requirements. The investigator is required to 
maintain an accurate and complete record of all written correspondence to and received from the 
IRB or EC and must agree to share all such documents and reports with the Sponsor.


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Confidentiality
All information generated in this study must be considered highly confidential and must not be 
disclosed to any persons not directly concerned with the study. However, authorized regulatory 
officials and Sponsor personnel will be allowed full access to the records. All medications provided 
and subject bodily fluids and/or other materials collected shall be used solely in accordance with 
this protocol.
Only unique subject numbers in eCRFs will identify subjects. Their full names may, however, be 
made known to a product regulatory agency or other authorized official if necessary.
Sponsor commits to comply with all applicable data protection laws and regulations and take all 
appropriate measures to ensure that subjects’ data is processed securely and appropriately. Sponsor 
adheres to the privacy principles of notice, choice, accountability for onward transfer, security, 
data integrity, purpose limitation, access, and enforcement regarding the collection, use, and 
retention of personal information from European Economic Area countries and Switzerland. In 
addition, Sponsor’s Global Commercial General Liability with Umbrella Liability and Global 
Products / Clinical Trial Liability policy includes coverage for the processing of subjects’ data.
15
Investigator Agreement (for Original Protocol)
I have read and understand the protocol (including the Investigator’s Brochure) and agree that it 
contains all the ethical, legal and scientific information necessary to conduct this study. I will 
personally conduct the study as described.
I will provide copies of the protocol to all physicians, nurses and other professional personnel 
responsible to me who will participate in the study. I will discuss the protocol with them to assure 
myself that they are sufficiently informed regarding the new study drug inclisiran, the concurrent 
medications, the efficacy and safety parameters and the conduct of the study in general. I am aware 
that this protocol must be approved by the IRB or EC responsible for such matters in the Clinical 
Study Facility where inclisiran will be tested prior to commencement of this study. I agree to 
adhere strictly to the attached protocol. I understand that this IRB or EC approved protocol will be 
submitted to relevant regulatory authorities by the Sponsor, as appropriate. I agree that clinical 
data entered on case report forms by me and my staff will be utilized by the Sponsor in various 
ways such as for submission to governmental regulatory authorities and/or in combination with 
clinical data gathered from other research sites, whenever applicable. I agree to allow Sponsor 
monitors and auditors full access to all medical records/source documents at the research facility 
for subjects screened or randomized in the study.


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I agree to provide all subjects with informed consent forms, as required by government and ICH 
regulations. I further agree to report to the Sponsor any adverse experiences in accordance with 
the terms of this protocol, ICH guideline, Part E6, Section 4.11 and applicable local regulations.
Principal Investigator
(Signature)
Date
Principal Investigator
(Printed Name)
Protocol Version
Institution Name


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16
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432.
Raal F, Scott R, Somaratne R, et al. (2012) Low-Density Lipoprotein Cholesterol-Lowering 
Effects of AMG 145, a Monoclonal Antibody to Proprotein Convertase Subtilisin/Kexin Type 9 
Serine Protease in Patients With Heterozygous Familial Hypercholesterolemia: The Reduction of 
LDL-C With PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder 
(RUTHERFORD) Randomized Trial. Circulation.;126(20):2408-17.
Ridker PM, Tardif JC, Amarenco P, et al. (2017) Lipid-reduction variability and antidrug-
antibody formation with bococizumab. N Engl J Med.:Apr 20;376(16):1517-1526. doi: 
10.1056/NEJMoa1614062. Epub 2017 Mar 17.
Roth EM, McKenney JM, Hanotin C, et al. (2012) Atorvastatin with or without an Antibody to 
PCSK9 in Primary Hypercholesterolemia. N Engl J Med.;367(20):1891-900.
Sabatine MS, Giugliano RP, Wiviott SD, et al. (2015) Efficacy and safety of evolocumab in 
reducing lipids and cardiovascular events. N Engl J Med.;372:1500-9.
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 
Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy 
Clin Immunol., 117(2):391-7.
Soutschek J, Akinc A, Bramlage B, et al. (2004) Therapeutic silencing of an endogenous gene by 
systemic administration of modified siRNAs. Nature.;432(7014): 173-8.
Stein EA, Mellis S, Yancopoulos GD, et al. (2012) Effect of a monoclonal antibody to PCSK9 
on LDL cholesterol. N Engl J Med.;366(12): 1108-18.


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Sullivan D, Olsson AG, Scott R, et al. (2012) Effect of a Monoclonal Antibody to PCSK9 on 
Low-Density Lipoprotein Cholesterol Levels in Statin-Intolerant Patients: The GAUSS 
Randomized Trial. JAMA.;308(23):2497-506.
Tabernero J, Shapiro GI, LoRusso, et al. (2013) First-in-Humans Trial of an RNA Interference
Therapeutic Targeting VEGF and KSP in Cancer Patients with Liver Involvement. Cancer 
Discov.;3(4):406-417.
WHO, World Health Organization Cardiovascular diseases. (2016)
http://.who.int/mediacentre/factsheets/fs317/en/
Zhang XL, Zhu QQ, Zhu L, et al. (2015) Safety and efficacy of anti-PCSK9 antibodies: a meta-
analysis of 25 randomized, controlled trials. BMC Med.;13:123.
Zhao Z, Tuakli-Wosornu Y, Lagace TA, et al. (2006) Molecular characterization of loss-of-
function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum 
Genet.;79(3):514-23.
Zimmermann TS, Lee AC, Akinc A, et al. (2006) RNAi-mediated gene silencing in non-human 
primates. Nature.;441(7089):111-4.


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Appendix A: Simon Broome diagnostic criteria for Familial 
Hypercholesterolemia
Definite Familial Hypercholesterolemia:
Required laboratory = high cholesterol levels:

Adult = Total cholesterol levels > 290 mg/dL (7.5 mmol/L) or LDL-C > 190 mg/dL (4.9 
mmol/L)

Child less than 16 years of age = Total cholesterol levels > 260 mg/dL (6.7 mmol/L) or LDL-
C > 155 mg/dL (4.0 mmol/L)
Plus at least one of the two:
1. Plus physical finding = tendon xanthomas, or tendon xanthomas in first or second degree 
relative 
OR
2. DNA-based evidence of an LDL-receptor mutation, familial defective Apo-B-100, or a 
PCSK9 mutation
Possible Familial Hypercholesterolemia:
Laboratory - high cholesterol levels:

Adult = Total cholesterol levels > 290 mg/dL (7.5 mmol/L) or LDL-C > 190 mg/dL 
(4.9 mmol/L)

Child less than 16 years of age = Total cholesterol levels > 260 mg/dL (6.7 mmol/L) or LDL-
C > 155 mg/dL (4.0 mmol/L)
Plus at least one of the two:
1. Family history of at least one of the following.
a. Family history of myocardial infarction at:
i.
Age 60 years or younger in first-degree relative
ii.
Age 50 years or younger in second-degree relative
OR
2. Family history of elevated total cholesterol
a. Greater than 290 mg/dL (7.5 mmol/L) in adult first- or second-degree relative
b. Greater than 260 mg/dL (6.7 mmol/L) in child, brother or sister aged younger than 16 
years
Source: Austin, et al, 2004.


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Appendix B: Requirements for background lipid lowering treatment
There should be no plans at the time of screening and randomization to modify the dose of statin 
or other lipid lowering medication such as ezetimibe for the duration of the trial. Unless the 
background lipid lowering treatment exceptions described below are met, subjects must have been 
treated with one of the following highly effective statins at the specified daily doses and at a stable 
dose, preferably for 6 weeks but for at least 30 days, prior to screening for the study:
1. atorvastatin, 40 or 80 milligrams (mg) once a day;
2. rosuvastatin, 20 or 40 mg, once a day;
3. simvastatin 40 mg, once a day or, if a subject has been on that dose for >1 year,
80 mg, once a day.
Combination medications that contain atorvastatin, rosuvastatin, or simvastatin components 
described at the aforementioned doses will be permitted.
Background lipid lowering treatment exceptions
The following background lipid lowering treatment exceptions are permitted:
1. Lower doses of statins due to partial statin intolerance:
Subjects may be on a lower dose of one of the highly effective statins described above if there is 
documented intolerance to any one of them (atorvastatin, rosuvastatin, or simvastatin) at the 
aforementioned doses. Intolerance to any dose of any statin must be documented as historical 
adverse events attributed to the statin in question, in the source documentation and eCRF.
2. Regulatory limitations:
Subjects may be on a lower dose of one of the highly effective statins described above if the highest 
locally approved dose for one of the stated statins is lower than those doses shown above (eg, in 
some countries, atorvastatin 20 mg, once a day, is the highest locally approved dose).
3. Alternative statins:
Subjects may be treated with other statins (pravastatin, fluvastatin, pitavastatin, or lovastatin), 
different from the highly effective statins listed above, if there is documented intolerance to any 
two different highly effective statins (atorvastatin, rosuvastatin, simvastatin) at the lowest available 
daily dose for at least one of those highly effective statins. Intolerance to any statin must be 
documented as historical adverse events attributed to the statin in question, in the source 
documentation and eCRF.


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4. No background statin therapy:
Subjects may be enrolled who are only on nonstatin lipid lowering therapy, if complete statin 
intolerance has been documented. Subjects with complete statin intolerance must be unable to 
tolerate at least two statins: one statin at the lowest available daily dose AND another statin at any 
dose. Intolerance to any statin must be documented as historical adverse events attributed to the 
statin in question, in the source documentation and eCRF. The sole exception, for which a subject 
may participate in the study with documentation of intolerance to only one statin, is a documented 
history of rhabdomyolysis attributed to that statin.


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Appendix C: 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 movements
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.
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.


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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.
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.


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
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.

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.
Reflex responses:
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).


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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.
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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Appendix D: 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: systolic blood pressure <90 millimeters of mercury (mmHg) or >30% decrease 
from that person’s Day 1 reading
*Low systolic blood pressure 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; Sampson et al, 2006.

SAP_001.pdf: 
Clinical Development 
KJX839
MDCO-PCS-17-02 (CKJX839A12302) / NCT03851705
A two-part (double-blind placebo-controlled/open-label) 
multicenter study to evaluate safety, tolerability, and efficacy 
of inclisiran in subjects with homozygous familial 
hypercholesterolemia (HoFH)
ORION-5
Document type:
Statistical Analysis Plan (SAP)  
EUDRACT number:
2018-000893-31
Document status:
Final Amendment v4.0
Release date:
23-Mar-2021
Number of pages:
49
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Table of contents
Table of contents..................................................................................................................2
1
INTRODUCTION ...............................................................................................................5
2
TRIAL DESIGN..................................................................................................................5
2.1
Type/Design of Trial................................................................................................5
2.2
Objectives of the Trial..............................................................................................6
2.3
Schematic Diagram of Trial Design.........................................................................7
2.4
Schedule and Sequence of Procedures.....................................................................7
3
GENERAL CONDUCT OF TRIAL..................................................................................11
3.1
Screening Period (Days –28 to –1) ........................................................................11
3.2
Randomization (Day 1)..........................................................................................11
3.3
Day 150..................................................................................................................12
3.4
Additional Dosing Visits (Days 90, 180, 270, 450, and 630)................................13
3.5
Additional Non-Dosing Clinic Visits (Days 330, 510 and 690)............................13
3.5.1
Day 330 .................................................................................................13
3.5.2
Day 510 .................................................................................................14
3.5.3
Day 690 .................................................................................................14
3.6
End of Study (EOS) Visit (Day 720 – 90 days post last dose) ..............................14
3.7
Interim Analysis.....................................................................................................14
3.7.1
Interim Safety Reviews .........................................................................15
3.8
Assessment of Safety .............................................................................................15
3.8.1
Adverse Events......................................................................................15
3.8.2
Demographics and Medical History......................................................15
3.8.3
Vital Signs .............................................................................................15
3.8.4
Electrocardiograms................................................................................15
3.8.5
Physical Examination............................................................................15
3.8.6
Neurological Evaluation........................................................................15
16
3.8.8
Clinical Laboratory Assessments ..........................................................16
3.8.9
Stored samples.......................................................................................17
3.9
Assessment of Efficacy..........................................................................................18
3.10
Assessment of Pharmacodynamics........................................................................18
18
4
ADVERSE EVENTS.........................................................................................................19


