Clinical trial NCT03397121
Conditions: Heterozygous Familial Hypercholesterolemia Elevated Cholesterol
Keywords: HeFH LDL-C Inclisiran
Sponsor: The Medicines Company
Start date: 2017-11-28; Completion date: 2019-09-17
Enrollment: 482 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase III, placebo-controlled, double-blind, randomized study in participants with HeFH and elevated LDL-C to evaluate the efficacy, safety, and tolerability of subcutaneous (SC) injection(s) of inclisiran. The study will be multicenter and international.

Detailed description:

Arms: arm 1: Inclisiran sodium 300 milligrams (mg) will be administered as a SC injection on Day 1, Day 90 then every 6 months. arm 2: Placebo will be administered as SC injections of saline solution on Day 1, Day 90 then every 6 months.
Interventions: intervention 1: Inclisiran intervention 2: Placebo
Intervention descriptions: intervention 1: Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis. intervention 2: Placebo will be supplied as sterile normal saline (0.9% sodium chloride in water for injection).

Protocol documents:
Prot_000.pdf: 
Inclisiran 
 
 ORION-9 (MDCO-PCS-17-03) 
The Medicines Company 
 
 Clinical Study Protocol 
 
 
Protocol No.: MDCO-PCS-17-03 (ORION-9) 
A Placebo-Controlled, Double-Blind, Randomized Trial to Evaluate the Effect Of 300 mg 
of Inclisiran Sodium Given as Subcutaneous Injections in Subjects with Heterozygous 
Familial Hypercholesterolemia (HeFH) and Elevated Low-Density Lipoprotein Cholesterol 
(LDL-C) 
CLINICAL STUDY PROTOCOL 
31 January 2019 
 
NCT03397121 


Confidential 
1 
Investigational New Drug 
INCLISIRAN 
A PLACEBO-CONTROLLED, DOUBLE-BLIND, RANDOMIZED 
TRIAL TO EVALUATE THE EFFECT OF 300 MG OF 
INCLISIRAN SODIUM GIVEN AS SUBCUTANEOUS 
INJECTIONS IN SUBJECTS WITH HETEROZYGOUS 
FAMILIAL HYPERCHOLESTEROLEMIA (HeFH) AND
ELEVATED LOW-DENSITY LIPOPROTEIN CHOLESTEROL 
(LDL-C) 
ORION-9 
Protocol No.: MDCO-PCS-17-03 
U.S.  IND No.:  127,589  
EudraCT No.:  2017-002472-30 
PROTOCOL VERSION: Global Amendment # 4 
Development Phase: 
III 
Sponsor: 
The Medicines Company 
8 Sylvan Way 
Parsippany, NJ 07054 
Issue Date: 
31 Jan 2019 
CONFIDENTIAL 
Property of The Medicines Company 
May not be used, divulged, published or otherwise disclosed without the consent of 
The Medicines Company 
This study will be conducted in compliance with Good Clinical Practice (GCP) and protection of the subject 
as required by the regulations and directives in operation at this time. 


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PROCEDURES IN CASE OF EMERGENCY 
Emergency Contact Information 
Role in Study 
Name 
Telephone Number 


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Study Protocol - Global Amendment 4 
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PROTOCOL SYNOPSIS 
Name of Sponsor/Company: The Medicines Company 
Name of Finished Product: Inclisiran for Injection 
Name of Active Ingredient: inclisiran sodium  
Title of Study: A placebo-controlled, double-blind, randomized trial to evaluate the effect of 300 mg of 
inclisiran sodium given as subcutaneous injections in subjects with heterozygous familial 
hypercholesterolemia (HeFH) and elevated low-density lipoprotein cholesterol (LDL-C) 
Phase of Development: III 
Study Centers: Multicenter, international study (approximately 100 sites); specific list is maintained by 
the Sponsor.  
Central Facilities: This list is maintained by the Sponsor 
Number of Subjects: Approximately 400 eligible subjects will be randomized (200 subjects 
randomized to inclisiran and 200 subjects randomized to placebo). Assuming about a 5% drop out rate, 
the sample size will be approximately 380 subjects that are evaluable for efficacy across the placebo and 
inclisiran dose groups. Due to faster than expected enrollment, actual enrollment was 482 subjects. 
Principal Investigator: 
Study Period: The estimated study period for the study will be 24 months from when the first subject is 
enrolled to when the last subject completes the study. 
Objectives: 
Primary: 
The primary objective is to evaluate the effect of inclisiran treatment on: 
 
LDL-C levels at Day 510 
 
Time adjusted percent change in LDL-C levels from baseline after Day 90 and up to Day 540 
levels 
 
Secondary: 
The secondary objectives are to evaluate the effect of inclisiran on: 
 
Proprotein convertase subtilisin/kexin type 9 (PCSK9), total cholesterol, ApoB, and non-high-
density lipoprotein cholesterol (HDL-C) at Day 510 
 
LDL-C and PCSK9 levels over time to Day 540 
 
Mean maximum reduction in LDL-C levels 
 
LDL-C and PCSK9 levels over time in individual subjects 
 
Other lipids, lipoproteins, apolipoproteins 
 
Proportion of subjects achieving prespecified LDL-C targets  
 
Safety and tolerability profile of inclisiran 
 
Exploratory: 
The exploratory objectives are to collect/evaluate the effect of inclisiran on the following: 
 
Cardiovascular (CV) events such as CV death, resuscitated cardiac arrest, non-fatal myocardial 
infarction (MI), and non-fatal stroke (ischemic and hemorrhagic) 
 
Response of LDL-C reduction by underlying causal mutations of HeFH 
 


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Methodology: This study is a Phase III, placebo-controlled, double-blind, randomized study in 
400 subjects with HeFH and elevated LDL-C despite maximum tolerated dose of LDL-C lowering 
therapies to evaluate the efficacy, safety, and tolerability of subcutaneous inclisiran injection(s). 
Subjects will be screened and approximately 400 eligible subjects will be randomized: 200 subjects will 
be randomized to inclisiran sodium 300 mg and 200 subjects randomized to placebo. Due to faster than 
expected enrollment, actual enrollment was 482 subjects. Treatment allocation will be stratified by 
country and by current use of statins or other lipid-modifying therapies. Each subject will receive four 
subcutaneous injections of blinded inclisiran or placebo on Day 1, Day 90, Day 270, and Day 450.  
On Day 1, all eligible subjects will be randomized and will receive the first subcutaneous (SC) injection 
of investigational product (inclisiran or placebo). After the first SC injection, the subject will be 
observed in the clinic for at least 4 hours post injection in order to have additional laboratory 
assessments and vital signs completed before being discharged. Subjects will return on Day 90, Day 270, 
and Day 450 to receive additional investigational product. During these subsequent dosing visits, 
subjects will be observed in the clinic for at least 30 minutes after administration of each injection and 
have additional laboratory assessments completed if needed. Subjects will also have in-clinic visits on 
Day 30, Day 150, Day 330, and Day 510 for follow-up and limited laboratory assessments. The end of 
study (EOS) visit will be conducted on Day 540. 
Pharmacodynamic assessments will be collected at various visits and include LDL-C levels as well as 
other lipids and lipoproteins (eg, total cholesterol, triglycerides, HDL-C, non-HDL-C, very low-density 
lipoprotein cholesterol [VLDL-C], apolipoprotein A1 [Apo-A1], apolipoprotein B [ApoB], 
lipoprotein(a) [Lp(a)], high sensitivity C-reactive protein [hsCRP], and PCSK9). 
All subjects will be invited to consent to pharmacogenetic analyses, unless underlying causal mutations 
of HeFH are well documented by a validated specialized laboratory. A blood sample will be collected, 
preferably during screening, only from subjects who sign a separate consent for pharmacogenetics. 
Safety assessments including adverse events (AEs), serious adverse events (SAEs), electrocardiograms 
(ECGs), concomitant medications, and safety laboratory parameters will also be collected during the 
study. In addition, formation of anti-drug antibodies (ADA) and further characterization of ADA will be 
evaluated. 
End of study evaluations will be conducted at the Day 540 visit. 
Subjects who have completed the study to Day 540 will be given the opportunity to enroll in a separate 
open-label long-term extension study to collect long-term safety and efficacy data for inclisiran.  
The independent Data Monitoring Committee (IDMC) will review safety data after the first 40 subjects 
receive the first SC injection of inclisiran or placebo and have completed 1 month follow-up. Thereafter 
the IDMC will review safety data every 3 months until the end of study (EOS) unless requested 
otherwise by the IDMC. A recommendation may be taken to stop or amend the study at any of these 
reviews. 
Diagnosis and Main Criteria for Selection:  
Subjects may be included if they meet all of the following inclusion criteria prior to randomization: 
1. Male or female subjects ≥18 years of age. 
2. History of HeFH with a diagnosis of HeFH by genetic testing; and/or a documented history of 
untreated LDL-C of >190 mg/dL, and a family history of FH, elevated cholesterol or early heart 
disease that may indicate FH (APPENDIX A) 
3. Stable on a low-fat diet (eg, NCEP) 


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4. Serum LDL-C ≥2.6 mmol/L (≥100 mg/dL) at screening 
5. Fasting triglyceride <4.52 mmol/L (<400 mg/dL) at screening. 
6. Calculated glomerular filtration rate >30 mL/min by estimated glomerular filtration rate (eGFR) 
using standardized local clinical methodology. 
7. 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) (APPENDIX B). 
8. Subjects not receiving statins must have documented evidence of intolerance to all doses of at 
least two different statins (APPENDIX B). 
9. Subjects on lipid-lower therapies (such as a 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. 
10. Subjects must be willing and able to give informed consent before initiation of any study-
related procedures and willing to comply with all required study procedures. 
 
Subjects will be excluded from the study if any of the following exclusion criteria apply immediately 
prior to randomization: 
1. Any uncontrolled or serious disease, or any medical or surgical condition, that may either 
interfere with participation in the clinical study, and/or put the subject at significant risk 
(according to investigator’s [or delegate] judgment) if he/she participates in the clinical study. 
2. An underlying known disease, or surgical, physical, or medical condition that, in the opinion of 
the investigator (or delegate) might interfere with interpretation of the clinical study results. 
3. New York Heart Association (NYHA) class IV heart failure or last known left ventricular 
ejection fraction <25%. 
4. Cardiac arrhythmia within 3 months prior to randomization that is not controlled by medication 
or via ablation. 
5. Major adverse cardiovascular event within 3 months prior to randomization. 
6. Uncontrolled severe hypertension: systolic blood pressure >180 mmHg or diastolic blood 
pressure >110 mmHg prior to randomization despite antihypertensive therapy. 
7. Active liver disease defined as any known current infectious, neoplastic, or metabolic 
pathology of the liver or unexplained elevations in alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), >3x the upper limit of normal (ULN), or total bilirubin >2x ULN at 
screening confirmed by a repeat abnormal measurement at least 1 week apart. 
8. Severe concomitant noncardiovascular disease that carries the risk of reducing life expectancy 
to less than 2 years. 
9. History of malignancy that required surgery (excluding local and wide-local excision), radiation 
therapy and/or systemic therapy during the three years prior to randomization. 
10. Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use 
at least two methods of highly effective contraception (failure rate less than 1% per year) (eg 
combined oral contraceptives, barrier methods, approved contraceptive implant, long- term 
injectable contraception, or 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 last menstrual period) 
AND more than 55 years of age. 


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b.
Postmenopausal women (as defined above) and less than 55 years of age with a negative
pregnancy test within 24 hours of randomization.
c.
Women who are surgically sterilized at least 3 months prior to enrollment.
11. Males who are unwilling to use an acceptable method of birth control during the entire study
period (ie, condom with spermicide).
12. Known history of alcohol and/or drug abuse within the last 5 years.
13. Treatment with other investigational products or devices within 30 days or five half˗lives of the 
screening visit, whichever is longer.
14. Planned use of other investigational products or devices during the course of the study.
15. 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.
16. Treatment (within 90 days of screening) with monoclonal antibodies directed towards PCSK9.
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. 
Test Product, Dose and Mode of Administration: Inclisiran sodium 300 mg (equivalent to 284 mg 
inclisiran) will be administered as a single SC injection on Day 1, Day 90, Day 270, and Day 450.  
Duration of Treatment: The expected duration of the subjects’ involvement in the study will be 
approximately 554 days which includes screening, investigational product administration, and the EOS 
period to Day 540. 

Screening: Day -14 to -1

Randomization, initiation of investigational product: Day 1

Treatment Phase:
o
Dosing: Day 1, Day 90, Day 270 and Day 450 (final dose)
o
Additional clinic visits: Day 30, Day 150, Day 330 and Day 510

EOS visit:  Day 540 (90 days after final dose)
Reference Therapy, Dose, and Mode of Administration: Placebo will be administered as SC 
injections of saline solution. Placebo volume will be matched to test product volume within each dose 
and injection ie, the 300 mg dose will be administered as 1.5 mL of placebo. 
Criteria for Evaluation: 
Efficacy: 
Primary Endpoints: 

Percentage change in LDL-C from baseline to Day 510

Time adjusted percentage change in LDL-C from baseline after Day 90 and up to Day 540. This
is the average percentage change in LDL-C from baseline over the period after Day 90 and up
to Day 540.


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Key Secondary Endpoints: 
 
Absolute change in LDL-C from baseline to Day 510 
 
Time adjusted absolute change in LDL-C from baseline after Day 90 and up to Day 540 
 
Percentage change from baseline to Day 510 in PCSK 9, total cholesterol, ApoB, and non-
HDL-C 
 
Other Secondary Endpoints: 
 
Mean maximum percentage change in LDL-C 
 
Absolute change from baseline to Day 510 in PCSK9, total cholesterol, ApoB and non-HDL-C 
 
Absolute change and percentage change in LDL-C from baseline to each assessment time up to 
Day 540 
 
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 Day 510 
 
Proportion of subjects in each group with greater or equal to 50% LDL-C reduction from 
baseline  
 
Absolute change and percentage change in other lipids, lipoproteins, apolipoproteins, and 
PCSK9 from baseline at each subsequent visit to Day 540 
 
Proportion of subjects in each group who attain global lipid targets for their level of 
atherosclerotic cardiovascular disease (ASCVD) risk 
 
Exploratory Endpoints: 
 
Incidence of CV death, resuscitated cardiac arrest, non-fatal MI, and non-fatal stroke (ischemic 
and hemorrhagic) 
 