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4.1
Adverse Event........................................................................................................19
4.2
AE Severity............................................................................................................19
4.3
Study Drug Causality.............................................................................................19
4.4
Serious Adverse Event...........................................................................................19
4.5
Additional Collection of Safety Data.....................................................................20
4.5.1
Special Situations ..................................................................................20
4.5.2
Other safety related information............................................................20
5
MEASURES TO MINIMIZE/AVOID BIAS....................................................................21
5.1
Blinded Study.........................................................................................................21
6
STATISTICAL PLAN.......................................................................................................21
6.1
Sample Size............................................................................................................21
6.2
Randomization .......................................................................................................21
6.3
General Statistical Considerations and Definitions ...............................................22
6.3.1
General Statistical Methods...................................................................22
6.3.2
Analysis Population...............................................................................22
6.3.3
Analysis Windows and Baseline ...........................................................23
6.3.4
Missing data handling............................................................................24
6.4
Statistical Analyses ................................................................................................24
6.4.1
Subject Disposition................................................................................24
6.4.2
Protocol Deviations ...............................................................................25
6.4.3
Demographic and Background Characteristics .....................................25
6.4.4
Study Drug Exposure ............................................................................26
6.4.5
Concomitant Medications......................................................................26
6.4.6
Efficacy Analysis...................................................................................26
6.4.7
Subgroup Analysis.................................................................................32
6.4.8
Safety Analysis......................................................................................33
7
COMPUTER METHODS .................................................................................................40
8
CHANGES TO ANALYSES SPECIFIED IN THE PROTOCOL ...................................40
9
REFERENCES ..................................................................................................................40
10 APPENDICES ...................................................................................................................41
10.1
Appendix 1: Details of MMRM Used for Efficacy Analyses................................41
10.2
Appendix 2: Multiple Imputation Washout Model................................................42
10.3
Appendix 3: Control-Based Pattern Mixture Model..............................................44
10.4
Appendix 4: Criteria for Potentially Clinically Significant and clinically 
significant Abnormal Laboratory Tests .................................................................46
10.5
Appendix 5: Additional Adverse Event Investigations..........................................47


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10.6
Appendix 6: Clinically Relevant Adverse Events at the Injection Site Preferred 
Terms .....................................................................................................................49
List of tables
Table 2-1
Study Design and Schedule of Assessments ...........................................9
Table 6-1
Analysis Windows for Each Scheduled Visit........................................23
Table 6-2
Subgroups for Analysis .........................................................................32
List of figures
Figure 2-1
Study Design ...........................................................................................7


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1
INTRODUCTION
Inclisiran (also referred to as KJX839) is a novel synthetic ribonucleic acid (RNA) interference 
(RNAi) therapeutic for injection (subcutaneous [SC] use) and used for the treatment of 
hypercholesterolemia. This document presents a statistical analysis plan (SAP) for study protocol 
MDCO-PCS-17-02 (CKJX839A12302)  Amendment 1 dated 08 Oct 2020, A two-part (double-
blind placebo-controlled/open-label) multicenter study to evaluate safety, tolerability, and efficacy 
of inclisiran in subjects with homozygous familial hypercholesterolemia (HoFH), referred to 
ORION-5 below.
2
TRIAL DESIGN
2.1
Type/Design of Trial
The ORION-5 study is a Phase III two-part (double-blind placebo-controlled/open-label) 
multicenter study in subjects with homozygous familial hypercholesterolemia (HoFH) to evaluate 
the safety, tolerability, and efficacy of subcutaneous inclisiran injection(s). This study has two 
sequential parts:

Part 1: 6-month (completion of Day 180) double-blind period in which subjects will be 
randomized to receive either inclisiran or placebo

Part 2: 18-month open-label follow-up period; placebo-treated subjects from Part 1 will be 
transitioned to inclisiran and all subjects will participate in an open-label follow-up period of 
inclisiran only
Informed consent will be obtained from subjects before the initiation of any study-specific 
procedures. Subjects who meet study inclusion/exclusion criteria will be instructed to continue to 
follow a National Cholesterol Education Program Adult Treatment Panel III (or comparable) diet 
and be required to maintain their current lipid lowering drug therapy for the duration of the study.
In this study, at least 45 subjects will be enrolled and randomized 2:1 to receive either inclisiran 
sodium 300 mg SC or placebo on Day 1. Inclisiran and placebo will both be administered by a 
health care provider. Subjects will be observed in the clinic for at least 30 minutes post injection 
before being discharged. A second dose of inclisiran or placebo will be given at Day 90. 
After completion of Part 1, the inclisiran-treated subjects from Part 1 will receive a third dose of 
inclisiran administered on Day 270 and subsequent doses on Day 450 and Day 630. The placebo-
treated subjects from Part 1 will be transitioned to inclisiran starting on Day 180, the start of the 
open-label, single arm follow-up period of inclisiran only (Part 2). Placebo-treated subjects will 
receive their first dose of inclisiran on Day 180 and then subsequently receive a dose of inclisiran 
on Day 270, Day 450, and Day 630.
Subjects on a documented regimen of LDL or plasma apheresis will be allowed to continue their 
same regimen during the study using approximately the same frequency/timing as done at baseline. 
When apheresis is performed on a study visit (Dosing or Non-Dosing), blood samples for 
measurement of LDL-C, other lipids and laboratory assessments must be collected before the 
apheresis. When apheresis is performed on a Dosing Visit, dosing must occur just after completion 
of the apheresis. The next scheduled apheresis must not occur within 72 hours of injection of 


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inclisiran. The subsequent study visit must occur at least 2 weeks after an apheresis was performed 
to ensure LDL-C levels measured during a study visit are not confounded by the apheresis.
Safety results including adverse events (AEs), serious adverse events (SAEs), electrocardiograms 
(ECGs), concomitant medications, and clinical laboratory parameters will be assessed at specified 
visits through to the end of study (EOS) visit. All AEs must be reported. Adverse events or 
abnormal test findings will be followed until the event (or its sequelae) or the abnormal test finding 
resolves, stabilizes at a level acceptable to the Sponsor/Investigator and/or returns to baseline 
values. Other safety related information that should be reported as AEs include injection site 
reactions, abnormal results of neurological, potential anaphylactic/hypersensitivity reactions, new 
onset of diabetes, and worsening of glycemic control.
Samples to detect formation of anti-drug antibodies (ADA; including binding and neutralizing 
antibodies) will be collected on Day 1 (prior to the injection) and at Day 90, Day 150, Day 330, 
and Day 720.
The primary endpoint will be measured at Day 150 after which placebo-treated subjects will be 
transitioned to inclisiran on Day 180. All subjects will be enrolled in a long-term open-label 
follow-up period through Day 720 (EOS).
Efficacy (pharmacodynamic) assessments will include measurement of the effects of inclisiran on 
levels of LDL-C, other lipoproteins including total cholesterol (TC), triglycerides, high density 
lipoprotein cholesterol (HDL-C), non-HDL-C, very low density lipoprotein cholesterol (VLDL-
C), apolipoprotein A1 (Apo-A1), apolipoprotein B (Apo-B), lipoprotein(a) [Lp(a)], and PCSK9. 
LDL-C is analyzed by beta-quantification (BQ) on Day 1, Day 150 and Day 720, and calculated 
using the Friedewald method on all visit days.
The safety and tolerability data from the double-blind and open label part of the study will be 
reviewed by an Independent Data Monitoring committee (IDMC) at pre-defined frequency. A 
recommendation will be made to continue, stop, or amend the study at any of these reviews.
After all subjects complete Part 1 of the study, a full set of statistical analyses specified in this SAP 
will be performed which include data from Part 1 and available data from Part 2 of this study. The 
data generated from this formal analysis may be used for potential submission to Health 
Authorities to support an indication in subjects with HoFH.
2.2
Objectives of the Trial
Primary Objective:
The primary objective of this study is to evaluate the effect of inclisiran treatment on:

Low-density lipoprotein cholesterol (LDL-C) levels at Day 150
Secondary Objectives:
The secondary objectives of this study are to evaluate the effect of inclisiran on:

LDL-C levels over time

Proprotein convertase subtilisin/kexin type 9 (PCSK9) levels over time

Other lipids, lipoproteins, and apolipoproteins


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
Individual responsiveness of subjects to inclisiran including proportion of subjects achieving 
prespecified global lipid guidelines for their indication 

Proportion of subjects with at least 30% LDL-C reduction from Day 1 over time
and to assess the:

Safety and tolerability profile of inclisiran
 
 
 
2.3
Schematic Diagram of Trial Design
The study design is presented in Figure 2-1:
Figure 2-1
Study Design
FUP=follow-up; V=visit
2.4
Schedule and Sequence of Procedures
The Schedule of Events/Assessments (Table 2-1) summarizes the study assessments by time point. 
This study consists of four periods: Screening, Randomization, Treatment, and End of Study.


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
Screening period (Days -28 to -1): occurs prior to randomization and consists of confirming 
eligibility and collecting baseline assessments. 

Randomization (Day 1): occurs on the day of initial administration of investigational product 
(inclisiran or placebo).

Treatment period (Day 1 through Day 690): occurs from the start of investigational product 
administration through the final clinic visit.

Dosing: Day 1 (inclisiran or placebo), Day 90 (inclisiran or placebo), Day 180 (inclisiran 
for placebo subjects switching to inclisiran), Day 270 (inclisiran), Day 450 (inclisiran), 
and Day 630 (inclisiran; final dose)

Additional clinic visits: Day 150, Day 180 (non-dosing visit for subjects randomized to 
the inclisiran arm), Day 330, Day 510, and Day 690

End of study (EOS) visit: Day 720 (90 days after final dose)
The expected duration of a subject’s participation in this study is approximately 734 days, which 
includes screening, investigational product administration, and the EOS period to Day 720.


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Schedule of Assessments
Table 2-1
Study Design and Schedule of Assessments
Screening
Randomization 
and Treatment
Treatment
EOS13
Visit
V1 
(baseline)
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
(90 days 
post last 
dose)
Timelines
Day -28 to 
-1
Day 1
Day 90
Day 150
Day 180
Day 270
Day 330
Day 450
Day 510
Day 630
Day 690
Day 720
Visit windows (+/-weeks)
1
3
3
3*
3*
3*
3*
3*
3*
3*
3*
Informed Consent
X
Medical history and prior 
meds
X
Assessment of eligibility1
X
X
β-HCG pregnancy test 2
X
X
X
X
X
X
X
X
X
X
X
Study drug administration (inclisiran)
X
X
X
X
X
Study drug administration 
(placebo; switch to inclisiran at Day 180)
X
X
X
X
X
X
Physical examination 3
X
X
Neurological examination4
X
X
X
X
Weight/Height/Waist 
circumference 5
X
X
X
X
X
Vital signs6
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
Fasted lipid 
profile/biomarkers7
X
X
X
X
X
X
X
X
X
X
X
X
Full serum chemistry 8
X
X
Limited serum chemistry 9
X
X
X
X
X
X
X
X
X
X


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Hematology and 
coagulation10
X
X
X
X
Urinalysis (local) 11
X
X
X
ADA assessment
X
X
X
X
X
Previous/concomitant 
meds
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
β-HCG=beta-human chorionic gonadotrophic hormone; ADA=anti-drug antibodies; BP=blood pressure; CPK=creatine phosphokinase; CV=cardiovascular; 
ECG=electrocardiogram; eGFR=estimated glomerular filtration rate; EOS=end of study; HbA1C=glycated hemoglobin A1C; HDL-C=high density lipoprotein 
cholesterol; HR=heart rate; LDL-C=low density lipoprotein cholesterol; SC=subcutaneous; V=visit
*: The visit window is extended to +/- 2 months during the COVID-19 pandemic, to allow on-site visits (rather than remote visits) to occur as much as possible.
1. Assessment of laboratory eligibility criteria will be based on central laboratory values obtained within timeframes defined in the inclusion and exclusion criteria.
2. Only in women of childbearing potential (performed locally, prior to any dosing, using central laboratory kit supplies; urine pregnancy test).
3. Physical examination is the responsibility of the principal investigator or medically qualified designee.
4. Full neurological examination will be performed as described in Appendix C of the protocol
5. Height will be measured at baseline only and used to calculate body mass index.
6. On dosing days, vital signs will be measured prior to injection. When available, an automated BP device is recommended for collection of BP and the result 
recorded to the nearest mmHg. The subject should be sitting at rest for at least 5 minutes prior to these assessments. One assessment for each vital sign 
(HR, BP) is required per applicable visit
7. See Section 3.9 for details of specific tests to be analyzed
8. See Section 3.8.8.3 for details of specific tests to be analyzed 
9. See Section 3.8.8.3 for details of specific tests to be analyzed 
10. See Section 3.8.8.1 and Section 3.8.8.2 for details of specific tests to be analyzed 
11. Performed locally using the central laboratory kit supplies
13. For subjects prematurely and permanently discontinued from study treatment, EOS visit will be scheduled as soon as possible. If decision to discontinue is 
made at a specific visit, this visit will become the EOS visit and EOS visit procedures should be followed.