Response of LDL-C reduction by underlying causal mutations of HeFH 
Safety: Adverse event, SAEs, vital signs, clinical laboratory values (hematology, coagulation testing, 
chemistry, and urinalysis), and electrocardiograms (ECGs) will be collected at specified visits through 
the EOS visit (Day 540). Cardiovascular events will be reported as AEs for the compilation of 
information on CV events such as CV death, resuscitated cardiac arrest, non-fatal MI, and non-fatal 
stroke (ischemic and hemorrhagic). In addition, formation of ADA and subsequent characterization of 
ADA will be evaluated for the investigational product. 
Statistical Methods: 
Sample Size and Power 
The sample size calculation was performed with the assumption (which was based on the observed 
results from a Phase II study) that the difference in change from baseline between the active dose group 
and the placebo group for LDL-C will be no less than 30 mg/dL, with a standard deviation of 20 mg/dL.  
Assuming about a 5% drop out rate, the sample size will be approximately 380 subjects that are 
evaluable for efficacy across the placebo and inclisiran dose groups. This sample size of at least 380 
evaluable subjects, will provide more than 90% power to detect a 30% reduction of LDL-C levels in the 
inclisiran group compared to the placebo group at one-sided significance level of 0.025. Due to faster 
than expected enrollment, actual enrollment was 482 subjects. This increased sample size will contribute 
additional safety data and not appreciably affect power calculations. 
Primary Endpoint Analysis: 
The family-wise type I error rate is controlled at one-sided significance level of alpha=0.025 by using a 
nested testing procedure. The percentage change in LDL-C from baseline to Day 510 will be tested first. 
If the null hypothesis is rejected at one-sided significance level of alpha=0.025 and superiority of 
inclisiran over placebo is claimed, then the time adjusted percentage change in LDL-C from baseline 
after Day 90 and up to Day 540 will be tested, also at one-sided significance level of alpha=0.025. 
Mixed-effect models for repeated measures (MMRM) will be performed on the percent change in 


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LDL-C from baseline to Day 510 to test the superiority of inclisiran over placebo. Missing data will be 
imputed using a multiple imputation washout model. Results will be combined using Rubin’s method. 
Time adjusted percentage change in LDL-C from baseline after Day 90 and up to Day 540 will be 
calculated from the MMRM with imputed data discussed above. Linear combinations of the estimated 
means after Day 90 and up to Day 540 will be used to compare treatments. Results will be combined 
using Rubin’s method.
Key Secondary Endpoint Analysis: 
The secondary efficacy endpoints will not be tested if either one of the co-primary efficacy endpoints’ 
null hypothesis failed to be rejected. 
The Hochberg procedure will be applied to control the family-wise type I error rate at one-sided 
significance level of alpha=0.025 for the key secondary endpoints. The key secondary endpoints will be 
analyzed using the same methods as in the primary efficacy analysis. 
Other Secondary and Exploratory Endpoint Analysis: 
The analysis of the secondary and exploratory endpoints will include descriptive and graphical 
summaries by treatment group. Least squares means (95% Confidence Intervals) will be provided for 
continuous variables. Nominal p-values will be provided when applicable. 
Interim Analysis: 
No interim analysis will be performed in this study. 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ................................................................................................................3 
LIST OF ABBREVIATIONS ........................................................................................................15 
1. 
INTRODUCTION ......................................................................................................18 
1.1. 
Background .................................................................................................................18 
1.1.1. 
Disease Overview .......................................................................................................18 
1.1.2. 
PCSK9 Biology and Target Rationale ........................................................................19 
1.1.3. 
Mechanism of RNA Interference ................................................................................20 
1.2. 
Inclisiran, an siRNA Therapeutic for Hypercholesterolemia .....................................20 
1.2.1. 
Nonclinical Studies .....................................................................................................21 
1.2.2. 
Clinical Studies ...........................................................................................................21 
1.2.2.1. 
Clinical pharmacology ................................................................................................21 
1.2.2.2. 
Clinical ........................................................................................................................22 
1.3. 
Known and Potential Risks and Benefits....................................................................23 
1.4. 
Study Rationale ...........................................................................................................23 
1.4.1. 
Study Rationale ...........................................................................................................23 
1.4.2. 
Dose Rationale ............................................................................................................23 
1.5. 
Study Population .........................................................................................................23 
2. 
STUDY OBJECTIVES AND PURPOSE ..................................................................24 
2.1. 
Primary Objective .......................................................................................................24 
2.2. 
Secondary Objectives .................................................................................................24 
2.3. 
Exploratory Objectives ...............................................................................................24 
3. 
STUDY DESIGN .......................................................................................................25 
3.1. 
Type/Design of Study .................................................................................................25 
3.2. 
Schematic Diagram of Study Design ..........................................................................25 
3.3. 
Primary Endpoints ......................................................................................................25 
3.4. 
Secondary Endpoints ..................................................................................................26 
3.5. 
Exploratory Endpoints ................................................................................................26 
3.6. 
Measures to Minimize/Avoid Bias .............................................................................27 
3.6.1. 
Blinded Study .............................................................................................................27 
4. 
SUBJECT POPULATION .........................................................................................28 


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4.1. 
Number of Subjects ....................................................................................................28 
4.2. 
Inclusion Criteria ........................................................................................................28 
4.3. 
Exclusion Criteria .......................................................................................................29 
4.4. 
Withdrawal Criteria ....................................................................................................30 
4.4.1. 
Withdrawal from Study Medication ...........................................................................31 
4.5. 
Stopping Criteria .........................................................................................................31 
4.5.1. 
Individual Subject Dosing Stopping Criteria ..............................................................31 
5. 
TREATMENT OF SUBJECTS ..................................................................................33 
5.1. 
Study Medications ......................................................................................................33 
5.1.1. 
Inclisiran .....................................................................................................................33 
5.1.2. 
Placebo ........................................................................................................................33 
5.1.3. 
Packaging and Labeling ..............................................................................................33 
5.1.4. 
Storage ........................................................................................................................34 
5.1.5. 
Accountability .............................................................................................................34 
5.1.6. 
Product Complaints ....................................................................................................34 
5.2. 
Concomitant Medications ...........................................................................................35 
5.2.1. 
Prohibited Concomitant Medications .........................................................................35 
5.2.2. 
Permitted Concomitant Medications ..........................................................................35 
5.3. 
Medical Management Guidelines ...............................................................................36 
5.3.1. 
Adverse events ............................................................................................................36 
5.3.2. 
Pregnancy ...................................................................................................................36 
5.4. 
Restrictions .................................................................................................................36 
5.5. 
Blinding ......................................................................................................................36 
5.5.1. 
Blinding of study medications ....................................................................................36 
5.5.2. 
Method and Maintenance of Blinding ........................................................................37 
5.6. 
UNBLINDING ...........................................................................................................37 
5.6.1. 
In the Event of an Emergency: Unblinding a Code ....................................................37 
6. 
SCHEDULE AND SEQUENCE OF PROCEDURES ...............................................38 
6.1. 
Schedule of Assessments ............................................................................................38 
6.2. 
General Conduct of the Study .....................................................................................41 
6.3. 
Screening Period (Days –14 to –1) .............................................................................41 
6.4. 
Randomization ............................................................................................................42 
6.5. 
Day 30 Visit ................................................................................................................43 