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3
GENERAL CONDUCT OF TRIAL
Written informed consent will be obtained for this study by the principal investigator or sub-
investigator from all subjects before the performance of any protocol-specific procedure.
Please see the Schedule of Assessments (Table 2-1) for a detailed schedule.
3.1
Screening Period (Days –28 to –1)
All screening laboratory tests will be collected and shipped to the Central Laboratory, with the 
exception of urinalysis and pregnancy test, which will be done in-house at the participating 
institution’s laboratory using the testing materials provided by the Central Laboratory. The 
results of all screening laboratory tests should be reviewed prior to enrollment. If results do not 
confirm subject eligibility or suggest any contraindication to treatment with inclisiran, and/or 
other required ancillary medication(s), the subject must not be enrolled.
The following procedures will be performed within 28 days prior to randomization:

Informed consent

Assessment of inclusion and exclusion criteria

Demographics and medical history including disease history (prior history related to the 
disease and prior use of disease related medication, e.g. monoclonal antibodies to PCSK9)

Pregnancy test (performed locally, using central laboratory supplies) (women of 
childbearing potential only)

Physical examination (including height, weight, and waist circumference)

Vital signs (blood pressure and heart rate) 

12-lead ECG

Fasting lipid profile/biomarkers 

Central clinical laboratory (limited serum chemistry, hematology and coagulation) 

Urinalysis (performed locally, using central laboratory supplies)

Previous and concomitant medications
 
Central laboratory blood draws should be performed after all other screening tests have been 
confirmed. Results must be available before the start of investigational product injection on 
Day 1 to confirm subjects meet eligibility criteria.
3.2
Randomization (Day 1)
Randomization should only occur once subject eligibility is confirmed and will be conducted 
via an automated interactive response technology (IRT) to assign subjects to investigational 
product. All treatment groups will be studied concurrently. At least 45 subjects are planned to 
be randomized 2:1 (inclisiran: placebo) for inclusion in the study.
The following procedures will be performed prior to the injection:


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
Assessment of inclusion and exclusion criteria

Pregnancy test (performed locally, prior to any dosing, using central laboratory supplies) 
(women of childbearing potential only)

Randomization

Neurological examination (Protocol Appendix C)

Vital signs: blood pressure and heart rate 

Fasting lipid profile/biomarkers  

Central clinical laboratory (full serum chemistry, hematology and coagulation) 

Urinalysis (performed locally, using central laboratory supplies)

Assessment of ADA 
The following procedures will be performed after the injection:

Recording of concomitant medications

AE/SAE reporting 
Investigational product (inclisiran or placebo) administration will occur at this visit for all 
subjects as per Protocol Section 5.1.1 and the Pharmacy Manual.
Subjects must be observed in the clinic for at least 30 minutes after injection.
Should a subject develop signs or symptoms of anaphylaxis when investigational product 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 logically possible).
If a local reaction around the injection site occurs that requires the subject to be seen between 
visits or if a reaction is noticeable on a subsequent visit, photographs of the injection site may 
be obtained if deemed necessary. Photographs should be submitted to the study inbox.
Detailed instructions for investigational product administration are found in the Pharmacy 
Manual. 
3.3
Day 150
The following assessments will be completed during this visit:

Pregnancy test (performed locally, prior to any dosing, using central laboratory supplies, if 
applicable) (women of childbearing potential only)

Weight and waist circumference

Fasting lipid profile/biomarkers

Assessment of ADA

Vital signs: blood pressure and heart rate

Central clinical laboratory (limited serum chemistry, hematology, and coagulation)

Neurological examination (Protocol Appendix C)

Recording of concomitant medications

AE/SAE reporting


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3.4
Additional Dosing Visits (Days 90, 180, 270, 450, and 630)
Subjects will return on Day 90 for a second investigational product injection. Subsequent 
inclisiran injections will be administered to all subjects on Day 270, Day 450 and Day 630. In 
addition, on Day 180 subjects originally randomized to the placebo group will be switched to 
inclisiran and receive their first dose of inclisiran on Day 180.
Note: For subjects randomized to the inclisiran arm, Day 180 will be a non-dosing visit but the 
same assessments as described below will be performed except for investigational product 
administration.
The following assessments will be completed during these visits prior to investigational product 
administration:

Pregnancy test (performed locally, prior to any dosing, using central laboratory supplies, if 
applicable) (women of childbearing potential only)

Vital signs: blood pressure and heart rate 

Weight and waist circumference (Day 180 only)

Fasting lipid profile/biomarkers

Assessment of ADA (Day 90 only)

Central clinical laboratory (limited serum chemistry)

Recording of concomitant medication

AE/SAE reporting
Administration of the investigational product is identical to Day 1 and is per Protocol 
Section 5.1.1 and the Pharmacy Manual.
Subjects must be observed in the clinic for at least 30 minutes after injection.
Should a subject develop signs or symptoms of anaphylaxis on days when investigational 
product 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 logically possible).
3.5
Additional Non-Dosing Clinic Visits (Days 330, 510 and 690)
Subjects will return to the clinic for dosing follow-up visits on Days 330, 510, and 690. 
Note: for subjects randomized to the inclisiran group the Non-dosing visit on Day 180 is 
described in Section 3.4. The following assessments will be completed during these visits:
3.5.1
Day 330

Pregnancy test (performed locally, using central laboratory supplies, if applicable) 
(women of childbearing potential only)

Weight and waist circumference 

Fasting lipid profile/biomarkers 

Assessment of ADA

Central clinical laboratory (limited serum chemistry)

Neurological examination


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
Recording of concomitant medications

AE/SAE reporting
3.5.2
Day 510

Fasting lipid profile/biomarkers

Central clinical laboratory (limited serum chemistry)

Recording of concomitant medications

AE/SAE reporting
3.5.3
Day 690

Pregnancy test (performed locally, using central laboratory supplies, if applicable) 
(women of childbearing potential only)

Fasting lipid profile/biomarkers

Central clinical laboratory (limited serum chemistry) 

Recording of concomitant medications

AE/SAE reporting
3.6
End of Study (EOS) Visit (Day 720 – 90 days post last dose)
A subject’s participation in the study is complete when the final visit, 90 days after the last dose 
of investigational product, has occurred. The following assessments will be completed during 
this visit:

Pregnancy test (performed locally, using central laboratory supplies, if applicable) (women 
of childbearing potential only)

Physical examination (including weight and waist circumference)

Neurological examination (Protocol Appendix C)

Vital signs: blood pressure and heart rate

12-lead ECG

Fasting lipid profile/biomarkers

Assessment of ADA

Central clinical laboratory (full serum chemistry, hematology and coagulation)

Urinalysis (performed locally, using central laboratory supplies)

Recording of concomitant medication

AE/SAE reporting

All ongoing AEs or abnormal test findings have been followed until the event (or its 
sequelae) or the abnormal test finding resolved, stabilized at a level acceptable to the 
Sponsor/Investigator and/or returned to baseline values
3.7
Interim Analysis
No formal interim analysis will be performed in this study. 


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3.7.1
Interim Safety Reviews
The independent Data Monitoring Committee (IDMC) will review safety data 90 days after the 
first 20 subjects receive the first injection of inclisiran or placebo. Thereafter the IDMC will 
review safety data every 3 months until all patients have reached Day 180 unless requested 
otherwise by the IDMC. A recommendation will be made to continue, stop or amend the study 
at any of these reviews. Following Day 180 unblinded data will be reviewed by the IDMC.
3.8
Assessment of Safety
3.8.1
Adverse Events
Subjects will be carefully monitored for adverse events (AEs) by the investigator during the 
designated study period (see Section 4).
3.8.2
Demographics and Medical History
Baseline demographic information will be collected during screening, and will include age, sex, 
and race/ethnicity.
Relevant medical history includes all ongoing medical or surgical issues and any statin 
intolerance documentation. Remote medical and surgical history >5 years from the time of 
screening should only be included if considered relevant to the study.
3.8.3
Vital Signs
Vital signs include heart rate and blood pressure. When available, an automated blood pressure 
device is recommended for collection of blood pressure and the result recorded to the nearest 
mmHg. The subject should be sitting at rest for at least 5 minutes prior to these assessments. 
One assessment for each vital sign (heart rate, blood pressure) is required per applicable visit.
3.8.4
Electrocardiograms
Twelve lead ECGs will be collected at the time points in the Schedule of Assessments (Table 
2-1) unless clinically indicated.
3.8.5
Physical Examination
The physical examination should include a focused examination, which may include general, 
respiratory, cardiovascular, abdominal, and extremities evaluations, and recording of weight, 
waist circumference, and height (baseline only). Clinically relevant changes from baseline will 
be collected as AE data.
3.8.6
Neurological Evaluation
A full neurological examination (Protocol Appendix C) will be performed as per the Schedule 
of Assessment (Table 2-1). Clinically relevant changes from baseline will be collected as AE 
data.


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3.8.8
Clinical Laboratory Assessments
Specimens will be obtained at the time points in the Schedule of Assessments (Table 2-1). If an 
apheresis is performed on a visit day, blood samples must be collected prior to the apheresis, 
and prior to the administration of study drug (on dosing visits).
Subjects will be in a fasted state for all clinical laboratory assessments. Screening laboratory 
tests will be performed by the Central Laboratory, with the exception of urinalysis and 
pregnancy test, which will be done in-house at the participating institution’s laboratory using 
testing materials supplied by the Central Laboratory. Results from these screening tests related 
to eligibility must be available before the start of investigational product injection on Day 1 to 
confirm subjects meet eligibility criteria. Details regarding the processing, shipping, and 
analysis of samples will be provided in the Laboratory Manual. Note: Efficacy laboratory 
assessments (e.g., LDL-C and PCSK9) are described in Section 3.9.
3.8.8.1
Hematology
Blood draws for hematology will include:

Hemoglobin, hematocrit, erythrocytes, reticulocytes, mean cell hemoglobin (MCH), mean 
corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), 
platelet count, white blood cell count with differential.
3.8.8.2
Coagulation
Blood draws for coagulation will include:

Prothrombin time (PT), international normalized ratio (INR), activated partial 
thromboplastin (aPTT).
3.8.8.3
Chemistry
Blood draws for chemistry will be performed per the Schedule of Assessments (Table 2-1). 
Analysis will vary based on visit day as follows:

Full serum chemistry - Baseline (Day 1) and EOS (Day 720) 
AST, ALT, alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), total bilirubin 
(TBIL), direct and indirect bilirubin, creatine phosphokinase (CPK), lactate, bicarbonate, 
uric acid, creatinine, urea (BUN), estimated glomerular filtration rate (eGFR), sodium, 
potassium, calcium, inorganic phosphate, chloride, albumin, total protein, glucose (fasting), 
glycated hemoglobin A1C (HbA1C), and tryptase (as required).

Limited serum chemistry - Screening, Days 90, 150, 180, 270, 330, 450, 510, 630, and 
690
ONLY: AST, ALT, ALP, GGT, TBIL, CPK, creatinine, eGFR, fasting glucose, HbA1C 
(not at Day 150, 330, or 510), and tryptase (as required).


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3.8.8.4
Inflammatory markers 
High sensitivity C-reactive protein (hsCRP) testing is performed routinely for safety throughout 
the study and is part of the central laboratory draws.
Tryptase and other inflammatory markers such as interleukin 6 (IL6), interferon-gamma (IFN 
γ) and tumor necrosis factor-alpha (TNF-α) may be performed from centrally stored sample 
aliquots at a later date, as required. Should a subject 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 logically possible).
3.8.8.5
Urinalysis
Urinalysis will be performed at the time points defined in the Schedule of Assessments (Table 
2-1) and evaluated by dipstick analyses at the investigational site (a standardized dipstick test 
will be supplied by the Central Laboratory). Urinalysis will be performed from a sample of mid-
stream urine. In case of abnormal results, microscopy and other assessments will be performed 
at the local laboratory and the abnormality recorded as an AE.
The following parameters will be assessed:

Nitrite, protein, glucose, ketone, urobilinogen, bilirubin, red blood cells/erythrocytes, 
white blood cells/leukocytes, pH, urine sediment (microscopic examination will be only 
performed in the event of abnormalities).
3.8.8.6
Urine Pregnancy
Urine pregnancy testing will be performed locally at the visits specified in the Schedule of 
Assessments (Table 2-1), using the supplies provided by the Central Laboratory.
3.8.8.7
Lipids / Lipoproteins
Lipids and lipoproteins assessments are described in Section 3.9. If an apheresis is performed 
on a visit day, blood samples must be collected prior to the apheresis, and prior to the 
administration of the study drug (on dosing visits).
3.8.8.8
Anti-drug Antibodies
A serum sample for analysis of the presence of antibodies will be collected at the time points in 
the Schedule of Assessments (Table 2-1). Collection will be prior to investigational product 
administration (injection) and per the Schedule of Assessments.
3.8.9
Stored samples
 
 
 
Biological samples 
for biomarker research will be retained on behalf of the Sponsor for a maximum of 15 years 
following the last subject's last visit in the study. Details regarding the collection, processing, 
storage, and shipping will be in the Study Laboratory Manual.