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6.6. 
Additional Dosing Visits (Days 90, 270, and 450) .....................................................43 
6.7. 
Additional NON DOSING Clinic Visits (Days 150, 330, and 510) ...........................43 
6.7.1. 
Day 150 .......................................................................................................................43 
6.7.2. 
Day 330 .......................................................................................................................44 
6.7.3. 
Day 510 .......................................................................................................................44 
6.8. 
End of Study (EOS) Visit (Day 540 – 90 days post last dose) ...................................44 
7. 
PROTOCOL ASSESSMENTS ..................................................................................46 
7.1. 
Assessment of Safety ..................................................................................................46 
7.1.1. 
Adverse Events ...........................................................................................................46 
7.1.2. 
Demographics and Medical History ...........................................................................46 
7.1.3. 
Vital Signs ..................................................................................................................46 
7.1.4. 
Physical Examination .................................................................................................46 
7.1.5. 
Neurological Evaluation .............................................................................................46 
7.1.6. 
Electrocardiograms .....................................................................................................46 
7.1.7. 
Cardiovascular Events ................................................................................................46 
7.1.8. 
Clinical Laboratory Assessments ...............................................................................46 
7.1.8.1. 
Hematology .................................................................................................................47 
7.1.8.2. 
Coagulation .................................................................................................................47 
7.1.8.3. 
Chemistry ....................................................................................................................47 
7.1.8.4. 
Inflammatory markers (IL6, IFN-γ, and TNF-α, hsCRP) ...........................................47 
7.1.8.5. 
Urinalysis ....................................................................................................................48 
7.1.8.6. 
Urine Pregnancy .........................................................................................................48 
7.1.8.7. 
Lipids / Lipoproteins ...................................................................................................48 
7.1.8.8. 
Anti-drug Antibodies ..................................................................................................48 
7.1.9. 
Stored samples ............................................................................................................48 
7.2. 
Assessment of Efficacy ...............................................................................................49 
7.2.1. 
Change from Day 1 in LDL-C ....................................................................................49 
7.2.2. 
Change from Day 1 in Lipids/Lipoproteins ................................................................49 
7.3. 
Assessment of Pharmacodynamics .............................................................................49 
7.4. 
Assessment of Pharmacogenetics ...............................................................................50 
8. 
ADVERSE EVENTS..................................................................................................51 
8.1. 
Definitions ..................................................................................................................51 
8.1.1. 
Adverse Event .............................................................................................................51 


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8.1.2. 
Serious Adverse Event ................................................................................................51 
8.1.3. 
Special Situations ........................................................................................................52 
8.2. 
Collection and Assessment of Adverse Events ..........................................................52 
8.2.1. 
Pre-existing Conditions ..............................................................................................52 
8.2.2. 
Adverse Event Severity ..............................................................................................52 
8.2.3. 
Relationship to Investigational Product ......................................................................52 
8.3. 
Requirements For Additional Safety Data Collection ................................................52 
8.3.1. 
Special Situations ........................................................................................................52 
8.3.2. 
Other safety related information .................................................................................53 
8.4. 
Procedure for Adverse Event Reporting .....................................................................53 
8.4.1. 
Serious Adverse Events (SAEs) .................................................................................53 
8.4.2. 
Non-Serious AEs ........................................................................................................54 
8.4.3. 
Special situations ........................................................................................................54 
8.4.3.1. 
Medication Errors .......................................................................................................54 
8.4.3.2. 
Pregnancy/Lactation Exposure ...................................................................................54 
8.5. 
Expectedness ...............................................................................................................55 
8.5.1. 
Expectedness Determination ......................................................................................55 
8.6. 
Study Stopping Criteria ..............................................................................................55 
8.6.1. 
Independent Data Monitoring Committee (IDMC) Stopping Rules ..........................55 
8.6.2. 
Sponsor Discontinuation Stopping Criteria ................................................................55 
9. 
DATA COLLECTION ...............................................................................................56 
10. 
STATISTICAL PLAN................................................................................................57 
10.1. 
Sample Size ................................................................................................................57 
10.2. 
RANDOMIZATION ..................................................................................................57 
10.3. 
General Statistical Considerations and Definitions ....................................................57 
10.3.1. 
General Statistical Methods ........................................................................................57 
10.3.2. 
Analysis Population ....................................................................................................57 
10.3.2.1. 
Intent-to-Treat (ITT) Population .................................................................................58 
10.3.2.2. 
Full Analysis Set (FAS) ..............................................................................................58 
10.3.2.3. 
Modified Intent-to-Treat (mITT) Population ..............................................................58 
10.3.2.4. 
Safety Population ........................................................................................................58 
10.3.3. 
Analysis Windows and Baseline ................................................................................58 
10.3.4. 
Missing Data Handling ...............................................................................................58 


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10.4. 
Statistical Analyses .....................................................................................................59 
10.4.1. 
Demographic and Background Characteristics ..........................................................59 
10.4.2. 
Investigational Product and Concomitant Medications ..............................................59 
10.4.3. 
Efficacy Analysis ........................................................................................................59 
10.4.3.1. 
Primary Efficacy Endpoints ........................................................................................59 
10.4.3.1.1. Sensitivity Analysis for Primary Efficacy Endpoints .................................................60 
10.4.3.2. 
Secondary Efficacy Endpoints ....................................................................................60 
10.4.3.3. 
Exploratory Endpoints ................................................................................................60 
10.4.4. 
Safety Analysis ...........................................................................................................60 
10.4.4.1. 
Adverse Events ...........................................................................................................60 
10.4.4.2. 
Laboratory Tests .........................................................................................................61 
10.4.4.3. 
Vital Signs ..................................................................................................................61 
10.4.4.4. 
Neurological Examinations ........................................................................................61 
10.4.4.5. 
Pharmacodynamic Parameters ....................................................................................61 
10.5. 
Interim Analysis ..........................................................................................................61 
10.5.1. 
Interim Safety Reviews ...............................................................................................61 
11. 
RECORDS RETENTION ..........................................................................................62 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................63 
12.1. 
Monitoring ..................................................................................................................63 
12.2. 
Auditing ......................................................................................................................63 
12.3. 
Protocol Deviations ....................................................................................................63 
13. 
ETHICS AND RESPONSIBILITY ............................................................................65 
13.1. 
Informed Consent .......................................................................................................65 
13.2. 
Institutional Review Board/Ethics Committee ...........................................................65 
14. 
CONFIDENTIALITY ................................................................................................66 
15. 
INVESTIGATOR AGREEMENT .............................................................................67 
16. 
REFERENCES ...........................................................................................................68 
APPENDIX A: SIMON BROOME DIAGNOSTIC CRITERIA FOR FAMILIAL 
HYPERCHOLESTEROLEMIA.................................................................................72 
APPENDIX B: REQUIREMENTS FOR BACKGROUND LIPID LOWERING 
TREATMENT ............................................................................................................73 
APPENDIX C: GENETIC INFORMED CONSENT....................................................................75 
APPENDIX D: RECOMMENDED NEUROLOGICAL EXAMINATION .................................76 


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APPENDIX E: SAMPSON CRITERIA FOR DIAGNOSING ANAPHYLAXIS........................81 
 
LIST OF TABLES 
Table 1: 
Investigational Product ...............................................................................................33 
Table 2: 
Schedule of Assessments ............................................................................................39 
 
LIST OF FIGURES 
Figure 1: 
Schematic Diagram of Study Design ..........................................................................25 