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3.9
Assessment of Efficacy
Subjects will be in a fasted state for all efficacy laboratory assessments of 
lipids/lipoproteins/biomarkers. Specimens will be obtained at the time points in the Schedule 
of Assessments (Table 2-1). Parameters to be assessed will include:

LDL-C, PCSK9, total cholesterol (TC), triglycerides, HDL-C, non-HDL-C, VLDL-C, 
Apo-A1, Apo-B, lipoprotein (a) [Lp(a)], and hsCRP.
LDL-C using ultracentrifugation will be done additionally at baseline, Day 150, and Day 720.
If an apheresis is performed on a visit day, blood samples must be collected prior to the 
apheresis, and, prior to the administration of the study drug (on dosing visits).
Calculated LDL-C will use the Friedewald calculation, as the Friedewald equation (LDL-C = 
TC – HDL-C – TG/5) is typically used in clinical practice. Reflexive testing of LDL-C using 
ultracentrifugation will be performed if triglycerides are > 400 mg/dL or LDL-C is < 40 mg/dL.
Blood samples for determination of LDL-C concentrations will be collected at the time points 
in the Schedule of Assessments (Table 2-1). For all study visits, LDL-C will be calculated 
(using the Friedewald method), in addition at baseline (Day 1), Day 150 and Day 720 LDL-C 
will be analyzed by BQ. Details regarding the collection, processing, shipping, and storage of 
the samples will be provided in a Laboratory Manual.
 
Plasma samples will be 
analyzed using a validated enzyme linked immunosorbent assay to determine PCSK9 protein 
concentration. Full details of the analytical methods used will be described in a separate 
bioanalytical report.
3.10
Assessment of Pharmacodynamics 
Assessment of lipids/lipoproteins as discussed in Section 3.9 will cover pharmacodynamics.
Pharmacodynamic biomarker samples will be collected and stored for up to 15 years following 
the completion of the last subject for research purposes to identify and/or verify biomarkers that 
are predictive of response to inclisiran treatment (in terms of efficacy, safety and tolerability).
 
 
 
 
 
 
 


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4
ADVERSE EVENTS
This section describes how adverse events will be collected per protocol; analysis methods will 
be described in Section 6.4.8.1.
4.1
Adverse Event
Any untoward medical occurrence in a patient or clinical trial subject administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment. An 
adverse event can therefore be any unfavorable and unintended sign (e.g., an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
4.2
AE Severity
The severity of AEs will be assessed by the Investigator using the 3-point scale below:
1 = Mild: Discomfort noticed, but no disruption to daily activity.
2 = Moderate: Discomfort sufficient to reduce or affect normal daily activity.
3 = Severe: Inability to work or perform normal daily activity.
4.3
Study Drug Causality
The relationship between the AE and the investigational product will be assessed by using a 
binary assessment. The investigator should determine whether there is a ‘Reasonable possibility’ 
or ‘No reasonable possibility’ that the investigational product caused the event based on the 
definitions below.
Reasonable possibility - There is a reasonable possibility that the administration of the 
investigational product caused the AE. There is evidence to suggest a causal relationship 
between the investigational product and the AE.
No reasonable possibility - There is no reasonable possibility that the administration of the 
investigational product caused the AE. There is no temporal relationship between the 
investigational product and event onset, or an alternative etiology has been established.
4.4
Serious Adverse Event
Any untoward medical occurrence that at any dose:

Results in death,

Is life-threatening, i.e., the subject was, in the opinion of the investigator, at immediate 
risk of death from the event as it occurred (it does not include an event that, had it 
occurred in a more severe form, might have caused death),

Results in a significant, persistent or permanent change, impairment, damage or disruption 
in the subject's body function/structure, physical activities and/or quality of life,

Requires in-subject hospitalization or prolongs hospitalization,

Is a congenital anomaly/birth defect, or

Is another medically significant event where medical and scientific judgement should be 
exercised in deciding whether other situations should be considered serious reactions, such 


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as important medical events that might not be immediately life threatening or result in 
death or hospitalization but might jeopardize the patient or might require intervention to 
prevent one of the other outcomes listed above. 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. Any suspected transmission via a medicinal product of an infectious agent is also 
considered a serious adverse reaction.
A distinction should be drawn between serious and severe AEs. Severity is an estimate or 
measure of the intensity of an AE, while the criteria for serious AEs are indications of adverse 
subject outcomes for regulatory reporting purposes. A severe AE need not necessarily be 
considered serious and a serious AE need not be considered severe. For example, nausea that 
persists for several hours may be considered severe nausea, but not an SAE. On the other hand, 
a MI that may be considered minor could be an SAE if it prolonged hospitalization.
4.5
Additional Collection of Safety Data
4.5.1
Special Situations
Special Situations designated for this study include:

Medication errors that fall into the following categories

wrong investigational product

wrong dose (including overdose, underdose, change in dosing regimen, strength, form 
concentration, amount)

wrong route of administration

wrong subject (i.e., not administered to the intended subject)

accidental exposure 

Pregnancy/lactation exposures with or without any AEs related to the parent or child 

Suspected transmission via a medicinal product of an infectious agent

Drug interactions
4.5.2
Other safety related information
Injection-site reactions (ISR) including individual signs or symptoms at the injection site 
following investigational product administration should be recorded on specifically designed 
eCRF pages. Photographs of ISR, if they were obtained during the study visits, should be 
forwarded to the study inbox if available.
Other safety related information that should be reported as adverse events in accordance with 
the process described in study protocol Section 8.4 (Hochberg 1988) include:

Abnormal neurological examination, e.g., peripheral sensory and motor evaluation, an 
assessment of gait, pain, position, strength and reflexes (Protocol Appendix C).

Potential anaphylactic reactions assessed by Sampson criteria (Protocol Appendix D). If 
Sampson criteria are positive, confirm by elevation of tryptase in blood plasma measured 
within 30 minutes of symptoms. 

Hyperglycemia-related AEs:


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Report ‘New onset of diabetes’ in subjects with no medical history of diabetes when: 

HbA1C becomes ≥ 6.5% and/or

Two consecutive values of fasting plasma glucose that are ≥ 126 mg/dL

If a new concomitant medication for control of plasma glucose is added, further 
information to assess for a diagnosis of new onset diabetes will be collected.
Report ‘Worsening of the glycemic control’ or ‘diabetic complications’ in subjects with a 
medical history of disease (HbA1C ≥ 6.5% at baseline) when:

HbA1C increases from baseline > 0.5% and/or

New concomitant medication or increase in dose of current antidiabetic therapy is 
initiated to improve the control of plasma glucose level.
5
MEASURES TO MINIMIZE/AVOID BIAS
5.1
Blinded Study
Part 1 of this study will employ double-blinded technique with a placebo control. 
Randomization via automated interactive response technology (IRT) will be used to assign 
subject to blinded investigational product. In addition, investigational product will be dispensed 
and administered in a blinded syringe. Blinding will minimize bias based on subject selection, 
baseline characteristics, clinical endpoint and AE reporting. Specifics on how the blind for the 
investigational product is maintained are provided in Protocol Section 5.5.
6
STATISTICAL PLAN
6.1
Sample Size
The sample size calculation was performed with the hypothesis that the difference of mean 
percent change from baseline to Day 150 between inclisiran and placebo will be > 20% (20% 
standard deviation) in subjects with HoFH when treated with inclisiran. The sample size of at 
least 45 subjects (randomized 2:1 to inclisiran : placebo), with at least 30 subjects in the 
inclisiran arm, will provide >80% power to detect a 20% reduction of placebo-adjusted LDL-C 
levels from baseline in the inclisiran group compared to that in the placebo at one-sided 
significance level of 0.025 based on two-sample t-test.
6.2
Randomization
Randomization should only occur once subject’s eligibility is confirmed and will be conducted 
via an automated interactive response technology (IRT) to assign subjects to blinded 
investigational product at 2:1 ratio to inclisiran versus placebo. Each subject will receive SC 
injections of blinded inclisiran or placebo on Day 1 and Day 90. The inclisiran-treated subjects 
will receive a third dose of inclisiran administered on Day 270 and subsequent doses on Day 
450 and Day 630. The placebo-treated subjects from Part 1 will transition to an open-label, 
single arm follow-up period of inclisiran only; placebo-treated subjects will receive their first 
dose of inclisiran on Day 180 and then subsequently receive a dose of inclisiran on Day 270, 
Day 450, and Day 630.


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6.3
General Statistical Considerations and Definitions
6.3.1
General Statistical Methods
All study-collected data will be summarized by treatment group using descriptive statistics, 
graphs, and/or raw data listings. Categorical variables will be summarized using counts and 
percentages. Percentages are based on the number of subjects in the analysis set for whom there 
are non-missing data, unless otherwise specified. Continuous variables, including changes from 
Day 1, will be summarized using descriptive statistics (n, mean, standard deviation [SD], 
median and interquartile range [first and third quartiles], minimum and maximum).
In general, any data captured during Part 1 (up to and including the Day 180 visit date) will be 
presented by treatment group (inclisiran or placebo).  Part 1 will begin on Day 1 (the date of 
first dose) and end on the Day 180 visit (Visit 4).  The Visit 4 date is the date that placebo 
treated subjects begin inclisiran dosing. Any assessments performed prior to inclisiran dosing 
for the placebo subjects will be included in the Part 1 analyses.  
Any data captured during Part 2 (after the Day 180 visit date) will be presented in two separate 
groups, (1) inclisiran since Day 1 and (2) placebo-to-inclisiran.  The column labels for these 
two groups will be inclisiran-inclisiran and placebo-inclisiran.  Note that data captured prior to 
the Day 180 visit date will not be included in the Part 2 presentations. Any data captured on the 
Day 180 visit date after the first inclisiran dose for placebo subjects will be included in the Part 
2 summaries. Any change from baseline summaries during Part 2 will utilize Day 1 (date of 
first dose) as the baseline.
Note that select analyses will summarize data over both parts of the study.  These analyses are 
described later in the SAP.
All p-values will be based on two-sided tests. All p-values will be rounded to three decimal 
places using the following algorithm. If the fourth digit of the p-value is less than or equal to 4, 
the p-value will be rounded down. If the fourth digit of the p-value is greater than or equal to 5, 
the p-value will be rounded up. All p-values rounded to 0.000 will be presented as ‘<0.0001’ 
and p-values that round to 1.000 will be presented as ‘1.000’.
Absolute change and percent change from baseline will be calculated as follows:

Absolute Change = Value at Day X – Baseline value.

Percent Change = (Absolute Change/Baseline value)*100%.
6.3.2
Analysis Population
The following populations will be used for data analyses and/or presentation.
6.3.2.1
Intent-to-Treat (ITT) Population
All subjects randomized into the study will comprise the intent-to-treat (ITT) Population. 
Treatment classification will be based on the randomized treatment. The ITT Population will 
be used as the primary population for efficacy.


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6.3.2.2
Modified Intent-to-Treat (mITT) Population
All randomized subjects who receive at least one dose of investigational product and have both 
the baseline and Day 150 follow-up LDL-C assessment will comprise the modified intent-to-
treat (mITT) Population. Treatment classification will be based on the randomized treatment.
6.3.2.3
Safety Population 
All subjects who received at least one dose of investigational product will comprise the Safety 
Population. Treatment classification will be based on the actual treatment received. A subject 
who receives any amount of inclisiran throughout the study will be analyzed within the 
inclisiran treatment group for the safety analyses. This will be primary population for the safety 
analyses and all Part 2 analyses.
6.3.3
Analysis Windows and Baseline
The analysis windows around each visit day are provided in Table 6-1 below.  These analysis 
windows will be used for all analyses by visit and supersede the visit windows provided in the 
protocol.  Data will be partitioned into Part 1/Part 2 first using the rules defined in Section 6.3.1 
then the analysis windows will be implemented.
Table 6-1
Analysis Windows for Each Scheduled Visit
Analysis Window
Scheduled Visit
From
To
Baseline
Before randomization/First 
Study Treatment
Day 90
Day 61
Day 120
Day 150
Day 121
Day 171
Day 180
Day 172
Day 225
Day 270
Day 226
Day 300
Day 330
Day 301
Day 390
Day 450
Day 391
Day 480
Day 510
Day 481
Day 570
Day 630
Day 571
Day 660
Day 690
Day 661
Day 705
Day 720
Day 706
No upper limit
Data collected at scheduled or unscheduled visits will be used in the analysis if they fall into an 
analysis window for a scheduled visit. If more than one visit (scheduled or unscheduled) is 
made within the window specified above for any scheduled visit, the non-missing assessment 
closest to the scheduled visit day will be used in the analysis for that visit. However, all data 
will be included in the subject data listings. 