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LIST OF ABBREVIATIONS 
ADA 
anti-drug antibodies 
AE 
adverse event 
ALP 
alkaline phosphatase  
ALT 
alanine aminotransferase  
Apo-A1 
apolipoprotein A1 
ApoB 
apolipoprotein B 
aPTT 
activated partial thromboplastin 
ASCVD 
atherosclerotic cardiovascular disease  
ASGPR 
asialoglycoprotein receptor 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BUN 
total protein urea 
CABG 
coronary artery bypass graft 
CFR 
Code of Federal Regulations 
CHD 
coronary heart disease 
CK 
creatine kinase 
Cmax 
maximum plasma concentration 
CPK 
creatine phosphokinase 
CRF 
case report form 
CT 
computed tomography 
CTA 
Computed tomographic angiography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
cardiovascular 
CVD 
cerebrovascular disease  
dL 
deciliter(s) 
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 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FH 
familial hypercholesterolemia 
GalNAc 
N-acetylgalactosamine 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
GPV 
Global Pharmacovigilance 
HbA1c 
glycated hemoglobin A1C 
HDL-C 
high density lipoprotein cholesterol 


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HeFH 
Heterozygous Familial Hypercholesterolemia 
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 
ISR 
injection site reaction 
ITT 
intent-to-treat 
IV 
intravenous 
LDL-C 
low density lipoprotein cholesterol 
LDLR 
low density lipoprotein receptor 
LNP 
lipid nanoparticles 
Lp(a) 
lipoprotein(a) 
Lp-PLA2 
lipoprotein-associated phospholipase A2 
MCH 
mean cell hemoglobin  
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MDCO 
The Medicines Company 
MDCT 
multidetector computed tomography 
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 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
NYHA 
New York Heart Association 
PAD 
peripheral arterial disease 
PCI 
percutaneous coronary intervention 
PCS 
potentially clinical significant 
PCSK9 
proprotein convertase subtilisin/kexin type 9 
PEF 
peak expiratory flow 
PT 
prothrombin time 
REML 
Restricted Maximum Likelihood 
RISC 
RNA-induced silencing complex 


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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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1. 
INTRODUCTION 
The Medicines Company is developing a novel synthetic ribonucleic acid (RNA) interference 
(RNAi) therapeutic, Inclisiran for Injection (subcutaneous [SC] use) 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 510. This study 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 (FH), 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 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 


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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. Preliminary reports indicate that treatment with such 
antibodies can lead to reduction of cardiovascular events compared with placebo [Hooper et 
al, 2005; Navarese et al, 2015; Zhang et al, 2015; Robinson et al, 2015; Sabatine et al, 2015]. 
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 (ASCVD) 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 low-density lipoprotein receptor (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; 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 


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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. This enzyme complex subsequently 
binds to its complementary mRNA sequence, mediating cleavage of the target mRNA and the 
suppression of the target protein encoded by the mRNA [Elbashir et al, 2001]. 
Since unmodified siRNAs are rapidly eliminated and do not achieve significant tissue 
distribution upon systemic administration [Soutschek et al, 2004], various formulations are 
currently used to target their distribution to tissues, and to facilitate uptake of siRNAs into 
the relevant cell type. One approach that has been used successfully in vivo, in animal 
models (including in rodents and nonhuman primates) and humans employs intravenous 
delivery of siRNA in lipid nanoparticle (LNP) formulations [Soutschek et al, 2004; 
Morrissey et al, 2005; Geisbert et al, 2006; 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, 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 
N-acetylgalactosamine (GalNAc) residues. 
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 asialoglycoprotein receptor (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 RNA-induced silencing complex (RISC), enabling it to cleave 


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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.  
Additional non-clinical studies are ongoing or planned. 
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 


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studies using hepatic P450 metabolic enzymes showed that inclisiran neither inhibited nor 
induced common hepatic metabolic pathways.  
Additional clinical pharmacology studies are ongoing or planned. 
1.2.2.2. 
Clinical 
Inclisiran has been studied in one completed Phase I (ALN-PCSSC-001) study (N=69) and 
one Phase II (ORION-1) study (N=501); dosing has completed in ORION-1 and the extended 
follow-up is ongoing.  
ALN-PCSSC-001: Doses up to 800 mg as a single dose and two doses or more doses up to 
500 mg were administered. 
ORION-1: Up to 500 mg as a single dose on Day 1 or two doses on Day 1 and Day 90 (100 
mg, 200 mg or 300 mg) were administered. 
The efficacy data generated in these two studies show robust and prolonged reductions in 
PCSK9 and LDL-C levels in plasma. PCSK9 was reduced from baseline by around 75%. 
Mean LDL-C was reduced by around 50% with one dose of 300 mg and 55% with two doses 
of 300 mg given 30 or 90 days apart in both the Phase I and the ORION-1 study, 
respectively. This effect is still significant 210 days after a single dose and remains at around 
a mean of 50% when measured 120 days after the second dose given at Day 90 in the 
ORION-1 study. Other lipids and lipoproteins are also modified as would be expected from a 
drug acting on PCSK9 with a potentially beneficial modification of the overall atherogenic 
lipid profile [Ray et al, 2017]. 
To date, no clinically relevant safety concerns have arisen in these studies of inclisiran; 
collection and analysis of data up to Day 360 is ongoing in the ORION-1 (Phase II) study. 
Based on these efficacy and safety data, 300 mg has been selected as the dose for subsequent 
clinical studies with a dosing at Day 1, Day 90, and every 6 months subsequently.  
Safety: 
In the ongoing Phase II (ORION-1) study with a follow up of more than 210 days, single 
doses of up to 500 mg on Day 1 or two doses (100 mg, 200 mg or 300 mg) (given 90 days 
apart) were also generally well tolerated and the majority of adverse events (AEs) in 
inclisiran-treated subjects with ASCVD and ASCVD risk equivalents were mild or moderate 
in intensity. Injection site reactions have been reported in around 5% of subjects receiving 
either one or two doses of inclisiran [Ray et al, 2017]. The emerging safety profile will be 
further evaluated in the ongoing Phase II (ORION 1) study and the subsequent planned 
studies. 
Efficacy: 
In the ongoing Phase II (ORION-1) study, in all single dose groups, maximal LDL-C 
reduction was observed between Day 30 and Day 60. At Day 30 the mean LDL-C reduction 
from baseline was approximately 45% to 55% and at Day 60 was 44% to 51% in a dose 
dependent fashion with doses of 200 mg, 300 mg and 500 mg. Mean LDL-C remained 
significantly reduced from baseline over the course of the study in all inclisiran groups to 
Day 210.  


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In all groups, maximal reduction is PCSK9 levels was observed at Day 30 and the mean 
reduction from baseline was 66%, 71% and 74% in the 200 mg, 300 mg and 500 mg groups 
respectively. 
In all double dose groups, maximal LDL-C reduction was observed after the second dose 
given at Day 90. At Day 120 the mean LDL-C reduction from baseline was 41% to 55% in a 
dose dependent fashion with doses of 100 mg, 200 mg and 300 mg.  
At Day 180, the mean LDL-C reduction was between 35% and 53% in a dose dependent 
fashion across the dose range. 
For subjects treated on Day 1 and Day 90, maximal reduction in PCSK9 levels was observed 
at Day 120 and the mean reduction from baseline was 60%, 73% and 75% with the 100 mg, 
200 mg and 300 mg dose groups respectively. PCSK9 levels remained significantly reduced 
compared to baseline over the course of the study to Day 210 in all groups. 
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. Injection site reaction 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 IB [Investigator’s Brochure].
1.4. 
Study Rationale 
1.4.1. 
Study Rationale 
The overall safety data from inclisiran in nonclinical studies and clinical data from the 
Phase I and Phase II study (ORION-1), and 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.  
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). The 300 mg dose of inclisiran will be administered on Day 1, Day 90, 
Day 270 and Day 450. 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 will be used for the entire 
duration of this study for subjects receiving inclisiran.  
1.5. 
Study Population 
This study will include male or female subjects ≥18 years of age with a history 
of Heterozygous Familial Hypercholesterolemia (HeFH) and elevated LDL-C. 


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2. 
STUDY OBJECTIVES AND PURPOSE 
2.1. Primary Objective 
The primary objective of this study is to evaluate the effect of inclisiran treatment on:  
 LDL-C levels at Day 510 
 Time adjusted percent change in LDL-C levels from baseline after Day 90 and up to 
Day 540 levels 
2.2. Secondary Objectives 
The secondary objectives of this study are to evaluate the effect of inclisiran on: 
 PCSK9, total cholesterol, ApoB and non-HDL-C at Day 510 
 LDL-C and PCSK9 levels over time to Day 540 
 Mean maximum reduction in LDL-C levels 
 LDL-C and PCSK9 levels over time in individual subjects 
 Other lipids, lipoproteins, apolipoproteins 
 Proportion of subjects achieving prespecified LDL-C targets  
 Safety and tolerability profile of inclisiran 
2.3. Exploratory Objectives 
The exploratory objectives of this study are to collect/evaluate the effect of inclisiran on the 
following: 
 CV events such as CV death, resuscitated cardiac arrest, non-fatal MI, and non-fatal 
stroke (ischemic and hemorrhagic) 
 Response of LDL-C reduction by underlying causal mutations of HeFH 


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3. 
STUDY DESIGN 
3.1. Type/Design of Study 
This study will be a Phase III, placebo-controlled, double-blind, randomized study in 
400 subjects with HeFH and elevated LDL-C despite maximum tolerated dose of LDL-C 
lowering therapies to evaluate the efficacy, safety, and tolerability of subcutaneous inclisiran 
injection(s). The study will be a multicenter, international study. Informed consent will be 
obtained from subjects before the initiation of any study-specific procedures. 
Subjects will be screened and approximately 400 eligible subjects will be randomized: 
200 subjects will be randomized to inclisiran sodium 300 mg and 200 subjects randomized to 
placebo. Due to faster than expected enrollment, actual enrollment was 482 subjects. 
Treatment allocation will be stratified by country and by current use of statins or other lipid-
modifying therapies. Enrollment of statin intolerant subjects will be capped at 15% of total 
study enrollment. Each subject will receive an injection on Day 1 of blinded inclisiran or 
placebo, a second injection on Day 90 and subsequent injections on Day 270 and Day 450. 
Subjects who have completed the study to Day 540 will be given the opportunity to enroll in 
a separate long-term extension study to collect long-term efficacy and safety data. 
3.2. Schematic Diagram of Study Design 
Figure 1: 
Schematic Diagram of Study Design 
 
 
FUP=follow-up; V=visit 
3.3. Primary Endpoints 
The primary endpoints of this study are:  
 Percentage change in LDL-C from baseline to Day 510 
 Time adjusted percentage change in LDL-C from baseline after Day 90 and up to Day 
540. This is the average percentage change in LDL-C from baseline over the period 
after Day 90 and up to Day 540. 
 
 


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3.4. Secondary Endpoints 
The key secondary endpoints of this study are: 
 Absolute change in LDL-C from baseline to Day 510 
 Time adjusted absolute change in LDL-C from baseline after Day 90 and up to Day 
540 
 Percentage change from baseline to Day 510 in PCSK9, total cholesterol, ApoB, and 
non-HDL-C 
The other secondary endpoints of this study are: 
 Mean maximum percentage change in LDL-C 
 Absolute change from baseline to Day 510 in PCSK9, total cholesterol, ApoB and 
non-HDL-C  
 Absolute change and percentage change in LDL-C from baseline to each assessment 
time up to Day 540 
 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 Day 510 
 Proportion of subjects in each group with greater or equal to 50% LDL-C reduction 
from baseline  
 Absolute change and percentage change in other lipids, lipoproteins, apolipoproteins, 
and PCSK9 from baseline at each subsequent visit to Day 540 
 Proportion of subjects in each group who attain global lipid targets for their level of 
ASCVD risk 
 Safety and tolerability profile of inclisiran as measured by AEs, SAEs, vital signs, 
clinical laboratory values, ECG measurements and formation of ADA and subsequent 
characterization of ADA 
3.5. Exploratory Endpoints 
The exploratory endpoints of this study are: 
 Incidence of CV death, resuscitated cardiac arrest, non-fatal MI, and non-fatal stroke 
(ischemic and hemorrhagic) 
 Response of LDL-C reduction by underlying causal mutations of HeFH 
 
 


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3.6. Measures to Minimize/Avoid Bias 
3.6.1. 
Blinded Study 
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.  


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4.
SUBJECT POPULATION
This will be a multicenter, international study in subjects with HeFH and elevated LDL-C 
despite maximum tolerated dose of LDL-C lowering therapies. 
4.1. Number of Subjects 
Approximately 400 subjects (at least 380 evaluable) will be randomized. Due to faster than 
expected enrollment, actual enrollment was 482 subjects. 
4.2. Inclusion Criteria 
Subjects may be included in the study if they meet all of the following criteria: 
1. Male or female subjects ≥18 years of age.
2. History of HeFH with a diagnosis of HeFH by genetic testing; and/or a documented
history of untreated LDL-C of >190 mg/dL, and a family history of FH, elevated
cholesterol or early heart disease may indicate FH (APPENDIX A)
3. Stable on a low-fat diet (eg, NCEP)
4. Serum LDL-C ≥2.6 mmol/L (≥100 mg/dL) at screening
5. Fasting triglyceride <4.52 mmol/L (<400 mg/dL) at screening.
6. Calculated glomerular filtration rate >30 mL/min by estimated glomerular filtration
rate (eGFR) using standardized clinical methodology.
7. 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).
8. Subjects not receiving statin must have documented evidence of intolerance to all
doses of at least two different statins (see APPENDIX B).
9. Subjects on lipid-lower therapies (such as a 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.
10. Subjects must be willing and able to give informed consent before initiation of any
study-related procedures and willing to comply with all required study procedures.


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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. 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.
2. An underlying known disease, or surgical, physical, or medical condition that, in the
opinion of the investigator (or delegate) might interfere with interpretation of the
clinical study results.
3. New York Heart Association (NYHA) class IV heart failure or last known left
ventricular ejection fraction <25%.
4. Cardiac arrhythmia within 3 months prior to randomization that is not controlled by
medication or via ablation.
5. Major adverse cardiovascular event within 3 months prior to randomization.
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 elevations in alanine aminotransferase (ALT),
aspartate aminotransferase (AST), >3x the upper limit of normal (ULN), or total
bilirubin >2x ULN at screening confirmed by a repeat abnormal measurement at least
1 week apart.
8. Severe concomitant noncardiovascular disease that carries the risk of reducing life
expectancy to less than 2 years.
9. History of malignancy that required surgery (excluding local and wide-local
excision), radiation therapy and/or systemic therapy during the three years prior to
randomization.
10. Females who are pregnant or nursing, or who are of childbearing potential and
unwilling to use at least two methods of highly effective contraception (failure rate
less than 1% per year) (eg, combined oral contraceptives, barrier methods, approved
contraceptive implant, long- term injectable contraception, or 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 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 randomization.
c.
Women who are surgically sterilized at least 3 months prior to enrollment.