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Unless otherwise specified, data collected from assessments that occur more than once prior to 
initiation of investigational product administration, the latest assessment will be considered the 
"Baseline" evaluation for analysis.
6.3.4
Missing data handling
6.3.4.1
Efficacy
The sponsor will diligently follow up each subject from randomization until the end of study 
(Day 720±3 weeks), and make every effort to keep each subject visit within the protocol 
specified window on all efficacy laboratory assessments of lipids/lipoproteins/biomarkers to 
keep missing data to the minimum regardless of whether a subject is on study treatment, uses 
ancillary therapies, experiences an adverse event, or adheres to the protocol. 
However, if missing LDL-C data, defined as data not available from either scheduled (within 
the protocol defined visit window) or unscheduled visits, occurs during Part 1 of the study up 
to Day 180 then that data will be imputed.
The primary method to impute missing data for the primary efficacy endpoint (percentage 
change in LDL-C from baseline to Day 150) during Part 1 of the study will be a multiple 
imputation washout model. The washout model will be performed on actual values, change and 
percentage change values are calculated after the imputation. All retrieved data for subjects who 
dropped out from study treatment are considered as non-missing data and will be utilized in all 
analyses. See Appendix 2 for full details of the multiple imputation washout model.
In addition, sensitivity analyses using MMRM without multiple imputation and a control-based 
pattern mixture model (PMM, see details in Appendix 3) will be performed on the primary and 
key secondary efficacy endpoints of Part 1 of the study to assess the impact of missing values. 
Unless otherwise specified, missing data for all parameters not listed in the primary and key 
secondary efficacy endpoints will not be imputed and will be excluded from the associated 
analysis. 
6.3.4.2
Safety
Safety analyses are based on observed values. Any missing safety data including laboratory 
data will not be imputed. For adverse events (AEs), any events with missing start or stop date 
will be considered as treatment emergent AEs. For concomitant medication, any medication 
with missing start or stop dates are considered as Day 1 concomitant medication. 
Adverse events with incomplete dates will be categorized as treatment emergent unless there 
was sufficient specificity to the onset date to document that the event began before the first dose 
of study medication. No missing dates will be imputed.
6.4
Statistical Analyses
6.4.1
Subject Disposition
Subject disposition will be summarized as follows:


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
The number of subjects who signed the informed consent form, are screen failures, are 
randomized, are treated (Safety Population), completed the study or who discontinued early 
along with reasons for early discontinuation (completion and discontinuation status will be 
broken out by study part) will be summarized overall and by site for all screened subjects.

The number of subjects in each analysis population along with reasons for exclusion from 
each analysis population will be summarized by study part and study part treatment group 
for all randomized subjects.

The number of subjects who complete the study or who discontinued early along with 
reasons for early discontinuation will be summarized by study part and study part treatment 
group for the ITT population.

The duration on study (number of days from the first date of treatment to the date of last 
recorded contact/participation date in the database) will be summarized by study part and 
study part treatment for the ITT population.

The number of subjects who are screened, screen failures, and randomized will be 
summarized by site for all screened subjects in Part 1 of the study.

The number of subjects in each study part and study part treatment group will be 
summarized by site for the ITT population.
Overall study completers are defined as a subject who completes the Day 720 visit.
A summary of inclusion/exclusion criteria will be provided by Part 1 treatment group (inclisiran 
or placebo) for all screened subjects and for the ITT population.
A summary of the number of subjects by visit will be provided by study part and study part 
treatment group for each analysis population.
6.4.2
Protocol Deviations
The number and percentage of subjects with any protocol deviations will be summarized by 
study part and study part treatment group. The protocol deviation categories are provided below.

Subjects with at least one protocol deviation 

Inclusion and/or exclusion criteria violation 

Laboratory assessments not drawn at Day 1, Day 150, Day 510 or Day 720 (EOS) visits 

Mis-dosing for any reason other than subject safety or withdrawal (defined as missing dose 
or a dose delayed by more than 30 days)

Prohibited concomitant medication / Change in baseline statin or other lipid-lowering 
therapy dose 

SAE form not reported to the sponsor within 24 hours 

Informed consent not signed prior to study entry 
6.4.3
Demographic and Background Characteristics
Subject demographics including age, age category (< 65 years vs ≥ 65 years; 18 to < 50, 50 to 
< 65, 65 to < 75, ≥ 75), race, gender, ethnicity, country, baseline characteristics such as body 
height, weight, BMI, waist circumference, current use of statins or other lipid-modifying 
therapies (yes, no), status of statin intolerance, baseline eGFR, genetic testing results, and 


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baseline diabetes status based on HbA1c and fasting glucose will be summarized by Part 1 
treatment group (inclisiran or placebo) using the ITT Population.
Medical history (targeted medical history, other medical history, and medical history of statin 
intolerance) will be summarized by Part 1 treatment group (inclisiran or placebo) using the ITT 
and Safety Populations.
6.4.4
Study Drug Exposure
Study drug administration will be summarized by study part by treatment group and by dosing 
visits (including missed doses and injection site location). Study drug administration will also 
be summarized over the entire study for subjects who received inclisiran in both parts of the 
study.
6.4.5
Concomitant Medications 
Summaries of each prior (pre-baseline, defined as medication stopped 1 day before first dose 
date of study medication) medication and concomitant (Day 1 or later, any medications started 
or continued after study medication on Day 1 are considered as Day 1 concomitant medication) 
medications will be provided by treatment group for the ITT and Safety Populations. Additional 
summaries will be provided for lipid modifying therapy use. Medications will be coded using 
the World Health Organization (WHO) drug dictionary (B3 WHO DDE+HD Sep 2018). 
Subjects will be counted only once within each period by medication. 
The statin intensity (low, moderate, high) will be defined by clinical review of the data 
according to American College of Cardiology/American Heart Association (ACC/AHA) 
classification of high intensity and based on the specific statin drug name, dose (unit), and 
frequency recorded in the data. For these analyses the moderate intensity group will include 
simvastatin 40 mg. A shift table for lipid modifying therapy statin intensity from baseline to 
Day 720 (EOS) will also be provided.  The statin intensity of the last statin taken on or prior to 
Day 720 (EOS) will be used for the post-baseline statin.
Note that prior and Day 1 summaries will be performed for Part 1 only.  Summaries of new or 
changed or shift analyses will be done for both parts.
6.4.6
Efficacy Analysis
This study is sufficiently powered to show the effect in the primary and key secondary endpoints, 
all other secondary 
 endpoints are supportive hence statistical testing on all other 
secondary 
 endpoints will be performed only if the null hypothesis on primary 
and the key secondary endpoints are rejected. No adjustment for multiplicity is planned among 
the other secondary 
 endpoints. Note that all testing will be performed for Part 
1 of the study only.
Testing of the primary and key secondary efficacy endpoints from Part 1 of the study will be 
carried out using a fixed sequential testing strategy for multiplicity where the tests will be 
carried out in the order they are listed below.  Each endpoint will be tested using a two-sided 
alpha of 0.05.  


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Efficacy data from both parts of the study will be summarized descriptively using actual values 
and change from baseline (where applicable) using observed cases without imputation.
The ITT Population will be the primary population for the efficacy analysis. Efficacy analyses 
will also be performed for the mITT Population as supportive analysis.
6.4.6.1
Primary Efficacy Endpoint
The primary efficacy endpoint is percent change from baseline to Day 150 in LDL-C. This 
endpoint is from Part 1 of the study.
The statistical hypotheses for the primary efficacy endpoint of the percentage change in LDL-
C from baseline to Day 150 are as follows:
H01:
The difference (inclisiran minus placebo), between subjects treated with 
inclisiran 300mg and placebo in the least squares mean percentage change in LDL-C 
from baseline at Day 150 = 0.
HA1:
The difference (inclisiran minus placebo), between subjects treated with 
inclisiran 300mg and placebo in the least squares mean percentage change in LDL-C 
from baseline at Day 150 < 0.
The primary endpoint will use a reflexive LDL-C approach: either calculated LDL-C (based on 
the Friedewald formula) will be used, or if the calculated LDL-C is less than 40 mg/dL or 
triglycerides are greater than 400 mg/dL, or calculated LDL-C is missing, directly measured 
(using ultracentrifugation) LDL-C will be used if it is available.
Missing values will be imputed for LDL-C after a reflexive approach using the multiple 
imputation (100 total imputed datasets) washout model specified in Appendix 2. The percentage 
change in LDL-C at each visit will be calculated after the missing data imputation has been 
performed.
The primary analysis will be conducted on the ITT population and based on an ANCOVA 
model on the percentage change in LDL-C from baseline to Day 150 on each multiply imputed 
dataset (100 total). The model will include the fixed effect of Part 1 treatment group (inclisiran 
or placebo) and baseline LDL-C as a covariate.
Treatment effects from these 100 ANCOVA analyses will then be combined using Rubin’s 
Method via the SAS PROC MIANALYZE procedure. The difference in the least squares means 
between treatment groups and corresponding two-sided 95% confidence interval will be 
provided. The p-value for testing equal mean percent change from baseline to Day 150 in LDL-
C will also be provided.
See Appendix 2 for more details on this analysis.
6.4.6.1.1 Sensitivity Analysis for Primary Efficacy Endpoint
In order to support the robustness of the conclusions drawn from the primary efficacy analysis, 
we will perform the following sensitivity analyses for data collected during Part 1 of the study. 

A control-based pattern-mixture model (PMM), following the methods described in Ratitch 
and O’Kelly 2011, will be utilized to explore the possibility of data missing not at random 
(MNAR) for subjects who discontinued the study. For subjects who discontinued the study 


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without any further follow-up data, their missing values after study discontinuation will be 
imputed under the assumption that their outcome would be similar to those in the placebo 
group with similar background characteristics. For subjects who did not discontinue the 
study, their intermittent missing values will be imputed based on the MAR assumption. 
Multiple imputations will be used to account for uncertainty in the imputation process and 
results from the imputed datasets will be combined using Rubin’s method (Rubin 1987). 
See Appendix 3 for more details on this analysis. Note that this analysis will only use visits 
up to Day 180 (Part 1 of the study).
The primary analysis will be conducted on the ITT population and based on a mixed-effects 
model for repeated measurements (MMRM) on the percentage change in LDL-C from 
baseline for each multiply imputed dataset (100 total). The model will include fixed effects 
for Part 1 treatment (inclisiran or placebo), visit (Days 90, 150, and 180), baseline value, 
and the interaction between treatment and visit. The Restricted Maximum Likelihood 
(REML) estimation approach will be used with the covariance structure set as “Unstructured” 
(refer to Appendix 1 for further details on the MMRM). A linear contrast at Day 150 will 
be used to compare treatment groups.
Treatment effects at Day 150 from these 100 MMRM analyses will then be combined using 
Rubin’s Method via the SAS PROC MIANALYZE procedure. The difference in the least 
squares means between treatment groups and corresponding two-sided 95% confidence 
interval will be provided for hypothesis testing.

A mixed model for repeated measurements (MMRM) analysis without multiple imputation, 
that assumes missing data are missing at random (MAR), will be performed. The model will 
include fixed effects for Part 1 treatment (inclisiran or placebo), visit (Days 90, 150, and 
180), baseline value, and the interaction between treatment and visit. The Restricted 
Maximum Likelihood (REML) estimation approach will be used with the covariance 
structure set as “Unstructured”. A linear contrast at Day 150 will be used to compare 
treatment groups. Refer to Appendix 1 for further details on the MMRM.

An ANCOVA model without multiple imputation at Day 150 will be performed using the 
mITT population.  The model will include the fixed effect of Part 1 treatment group 
(inclisiran or placebo) and baseline LDL-C as a covariate.

A two-sample t-test utilizing observed cases (without imputation) will be performed to 
compare Part 1 treatment groups (inclisiran or placebo) on the percent change from baseline 
to Day 150 in LDL-C.

A Wilcoxon rank-sum test, a nonparametric method, utilizing observed cases (without 
imputation) will be performed to compare Part 1 treatment groups (inclisiran or placebo) on 
the percent change from baseline to Day 150 in LDL-C.

A tipping point analysis will be performed to search for the tipping point that reverses the 
study conclusion. In the tipping point analysis, we will independently vary the deltas in the 
Part 1 treatment groups (inclisiran group progressively worse while the placebo group is not 
impacted and inclisiran group progressively worse while the placebo group progressively 
improves) until the hypothesis test on the primary efficacy endpoint becomes statistically 
insignificant. 


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6.4.6.2
Secondary Efficacy Endpoints
The key secondary efficacy endpoints will not be tested if the primary efficacy endpoint’s null 
hypothesis failed to be rejected.  The key secondary efficacy endpoints will be tested in a 
sequential manner. These endpoints are all from Part 1 of the study.
The key secondary efficacy endpoints of this study include:

Absolute change in LDL-C from baseline to Day 150.