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11. Males who are unwilling to use an acceptable method of birth control during the 
entire study period (ie, condom with spermicide). 
12. Known history of alcohol and/or drug abuse within the last 5 years. 
13. Treatment with other investigational products or devices within 30 days or five 
half˗lives of the screening visit, whichever is longer. 
14. Planned use of other investigational products or devices during the course of the 
study. 
15. 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. 
16. Treatment (within 90 days of screening) with monoclonal antibodies directed towards 
PCSK9. 
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) 


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The applicable reason above will be recorded in the eCRF. 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 data collected up until the time of subject 
withdrawal is to be entered into the eCRF. In addition, every attempt should be made to 
collect follow-up information except for those subjects who specifically withdraw consent 
release of such information. All procedures and laboratory specimens or tests requested for 
evaluation following administration of the investigational product should be carried out when 
possible whether or not a subject continues to receive treatment according the protocol. The 
attempts and any reason(s) for missing data as a result of the withdrawal will be captured in 
the source. 
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. 
The IDMC will be notified. 
It is imperative to obtain complete follow-up data (through Day 540 procedures) for all 
randomized subjects whether or not they receive their assigned treatment or have 
discontinued investigational product. 
4.5. Stopping Criteria 
4.5.1. 
Individual Subject Dosing Stopping Criteria 
During the double-blind, active treatment phase subjects will have clinic visits at regular 
intervals. Dosing with blinded 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%)


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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 blinded 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 
Investigational product (inclisiran) information is described in Table 1. 
Table 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 vial (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 pharmacist or qualified designee will prepare the 
investigational product under aseptic conditions to be administered to the subject on that day.  
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 2). 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 
Placebo will be supplied by The Medicines Company to clinical study site as sterile normal 
saline (0.9% sodium chloride in water for injection) for SC injection. The placebo vials will 
be blinded and look identical to the inclisiran vials. Placebo will be administered as an SC 
injection in an amount matched to the doses within the active inclisiran arm (Table 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 vials, inclisiran or placebo, will look identical.  
Medication labels will comply with regulatory requirements. The storage conditions for each 
medication provided will be described on the medication label. 


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The Inclisiran for Injection (SC use) is packaged in a glass vial (vials contain 300 mg of 
inclisiran sodium [equivalent to 284 mg of inclisiran per 1.5 mL]). The container closure 
system consists of a Type I glass vial, a Teflon-faced bromobutyl 13 millimeter stopper, and 
a flip off Truedge aluminum seal. Each vial will have a yellow shroud over the vial to 
maintain the blind. 
5.1.4. 
Storage 
Investigational product will be stored at room temperature (up to 25°C [77°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 (eg, empty vials) 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 Complaints 
Sites are required to report any product complaints to The Medicines Company (MDCO) 
immediately but no later than 24 hours from the time of awareness, by phone or e-mail as 
follows: 
Product Complaint: Is defined as any written, electronic, or oral communication that alleges 
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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Technical Quality Complaint: A report of dissatisfaction with the product with regard to its 
efficacy, strength, integrity, purity, or quality; thus a potential failure to meet product 
specifications. 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 bottle, 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 vial, 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.

An indication that the product did not meet its pharmacologic effect, ie, lack of
efficacy.

Medical Device Incidents.
5.2. Concomitant Medications 
5.2.1. 
Prohibited Concomitant Medications 
The following medications/treatments are not permitted to be added during the study: 

Medications prescribed to lower LDL-C (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-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


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
Prescription medications prescribed to treat preexisting medical conditions such as
diabetes and hypertension

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 (or a study subject’s partner) 
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. 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 
This is a double-blind placebo-controlled study. Study medication will be blinded prior to 
distribution to the site. Each investigational product vial, inclisiran or placebo, will contain a 
yellow shroud to blind the vial.  
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. 


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5.5.2. 
Method and Maintenance of Blinding 
Investigational product will be blinded prior to distribution to sites. All vials of 
investigational product (inclisiran/placebo) will contain a yellow shroud over the glass vial. 
In addition, all study sites will be provided a bulk supply of single use syringes that will be 
used to withdraw investigational product from the vial and to administer investigational 
product to randomized study subjects. 
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. 
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 
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. 


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6.
SCHEDULE AND SEQUENCE OF PROCEDURES
The Schedule of Assessments (Table 2) summarizes the study assessments by time point. 
This study consists of four periods: Screening, Randomization, Treatment, and End of Study. 

Screening period (Days -14 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.

Treatment period (Day 1 through Day 510): occurs from the start of investigational
product administration through the final clinic visit.
o
Dosing: Day 1, Day 90, Day 270, and Day 450 (final dose)
o
Additional clinic visits: Day 30, Day 150, Day 330, and Day 510

End of study (EOS) visit: Day 540 (90 days after final dose)
The expected duration of a subject’s participation in this study is approximately 554 days 
from screening/informed consent to the EOS, which occurs 90 days after the final dose of 
investigational product.   
6.1. Schedule of Assessments 
The schedule of assessments is provided in Table 2. 


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Table 2: 
Schedule of Assessments 
Screening 
Randomization 
Treatment 
EOS1
Visits 
V1 
(baseline) 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 (90 days post last 
dose) 
Timelines 
Day -14 to -1 
Day 1 
Day 30 
Day 90
Day 150 
Day 270 
Day 330 
Day 450
Day 510 
Day 540 
Visit windows (± days) 
±2 
±30 
±30 
±30 
±30 
±30 
±14 
±14 
Informed consent 
X 
Assessment of eligibility
X 
X2 
Demographics and medical 
history 
X 
Pregnancy test
X3 
X3 
X3 
X3 
X3 
X3 
X3 
Randomization 
X 
Investigational product 
administration 
X4,5 
X4,5 
X4,5 
X4,5 
Physical examination
X 
X 
Neurological examination 
X 
X 
Weight/height/waist 
circumference
X6 
X 
Vital signs7 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
X 
Fasted lipid 
profile/biomarkers8
X 
X 
X 
X 
X 
X 
X 
X 
X 
ADA 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
Full Serum chemistry10 
X 
X 
Limited serum chemistry10 
X 
X 
X 
X 
X 
X 
X 
Urinalysis (local)11 
X 
X 
X 
Hematology and 
coagulation12 
X 
X 
X 
X 
Pharmacogenetic sample13 
X 
Previous/concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs/SAE  reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ADA=anti-drug antibodies; AE=adverse event; ECG=electrocardiogram; EOS=end of study; V=visit; SAE=serious adverse event  
1. For subjects who decide to prematurely and permanently discontinue from study treatment and who decline further follow-up visits, 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.
2. Assessment of laboratory eligibility criteria will be based on central laboratory values obtained within timeframes defined in the inclusion and exclusion criteria.
3. Only in women of childbearing potential (performed locally, prior to any dosing, using central laboratory kit supplies; urine pregnancy test)