Percentage change in Apo-B from baseline to Day 150.

Percentage change in non-HDL-C from baseline to Day 150.

Percentage change in total cholesterol from baseline to Day 150.

Proportion of subjects in each group with ≥ 30% LDL-C reduction from baseline at Day 
150.
The following analyses will be performed for the absolute change in LDL-C, percentage change 
in Apo-B, percentage change in non-HDL-C, and percentage change in total cholesterol from 
baseline to Day 150.

An ANCOVA model with the fixed effect of Part 1 treatment group (inclisiran or placebo) 
and baseline value as a covariate, using the same multiply imputed washout model that was 
used for the primary efficacy endpoint analysis will be used to compare Part 1 treatments 
(inclisiran or placebo) at Day 150. (Refer to Appendix 3 for details).  This will be the 
primary analysis for the key secondary efficacy endpoints.

A control-based pattern-mixture model (PMM), using the same imputed datasets and 
MMRM model that was used for the primary efficacy endpoint sensitivity analysis will be 
used to compare Part 1 treatments (inclisiran or placebo) at Day 150. Multiple imputations 
will be used to account for uncertainty in the imputation process and results from the 
imputed datasets will be combined using Rubin’s method. (Refer to Appendix 3 for details).  

A mixed model for repeated measurements (MMRM) analysis without multiple imputation, 
that assumes missing data are missing at random (MAR), will be performed. The model will 
include fixed effects for Part 1 treatment (inclisiran or placebo), visit (Days 90, 150, and 
Day 180), baseline value, and the interaction between treatment and visit. The Restricted 
Maximum Likelihood (REML) estimation approach will be used with the covariance 
structure set as “Unstructured”. A linear contrast at Day 150 will be used to compare Part 1 
treatment groups. This will be a sensitivity analysis for the key secondary efficacy endpoints. 
Refer to Appendix 1 for further details on the MMRM.
The number and percentage of subjects with greater or equal to 30% LDL-C reduction will be 
presented at Day 150 by Part 1 treatment group (inclisiran or placebo).  Part 1 treatments will 
be compared using a logistic regression model with treatment as the effect.  The odds ratio and 
95% confidence intervals for the odds ratio will be provided.  The multiply imputed datasets 
created from both the washout model and the control-based PMM will be utilized in this 
analysis.
The other secondary efficacy endpoints of this study are:


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
Percentage change and absolute change in LDL-C from baseline to each assessment time 
up to Day 720 (i.e., Days 90, 150, 180, 270, 330, 450, 510, 630, 690, and 720) 

A MMRM analysis will be utilized to compare Part 1 treatment groups on percentage 
change and absolute change in LDL-C until Day 180 utilizing the same model that was 
used for the primary and key secondary efficacy endpoints.  Note that the Day 150 
comparisons are already included in the primary and key secondary efficacy analyses. 
Percentage change and absolute change from baseline in LDL-C will be summarized 
descriptively over time by Part 1 treatment group (inclisiran or placebo) up until Day 
180 and then by Part 2 treatment group (inclisiran or placebo/inclisiran) from Day 270 
through Day 720. 

Directly measured (using ultracentrifugation) LDL-C results will also be summarized 
descriptively over time by Part 1 treatment group (inclisiran or placebo) up until Day 
180 and then by the Part 2 treatment group (inclisiran or placebo/inclisiran) at Day 720.  

Percentage change and absolute change from baseline to Days 90, 150, 180, 330, 510, 690, 
and 720 in PCSK9 

A MMRM analysis will be utilized to compare Part 1 treatment groups on percentage 
change and absolute change in PCSK9 until Day 180 utilizing the same model that was 
used for the key secondary efficacy endpoint. Percentage change and absolute change 
from baseline in PCSK9 will also be summarized descriptively over time by Part 1 
treatment group (inclisiran or placebo) up until Day 180 and then by Part 2 treatment 
group (inclisiran or placebo/inclisiran) from Day 270 through Day 720. 

Percentage change and absolute change from baseline to Days 90, 150, 180, 270, 330, 450, 
510, 630, 690, and 720 in total cholesterol, Apo-B, and non-HDL-C for subjects receiving 
inclisiran

A MMRM analysis will be utilized to compare Part 1 treatment groups on percentage 
change and absolute change for each endpoint (total cholesterol, Apo-B, and non-HDL-
C) until Day 180 utilizing the same model that was used for the key secondary efficacy 
endpoints. Note that the Day 150 comparisons are already included in the key secondary 
efficacy analyses. Percentage change and absolute change from baseline in each 
endpoint will also be summarized descriptively over time by Part 1 treatment group 
(inclisiran or placebo) up until Day 180 and then by Part 2 treatment group (inclisiran 
or placebo/inclisiran) from Day 270 through Day 720. 

Individual responsiveness of subjects defined as the number of subjects reaching on 
treatment LDL-C levels of < 25 mg/dL, < 50 mg/dL, < 70 mg/dL, and < 100 mg/dL at Days 
90, 150, 180, 270, 330, 450, 510, 630, 690, and 720 including proportion of subjects in each 
group who attain global lipid targets for their indication

The number and percentage of subjects who reach the various LDL-C levels and who 
attain global lipid targets (< 70 mg/dL for ASCVD subjects and < 100 mg/dL for 
ASCVD risk equivalent subjects) will be presented over time and at any time point 
(separately for each Part) by Part 1 treatment group (inclisiran or placebo) up until Day 
180 and then by Part 2 treatment group (inclisiran or placebo/inclisiran) from Day 270 
through Day 720.  Part 1 treatments will be compared using the number of subjects who 
attain global lipid targets at any visit up until Day 180 using a logistic regression model 


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with Part 1 treatment as the effect.  The odds ratio and 95% confidence intervals for the 
odds ratio will be provided.

Proportion of subjects in each group with greater or equal to 20% and 30% LDL-C reduction 
from baseline at Days 90, 150, 180, 270, 330, 450, 510, 630, 690, and 720

The number and percentage of subjects with greater or equal to 20% and 30% LDL-C 
reductions will be presented over time and at any time point (separately for each Part) 
by Part 1 treatment group (inclisiran or placebo) up until Day 180 and then by Part 2 
treatment group (inclisiran or placebo/inclisiran) from Day 270 through Day 720.  Part 
1 treatments will be compared using the number of subjects with greater or equal to 
20% or 30% LDL-C reductions at any visit up until Day 180 using a logistic regression 
model with Part 1 treatment as the effect.  The odds ratio and 95% confidence intervals 
for the odds ratio will be provided. Note that the Day 150 comparison for the ≥ 30% 
analysis noted here will use observed data (without imputation), the key secondary 
efficacy analysis.

Absolute change and percentage change in other lipids, lipoproteins, apolipoproteins, and 
PCSK9 from baseline at each subsequent visit to Day 720

A MMRM analysis will be utilized to compare Part 1 treatment groups on percentage 
change and absolute change for each endpoint until Day 180 utilizing the same model 
that was used for the key secondary efficacy endpoint. Percentage change and absolute 
change in each endpoint will also be summarized descriptively over time by Part 1 
treatment group (inclisiran or placebo) up until Day 180 and then by Part 2 treatment 
group (inclisiran or placebo/inclisiran) from Day 270 through Day 720. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.4.7
Subgroup Analysis 
Analysis of efficacy and safety will also be performed for subgroups of interest include the 
following. Note that not all variables will be summarized for all subgroups.
Table 6-2
Subgroups for Analysis
Table # [1]
 
Categories and comments
1
Baseline LDL-C 
≤ vs > median
2
Baseline PCSK9
≤ vs > median
3
Sex
Male vs Female
4
Age group
≤ vs > median
5
Race
White vs Asian
6
Region
Europe (Israel/Russia/Serbia/Ukraine) 
vs 
Non-Europe (Hong Kong/South Africa/Taiwan/Turkey)
7
Apheresis
Yes vs no
[1] Numbers provide the order that the subgroups will be presented.
* Subgroups with small number of patients will be combined for analysis purpose.


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Baseline variables to be analyzed by subgroup (1 - Baseline LDL-C and 2 - 
Baseline PCSK9):
Disposition
Demographics and Baseline Characteristics
Day 1 Lipid Modifying Therapy Usage
New or Changed Lipid Modifying Therapy Usage
Efficacy variables to be analyzed by subgroup (1 – 9):
Primary: Percentage change in LDL-C from baseline to Day 150 – ANCOVA – Washout Imputation
Key Secondary: Absolute change in LDL-C from baseline to Day 150 – ANCOVA – Washout Imputation
Key Secondary: Percentage change in Apo-B from baseline to Day 150 – ANCOVA – Washout 
Imputation
Key Secondary: Percentage change in non-HDL-C from baseline to Day 150 – ANCOVA – Washout 
Imputation
Key Secondary: Percentage change in total cholesterol from baseline to Day 150 – ANCOVA – Washout 
Imputation
Other Secondary: Percentage change and absolute change in PCSK9 from baseline to Day 150 - 
MMRM 
6.4.8
Safety Analysis
The safety objectives of this study are to evaluate the safety and tolerability profile of inclisiran.
Safety variables will be summarized by study part (note that a select set of AE tables will be 
created that summarize AE data over both parts of the study for subjects who received inclisiran 
the entire study (in both Parts 1 and 2). Data captured during Part 1 (up to and including the 
Day 180 visit) will be presented by Part 1 treatment group (inclisiran or placebo). Data captured 
during Part 2 (after the Day 180 visit date) will be presented by Part 2 treatment group (inclisiran 
or placebo/inclisiran).
6.4.8.1
Adverse Events
The Medical Dictionary for Regulatory Activities (MedDRA) dictionary (v21.1) will be used 
for coding AEs. An AE (classified as preferred term) occurring during the treatment period will 
be counted as a treatment emergent AE (TEAE) either if it is not present at Day 1 before 
treatment or if it is present before treatment but increased in severity during the treatment period.
The following summary tables will be presented by study part: 

Overall Summary of TEAEs

TEAEs by SOC and PT

TEAEs by PT

Common (2 or more subjects with an AE within either treatment group) by PT

TEAEs by SOC, PT, and Severity

TEAEs by SOC, PT, and Relationship to Study Drug

Related TEAEs by SOC, PT, and Severity


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
Treatment Emergent Serious AEs (TESAEs) by SOC and PT

TESAEs by PT

TESAEs by SOC, PT, and Severity

TESAEs by SOC, PT, and Relationship to Study Drug

Related TESAEs by SOC, PT, and Severity

TEAEs Leading to Withdrawal of Study Treatment by SOC and PT

TEAEs with a Fatal Outcome by SOC and PT 
The following summary tables will also be presented for subjects who received inclisiran the 
entire study (in both Parts 1 and 2):

TEAEs by SOC and PT

Related TEAEs by SOC, PT, and Severity

Treatment Emergent Serious AEs (TESAEs) by SOC and PT

TEAEs Leading to Withdrawal of Study Treatment by SOC and PT
If more than one event occurred with the same preferred term for the same subject, the subject 
will be counted only once for that preferred term using the most severe or related occurrence 
for the summary by severity, or relationship to study drug, respectively. 
For common (2 or more subjects with an AE within either treatment group) TEAEs, serious 
TEAEs and TEAEs leading to withdrawal of study medication, risk ratios along with 95% 
confidence intervals will be presented to compare treatment groups with respect to risk.
The following additional adverse events (Refer to Appendix 5) will also be assessed:
1. Adverse Events at the Injection Site
2. Hepatic events
3. Renal events
4. Hypersensitivity
5. Neurological events and Neurocognitive disorders
6. Ophthalmological events
Clinically relevant TEAEs at the injection site will also be tabulated. See Appendix 6 for a list 
of clinically relevant injection site preferred terms.
The time to the first TEAE at the injection site will also be summarized during Part 1 of the 
study.  Only subjects with a TEAE at the injection site will be included in the analysis. The time 
(hours) will be calculated from the date of the most recent administration of study drug. The 
duration of the TEAE will also be summarized.  The same analyses will be performed for each 
individual TEAE PT at the injection site.  The time to the first clinically relevant adverse event 
at the injection site will be analyzed similarly.
Any immune-related events will be identified in the SOC of immune system disorders.
Listings will be presented for subjects with SAEs/AEs leading to a discontinuation or death. 
Listings of SAEs and Death will also be provided.


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Additional Analysis of Adverse Events for ClinicalTrials.gov and EudraCT:
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on <on-
treatment/treatment emergent> adverse events which are not serious adverse events with an 
incidence greater than 2% and on <on-treatment/treatment emergent> serious adverse events 
and SAE suspected to be related to study treatment will be provided by system organ class and 
preferred term on the safety set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's 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.
6.4.8.2
Laboratory Tests
Laboratory values will be summarized by treatment group in each study part, including the 
observed value, changes and percent changes from baseline at each time point. 
A shift analysis using the normal range (except for eGFR and HbA1c) will be done which counts 
the number of subjects with a low, normal or high value at baseline and a low, normal or high 
value post baseline. 
The following ranges will be used for eGFR and HbA1c

For eGFR, the categories will be Severe = < 30 mL/min/1.73m2; Moderate = ≥ 30 to < 60 
mL/min/1.73m2; Mild = ≥ 60 to < 90 mL/min/1.73m2; and Normal = ≥ 90 mL/min/1.73m2.

For HbA1c, the categories will be ≤ 5.6%, ≥ 5.7% to ≤ 6.4%, and ≥ 6.5%.
The baseline and worst post-baseline value will be utilized for the shift tables.  Note that the 
shift table dealing with the fasting glucose parameter will require the lab sample to be taken 
while fasting.  Samples taken while the subject was not fasting will not be analyzed.
The number and percentage of subjects with potentially clinically significant (PCS) laboratory 
values and clinically significant (CS) laboratory values (refer to Appendix 4 for the criteria) 
will be summarized by treatment group in each study part.  Hemoglobin A1c criteria is explicitly 
stated in Appendix 4. All other PCS and CS criteria are met when both of the following occur:

Post-baseline values meet the thresholds listed in Appendix 4

Baseline values or any prior post-baseline values do not meet the thresholds listed in 
Appendix 4
PCS chemistry laboratory values will also be classified as follows:

Abnormal baseline: 


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
Non HbA1c: > 1 and ≤ 3 x ULN at baseline and > 1 and ≤ 3 x ULN at final visit

HbA1c: ≥ 6.5% at baseline and ≥ 6.5% and ≥ 0.5% change from baseline at final visit

Elevated further: 

Non HbA1c: > 1 and ≤ 3 x ULN at baseline or post baseline and becoming > 3 x ULN 
post baseline

Final visit: 

Non HbA1c: > 1 and ≤ 3 x ULN at final visit only but not at baseline or previous visits

HbA1c: ≥ 6.5% and ≥ 0.5% change from baseline at final visit only but not at baseline 
or previous visits

Persistently elevated: 

Non HbA1c: > 1 and ≤ 3 x ULN at a post baseline visit and remains > 1 and ≤ 3 x ULN 
until final visit

HbA1c: ≥ 6.5% and ≥ 0.5% change from baseline at a post baseline visit and remains 
≥ 6.5% and ≥ 0.5% change from baseline until final visit

Resolved: 

Non HbA1c: > 1 and ≤ 3 x ULN at baseline or post baseline, resolved to < ULN at any 
post baseline visit, and remaining < ULN at final visit

HbA1c: ≥ 6.5% at baseline or ≥ 6.5% and ≥ 0.5% change from baseline for post-
baseline, resolved to < 6.5% and < 0.5% change from baseline at any post baseline visit, 
and remaining < 6.5% and < 0.5% change from baseline at final visit
Separate listings of all subjects with PCS and CS laboratory values will be presented. Subjects 
will appear once per lab parameter but may appear under multiple lab parameters. The worst 
post-baseline value will be utilized in the analyses.
The number and percentage of subjects satisfying Hy’s Law will also be tabulated by treatment 
group in each study part based on the following lab findings:

Any elevated post-baseline aminotransferases defined as: 

ALT > 3 x ULN or 

AST > 3 x ULN

Elevated post-baseline serum total bilirubin (TBL) > 2 x ULN and serum alkaline 
phosphatase (ALP) levels < 2 x ULN
Subjects must meet all of the criteria listed above at the same time point and have normal lab 
parameters (ALT, AST, TBL) at baseline to be considered a Hy’s Law case.  A second summary 
will be presented that includes all subjects who meet all of the criteria listed above at the same 
time point without regard to the baseline lab parameter results.
6.4.8.3
Diabetes Assessment
Diabetes will be assessed in each study part by the analysis of:

TEAEs

change in glucose-related laboratory values over time

shifts from baseline in glucose control category and,


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
incidence of post-baseline new onset of diabetes.
Note that diabetes related tables dealing with the fasting glucose parameter will require the lab 
sample to be taken while fasting.  Samples taken while the subject was not fasting will not be 
analyzed.
6.4.8.3.1 Diabetes TEAE
New onset/worsening of diabetes will be identified using SMQ and AE terms (refer to Appendix 
5 on Standardized MedDRA Queries (SMQ) and AE terms).  The analysis will be performed 
for all subjects and then by baseline diabetes status.  A subject will be identified as being 
diabetic at baseline if the targeted medical history notes that the subject is diabetic or the 
baseline HbA1c value is ≥ 6.5%.  
6.4.8.3.2 Change in Glucose-related Laboratory Values over Time
This analysis only utilizes laboratory data (fasting glucose and HbA1c).  The change from 
baseline to the last on-treatment observation and the worst on-treatment observation will be 
summarized separately for fasting glucose and HbA1c overall and then by baseline glucose 
control status.  Baseline glucose control status will be identified separately for fasting glucose 
and HbA1c using the values provided in the table below (note that medical history will not be 
taken into account for this analysis).  Figures will also be created showing mean fasting glucose 
and HbA1c values over time by baseline glucose control status.
Parameter
Baseline Glucose Control Status
Baseline Laboratory Values*
Normal
< 100 mg/dL
Impaired 
≥ 100 to < 126 mg/dL
Fasting Glucose
Diabetes 
≥ 126 mg/dL
Normal
< 5.7%
Impaireda
≥ 5.7 to < 6.5%
HbA1c
Diabetes 
≥ 6.5%
*Using average of Screening and Day 1 fasting glucose values.  If one fasting glucose value is missing 
(Screening or Day 1), the assessment will be based on the available data.
6.4.8.3.3 Shifts from Baseline in Glucose Control Category 
Shifts from baseline in glucose control category will be summarized two different ways.  The 
change from baseline to the worst-on-treatment and then again for the last-on-treatment 
laboratory values will be used to classify the on-treatment glucose control category.  Note that 
medical history will not be taken into account for this analysis. If consecutive fasting glucose 
measurements fall in two separate categories, or if only one pre- or post-baseline fasting glucose 
measurement is available, then the classification will be based on the HbA1c measurements 
only. If HbA1c is missing then both consecutive fasting glucose measurements must fall in a 
category otherwise the lower category will be used.


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Shift Category*
Baseline Values**
Post-baseline Values
Normal to Normal 
(no change)
Fasting glucose < 100 mg/dL on 
Screening or Day 1
AND
HbA1c < 5.7%
Fasting glucose < 100 mg/dL on 
two consecutive occasions
AND
HbA1c < 5.7%
Normal to Impaired
Fasting glucose < 100 mg/dL on 
Screening or Day 1
AND
HbA1c < 5.7%
Fasting glucose ≥ 100 and < 126 
mg/dL on two consecutive 
occasions
OR
HbA1c ≥ 5.7 and < 6.5% 
Normal to Diabetes
Fasting glucose < 100 mg/dL on 
Screening or Day 1
AND
HbA1c < 5.7%
Fasting glucose ≥ 126 mg/dL on 
two consecutive occasions
OR
HbA1c ≥ 6.5%
Impaired to Normal
Fasting glucose ≥ 100 and < 126 
mg/dL on Screening and Day 1
OR
HbA1c ≥ 5.7 and < 6.5%
Fasting glucose < 100 mg/dL on 
two consecutive occasions
AND
HbA1c < 5.7%
Impaired to Impaired
(no change)
Fasting glucose ≥ 100 and < 126 
mg/dL on Screening and Day 1
OR
HbA1c ≥ 5.7 and < 6.5%
Fasting glucose ≥ 100 and < 126 
mg/dL on two consecutive 
occasions
OR
HbA1c ≥ 5.7 and < 6.5%
Impaired to Diabetes
Fasting glucose ≥ 100 and < 126 
mg/dL on Screening and Day 1
OR
HbA1c ≥ 5.7 and < 6.5%
Fasting glucose ≥ 126 mg/dL on 
two consecutive occasions
OR
HbA1c ≥ 6.5%
Diabetes to Normal
Fasting glucose ≥ 126 mg/dL on 
Screening and Day 1
OR
HbA1c ≥ 6.5%
Fasting glucose < 100 mg/dL on 
two consecutive occasions
AND
HbA1c < 5.7%
Diabetes to Impaired
Fasting glucose ≥ 126 mg/dL on 
Screening and Day 1
OR
HbA1c ≥ 6.5%
Fasting glucose ≥ 100 and < 126 
mg/dL on two consecutive 
occasions
OR
HbA1c ≥ 5.7 and < 6.5%
Diabetes to Diabetes 
(no change)
Fasting glucose ≥ 126 mg/dL on 
Screening and Day 1
OR
HbA1c ≥ 6.5%
Fasting glucose ≥ 126 mg/dL on 
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.
** If one fasting glucose value is missing (Screening or Day 1), the assessment will be based on the 
available data.


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6.4.8.3.4 Incidence of Post-baseline New-Onset of Diabetes
The number of subjects who shift from no diabetes at baseline (defined as no medical history 
of diabetes in the targeted medical history CRF, HbA1c < 6.5% at baseline, and fasting glucose 
< 126 mg/dL at baseline (note that baseline is defined as the average of Screening and Day 1 
fasting glucose values, if one fasting glucose value is missing (Screening or Day 1), the 
assessment will be based on the available data) to diabetes will be summarized. A 4-component 
definition of diabetes will be utilized.  The 4 components are provided below.  
Diabetic TEAEs identified by the SMQ search (see Appendix 5), or
Post-baseline fasting 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 subjects who have any of the 4 components will be summarized (post-baseline 
new-onset of diabetes) along with each component.  This analysis will be performed for those 
subjects who have fasting glucose at baseline < 100 mg/dL and then for those with fasting 
glucose at baseline ≥ 100 and < 126 mg/dl (normoglycemic).  
The time to new-onset diabetes will also be summarized during Part 1 of the study.  Only 
subjects 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.
6.4.8.4
Anti-Drug Antibody
ADA is being assessed and will be listed in a separate ADA report. If there are ADA findings, 
further characterization and additional evaluations may be performed on safety and efficacy 
parameters.
6.4.8.5
Vital Signs
Observed value, change, and percent change from Day 1 in vital signs will be summarized 
descriptively at each scheduled time point by treatment group in each study part. 
The change from baseline to EOS will also be summarized by the following categories:

Systolic blood pressure (mmHg): 

≤ -20 

> -20 to ≤ -10 

> -10 to ≤ -5

> -5 to < 5

≥ 5 to < 10

≥ 10 to < 20

≥ 20

Diastolic blood pressure (mmHg): 

≤ -10

> -10 to ≤ -5


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
> -5 to ≤ -3

> -3 to < 3

≥ 3 to < 5

≥ 5 to < 10

≥ 10
6.4.8.6
Electrocardiograms
The percentage of subjects with abnormal ECG findings reported as AEs will be summarized 
by treatment group in each study part within the overall assessment of cardiac safety.
6.4.8.7
Neurological Examinations
The percentage of subjects with a treatment-emergent abnormal neurological event and the 
specific abnormality reported as adverse events, will be summarized by treatment group in each 
study part.
7
COMPUTER METHODS
Statistical analyses will be performed using SAS (version 9.4 or later version).
8
CHANGES TO ANALYSES SPECIFIED IN THE PROTOCOL
The following item was changed between the Protocol Amendment 1 and current SAP:

the time biological samples are stored after the end of the study was extended from 1 
year to 15 years.
9
REFERENCES
Hochberg Y (1988) A sharper Bonferroni procedure for multiple tests of significance. 
Biometrika.;75:800-2.Protocol MDCO-PCS-17-08 Amendment 2 
Ratitch B, O’Kelly M (2011) Imputation of Pattern-Mixture Models Using Standard 
SAS/STAT Procedures, PharmaSUG2011 - Paper SP04.
Rubin, D.B. (1987) Multiple Imputation for Nonresponse in Surveys, New York: John Wiley 
& Sons, Inc.


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10
APPENDICES
10.1
Appendix 1: Details of MMRM Used for Efficacy Analyses
A number of Part 1 efficacy analyses will utilize a mixed-effects model for repeated measures 
(MMRM).  The models will generally include fixed effects for treatment, visit, baseline value, 
and the interaction between treatment and visit.  The visits will include Days 90, 150, and 180, 
with Day 150 as the primary time-point. Linear combinations of the estimated means will be 
created for the various hypothesis tests. 
The Restricted Maximum Likelihood (REML) estimation approach will be used with the 
covariance structure set as “Unstructured.”  The least squares means will be calculated for each 
treatment at each visit.  
The analysis will be carried out using the SAS PROC MIXED procedure. 
Sample SAS statements follow:
ods output LSmeans=estimates;
ods output Diffs=lsdiffs;
Proc Mixed Data=ldl_data;
  Class treatment visit_day subject_id;
  Model percent_change = treatment|visit_day base_value/DDFM=KR;
repeated visit_day/type=UN subject=subject_id;
LSMeans treatment*visit_day/cl pdiff=control('0' '150’);
run;
(where ('0' '150') is the value of the placebo [‘0’] at day 150 
[‘150’] in interaction term treatment*visit_day)


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10.2
Appendix 2: Multiple Imputation Washout Model 
A multiple imputation washout model will be utilized for the Part 1 primary efficacy analysis 
of the percentage change in LDL-C from baseline to Day 150 endpoint.  Note that this model 
will also be used for the key secondary efficacy endpoints also. The washout model can be 
thought of as a modified control-based Pattern-Mixture Model (PMM) that will be used to 
explore the possibility of data missing not at random (MNAR) for subjects who discontinued 
the study early.  For subjects who discontinued the study early, their missing values will be 
imputed under the assumption that their outcome would be similar to those in the placebo group 
with similar background characteristics. For subjects in the inclisiran group only missing Day 
150 values will be imputed.  For subjects in the placebo group their missing values over all 
visits after early termination will be imputed based on the missing at random (MAR) assumption. 
Multiple imputation will be used to account for uncertainty in the imputation process and results 
from the imputed datasets will be combined using Rubin’s method.  Further details are provided 
below.
Windowing will be performed first (see Section 6.3.3) and any missing data will be imputed 
using the following steps.
For the subjects in the inclisiran group who received 2 doses (Day 1 and Day 90) and have data 
present at Day 180 (considered to have completed Part 1 of the study) the following variables 
will be included in a multiple imputation procedure (SAS PROC MI), this assumes missing data 
are MAR:

Baseline value of efficacy measurement (continuous)

Observed value of efficacy measurement at Day 150 from the inclisiran group 
(continuous)
For the remaining subjects in the inclisiran group the following variables will be included in a 
multiple imputation procedure (SAS PROC MI), this assumes missing data are MNAR:

Baseline value of efficacy measurement (continuous)

Observed value of efficacy measurement at Day 150 from the placebo group (continuous)
For the placebo group the following variables will be included in a multiple imputation 
procedure (SAS PROC MI), this assumes missing data are MAR:

Baseline value of efficacy measurement (continuous)

Observed value of efficacy measurement at Day 90 (continuous)

Observed value of efficacy measurement at Day 150 (continuous)

Observed value of efficacy measurement at Day 180 (continuous)
1. Intermittent missing data in the placebo treatment group will be imputed using MCMC 
methods, assuming MAR.  SAS PROC MI will be utilized for this step using the MCMC 
impute=monotone option. A total of 100 datasets will be created.  These datasets will be 
utilized in Step #2.
2. The remaining missing values in the placebo group with a monotone missing data pattern 
will be imputed in this step.  Missing data will be imputed assuming data are MAR.  Only 
subjects in the placebo group will be utilized in this step.  SAS PROC MI will be used to 


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impute missing values utilizing the monotone reg option. This will be performed for the 100 
datasets.  After this step, the 100 datasets will be fully imputed through Day 180 for the 
placebo treatment group.  These datasets will be utilized in Step #4.
3. Subjects in the inclisiran group who received 2 doses of study medication, have the Day 
150 value missing, and have evaluable data at Day 180 will be included in this step.  Missing 
values at Day 150 will be imputed assuming data are MAR.  Only subjects in the inclisiran 
group will be included in this step.  Observed Baseline and Day 150 data will be utilized to 
impute missing Day 150 data utilizing SAS PROC MI.  This will be performed 100 times 
to create 100 datasets that are fully imputed at Day 150.
4. The remaining missing values at Day 150 in the inclisiran group will be imputed in this step. 
Note that the subjects with imputed inclisiran Day 150 data from Step #3 will not be utilized 
in this step. Control-based PMM imputation will be performed. With this imputation model, 
the missing efficacy measurements in the inclisiran group will not be constructed from the 
observed data in the inclisiran group but rather from the observed and imputed data in the 
placebo group at Day 150.  Baseline data will also be utilized in the imputation.  The MNAR 
statement in SAS PROC MI will be used to impute missing values. This will be performed 
for the 100 datasets.  
5. The imputed data from Step #3 will be combined with the imputed data from Step #4 to 
create 100 fully imputed datasets.
6. A total of 100 fully imputed datasets will be created (M=100). Since multiple imputation is 
a stochastic method, slight differences in output can be expected for different initial states 
of the random number generator. The seed numbers will be identified in the SAS programs 
to allow for reproducibility.
7. After the missing data imputation is completed using the above steps, absolute 
change/percentage change values will be calculated in each of the imputed datasets at each 
visit.
8. These 100 datasets will be analyzed using ANCOVA models with fixed effect of treatment 
group and baseline LDL-C as a covariate for the percent change of LDL-C from baseline to 
Day 150 primary efficacy endpoint.
9. Treatment effects (difference in LS means between treatments) from these 100 analyses will 
then be combined using Rubin’s Method via SAS PROC MIANALYZE procedure for each 
endpoint.  The p-value will also be provided.


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10.3
Appendix 3: Control-Based Pattern Mixture Model
A control-based Pattern-Mixture Model (PMM) will be used to explore the possibility of data 
missing not at random (MNAR) for subjects who discontinued during Part 1 of the study. For 
subjects who discontinued the study without any further follow-up data, their missing values 
after study discontinuation will be imputed under the assumption that their outcome would be 
the similar to those in the placebo group with similar background characteristics. For subjects 
who did not discontinue the study, their intermittent missing values will be imputed based on 
the MAR assumption. Multiple imputation will be used to account for uncertainty in the 
imputation process and results from the imputed datasets will be combined using Rubin’s 
method.  Further details are provided below.
Windowing will be performed first (Section 6.3.3) and any missing data will be imputed using 
the following steps.
The covariates and baseline characteristics which can be predictive of the response will be 
included in a multiple imputation procedure (SAS PROC MI) and will include the following:

Baseline value of efficacy measurement (continuous)

Observed value of efficacy measurement at Day 90 (continuous)

Observed value of efficacy measurement at Day 150 (continuous)

Observed value of efficacy measurement at Day 180 (continuous)
1. Intermittent missing data will be imputed using MCMC methods, assuming MAR, within 
each treatment group.  SAS PROC MI will be utilized for this step using the MCMC 
impute=monotone option. A total of 100 datasets will be created.  These datasets will be 
utilized in Step #2.
2. The remaining missing values with a monotone missing data pattern will be imputed in this 
step. Control-based PMM imputation will be performed. With this imputation model, the 
missing efficacy measurements in the inclisiran group will not be constructed from the 
observed data in the inclisiran group but rather from the observed data in the placebo group. 
We will also use this model to impute missing efficacy measurements in the placebo group. 
The MNAR statement in SAS PROC MI will be used to impute missing values under the 
aforementioned assumptions. This will be performed for the 100 datasets.  After this step, 
the 100 datasets will be fully imputed.
3. A total of 100 fully imputed datasets will be created (M=100). Since multiple imputation is 
a stochastic method, slight differences in output can be expected for different initial states 
of the random number generator. The seed numbers will be identified in the SAS programs 
to allow for reproducibility.
4. After the missing data imputation is completed using the above steps, absolute 
change/percentage change values will be calculated in each of the imputed datasets at each 
visit.
5. These 100 datasets will be analyzed using the MMRM described in Appendix 1 for the 
primary efficacy endpoint and key secondary efficacy endpoint.


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6. Treatment effects (difference in LS means between treatments) from these 100 analyses will 
then be combined using Rubin’s Method via SAS PROC MIANALYZE procedure for each 
endpoint. The p-value will also be provided.


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10.4
Appendix 4: Criteria for Potentially Clinically Significant and 
clinically significant Abnormal Laboratory Tests
Hemoglobin A1C criteria is explicitly stated in the table below. 
All other criteria are met when both of the following occur:

Post-baseline values meet the thresholds below

Baseline values or any previous post-baseline values do not meet the thresholds below
Parameter
Unit
Lower 
Boundary
Upper Boundary 
Hematology
Hematocrit
%
 0.8 × LLN
N/A
Hemoglobin
g/dL
 10 g/dL
N/A
Platelet Count
10^9/ L
 75*
 700*
White Blood Cell Count
10^9/L
 2.8
 16
Serum Chemistry
Alanine Aminotransferase (ALT/SGPT)
U/L
N/A
 1 and  3 × ULN
Alanine Aminotransferase (ALT/SGPT)
U/L
N/A
  and  5 × ULN*
Alanine Aminotransferase (ALT/SGPT)
U/L
N/A
  and  10 × ULN*
Alanine Aminotransferase (ALT/SGPT)
U/L
N/A
  and  20 × ULN*
Alanine Aminotransferase (ALT/SGPT)
U/L
N/A
  × ULN*
Alkaline Phosphatase
U/L
N/A
  × ULN*
Aspartate Aminotransferase (AST/SGOT)
U/L
N/A
 1 and  3 × ULN
Aspartate Aminotransferase (AST/SGOT)
U/L
N/A
  and  5 × ULN*
Aspartate Aminotransferase (AST/SGOT)
U/L
N/A
  and  10 × ULN*
Aspartate Aminotransferase (AST/SGOT)
U/L
N/A
  and  20 × ULN*
Aspartate Aminotransferase (AST/SGOT)
U/L
N/A
  × ULN*
Creatine Kinase (CK)
U/L
N/A
 1 and  3 × ULN
Creatine Kinase (CK)
U/L
N/A
 3 and  5 × ULN
Creatine Kinase (CK)
U/L
N/A
 5 × and  10 x ULN*
Creatine Kinase (CK)
U/L
N/A
 10 and  20 × ULN*
Creatine Kinase (CK)
U/L
N/A
  × ULN*
Hemoglobin A1C
%
N/A
≥ 6.5% and ≥ 0.5% 
change from baseline 
Serum Creatinine
mg/dL
N/A
≥ 50% increase from 
Baseline or > 2 mg/dL*
Total Bilirubin
mg/dL
N/A
  × ULN*
LLN: Lower limit of the standard reference (normal) range; ULN: Upper limit of the standard 
reference (normal) range; N/A is Not Applicable.
*Clinically significant laboratory boundaries.


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10.5
Appendix 5: Additional Adverse Event Investigations
1. Adverse Events at the Injection Site

Injection site reaction (HLT)
2. Hepatic events

Drug related hepatic disorders - comprehensive search (SMQ, broad and narrow)  
3. Renal events 

Acute kidney injury (SMQ, broad and narrow)
4. New onset/worsening of diabetes 

Hyperglycemia/new onset diabetes mellitus (SMQ, narrow)

Diabetic Complications (HLGT)

Diabetes Mellitus (HLT) 

Carbohydrate tolerance analyses HLT, excluding PT “Blood glucose decreased” 
5. Hypersensitivity 

Hypersensitivity' (SMQ, broad and narrow) excluding 

PTs ‘infusion site %’ (‘'infusion site dermatitis', 'infusion site eczema’, 'infusion 
site hypersensitivity', 'infusion site rash', 'infusion site urticaria', 'infusion site 
vasculitis) and 

PTs ‘injection site %’ ('injection site dermatitis', 'injection site eczema’, 'injection 
site hypersensitivity', 'injection site rash', 'injection site urticaria' and 'injection 
site vasculitis')
6. Neurological events and neurocognitive disorders

Neurological events 

Demyelination, (SMQ, broad and narrow) 

Peripheral neuropathy, (SMQ, broad and narrow)

Neurocognitive disorders 

Deliria (including confusion), (HLGT)

Cognitive and attention disorders and disturbances, (HLGT)

Dementia and amnestic conditions, (HLGT)

Disturbances in thinking and perception (HLGT)

Mental impairment disorders (HLGT)
7. Ophthalmologic events

Optic nerve disorders, (SMQ, broad and narrow) 

Retinal disorders, (SMQ, narrow) 

Corneal disorders, (SMQ, narrow)
  


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
 
 
 


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10.6
Appendix 6: Clinically Relevant Adverse Events at the Injection 
Site Preferred Terms
Injection site atrophy
Injection site cellulitis
Injection site dermatitis
Injection site eczema
Injection site erythema
Injection site fibrosis
Injection site granuloma
Injection site hypersensitivity
Injection site infection
Injection site inflammation
Injection site ischaemia
Injection site lymphadenopathy
Injection site necrosis
Injection site nerve damage
Injection site photosensitivity reaction
Injection site pruritus
Injection site pustule
Injection site rash
Injection site reaction
Injection site recall reaction
Injection site scar
Injection site thrombosis
Injection site ulcer
Injection site urticaria
Injection site vasculitis
Injection site vesicles