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4. Subjects will be observed in the clinic for at least 4 hours following the first injection only (Randomization visit) and 30 minutes for each subsequent visit in order to have 
additional vital and/or laboratory assessments completed if needed.  
5. For any suspected episode of anaphylaxis, the investigator will need to collect a blood sample for tryptase within 30 minutes of an onset of anaphylaxis (or as soon as logically 
possible). 
6. Height will be measured at baseline only and used to calculate body mass index. 
7. On Day 1 vital signs will be measured prior to injection and 4 hours post injection; all other visits, vital signs will be measured only 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. 
8. See Section 7.2 for details of specific tests to be analyzed. 
9. ADA serum samples will be collected on Day 1 prior to injection and 4 hours after injection. At all other visits, ADA serum samples will be collected prior to injection only, if 
an injection is scheduled for that visit. As presented in Section 6, serum samples for analysis are collected at every visit but assessment of ADA will only occur for samples 
collected at the following visits: Randomization (prior to injection), Day 30, Day 150, Day 330, and Day 510. Samples will be stored for assessment (if needed) for samples 
collected at the following visits: Randomization (after injection), Day 90, Day 270, Day 450, End of Study Visit. 
10. See Section 7.1.8.3 for details of specific tests to be analyzed. 
11. See Section 7.1.8.5 for details of specific tests to be analyzed. 
12. See Section 7.1.8.1 and Section 7.1.8.2 for details of specific tests to be analyzed.  
13. Sample may be taken during screening or anytime during study to be processed and stored, but only after separate consent has been signed. 
 


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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 2) for a detailed schedule and Section 7 for 
details of all tests required in each panel. 
6.3. 
Screening Period (Days –14 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 14 days prior to randomization: 

Informed consent

Assessment of inclusion and exclusion criteria

Demographics and medical history

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 7.1.8)

Urinalysis (performed locally, using central laboratory supplies)

Previous and concomitant medications

AE/SAE reporting (beginning from time of consent)

Pharmacogenetics (stored samples, only if separate consent has been signed)
(APPENDIX C)
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 7.1.8 and Section 7.2 for details of laboratory tests performed during the screening 
period. 


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6.4. 
Randomization 
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. A total of 400 randomized subjects are planned for inclusion in the 
study: 200 subjects per group. Due to faster than expected enrollment, actual enrollment was 
482 subjects. 
The following procedures will be performed prior to the injection: 

Assessment of inclusion and exclusion criteria

Pregnancy test (performed locally, using central laboratory supplies) (women of
childbearing potential only)

Randomization

Neurological examination (APPENDIX D)

Vital signs: blood pressure and heart rate (Section 7.1.3)

12-lead ECG

Fasting lipid profile/biomarkers (Section 7.2)

Central clinical laboratory (full serum chemistry, hematology and coagulation)
(Section 7.1.8)

Urinalysis (performed locally, using central laboratory supplies)

Assessment of ADA (Section 7.1.8.8)
The following procedures will be performed after the injection: 

Vital signs: blood pressure and heart rate (4 hours after injection) (Section 7.1.3)

Collection and storage of serum samples for possible future use to detect the
formation of ADA (4 hours after injection)

Concomitant medications

AE/SAE reporting
Investigational product 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 4 hours 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 patient 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.  Photographs should be submitted to the study inbox. 


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Detailed instructions for investigational product administration are found in the Pharmacy 
Manual.  
6.5. 
Day 30 Visit 
Subjects will return to the clinic for a follow-up visit 30 days following the first dose of 
investigational product. The following assessment will be completed during this visit: 
 Assessment of ADA (Section 7.1.8.8) 
 Concomitant medications 
 AE/SAE reporting  
6.6. 
Additional Dosing Visits (Days 90, 270, and 450) 
Subjects will return on Day 90 for a second investigational product injection. Subsequent 
investigational product injections will be administered on Day 270 and Day 450.  
The following assessments will be completed during these visits prior to investigational 
product administration: 
 Pregnancy test (performed locally, 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) 
 Collection and storage of serum samples for possible future use to detect the 
formation of ADA (Section 7.1.8.8) 
 Central clinical laboratory (limited serum chemistry) (Section 7.1.8) 
 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 150, 330, and 510) 
Subjects will return to the clinic for dosing follow-up visits 60 days following each dose of 
investigational product. The following assessments will be completed during these visits: 
6.7.1. 
Day 150 
 Fasting lipid profile/biomarkers (Section 7.2) 


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
Assessment of ADA (Section 7.1.8.8)

Central clinical laboratory (limited serum chemistry and hematology and coagulation)
(Section 7.1.8)

Concomitant medications

AE/SAE reporting
6.7.2. 
Day 330 

Fasting lipid profile/biomarkers (Section 7.2)

Assessment of ADA (Section 7.1.8.8)

Central clinical laboratory (limited serum chemistry) (Section 7.1.8)

Concomitant medications

AE/SAE reporting
6.7.3. 
Day 510 

Pregnancy test (performed locally, using central laboratory supplies, if applicable)
(women of childbearing potential only)

Fasting lipid profile/biomarkers (Section 7.2)

Assessment of ADA (Section 7.1.8.8)

Central clinical laboratory (limited serum chemistry) (Section 7.1.8)

Concomitant medications

AE/SAE reporting
6.8. 
End of Study (EOS) Visit (Day 540 – 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 D)

Vital signs: blood pressure and heart rate (Section 7.1.3)

12-lead ECG

Fasting lipid profile/biomarkers (Section 7.2)

Collection and storage of serum samples for possible future use to detect the
formation of ADA (Section 7.1.8.8)


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 Central clinical laboratory (full serum chemistry, hematology and coagulation) 
(Section 7.1.8) 
 Urinalysis (performed locally, using central laboratory supplies) 
 Concomitant medication 
 AE/SAE reporting 
 All ongoing SAEs have been followed to resolution (Section 8.4.1) 


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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 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. 
7.1.4. 
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 and EOS visit only).  
7.1.5. 
Neurological Evaluation 
A full neurological examination (APPENDIX D) will be performed as per the Schedule 
of Assessment (Table 2). 
7.1.6. 
Electrocardiograms 
Twelve lead ECGs will be collected at the time points in the Schedule of Assessments (Table 
2) only, unless clinically indicated.
7.1.7. 
Cardiovascular Events 
Information on CV events such as CV death, resuscitated cardiac arrest, non-fatal MI, and 
non-fatal stroke (ischemic and hemorrhagic) will be collected as AE data. 
7.1.8. 
Clinical Laboratory Assessments 
Specimens will be obtained at the time points in the Schedule of Assessments (Table 2). 
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


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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. 
7.1.8.1. 
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.  
7.1.8.2. 
Coagulation 
Blood draws for coagulation will include: 
 Prothrombin time (PT), international normalized ratio (INR), activated partial 
thromboplastin (aPTT). 
7.1.8.3. 
Chemistry 
Blood draws for chemistry will be performed per the Schedule of Assessments (Table 2). 
Analysis will vary based on visit day as follows: 
 Full serum chemistry - Baseline (Day 1) and EOS (Day 540)  
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, 270, 330, 450 and 510  
ONLY: AST, ALT, ALP, GGT, TBIL, CPK, creatinine, eGFR, fasting glucose, 
HbA1C (not at Day 150, 330 and 510) and tryptase (as required).  
7.1.8.4. 
Inflammatory markers (IL6, IFN-γ, and TNF-α, hsCRP) 
The hsCRP 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). 


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7.1.8.5. 
Urinalysis 
Urinalysis will be performed at the time points defined in the Schedule of Assessments 
(Table 2) 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). 
7.1.8.6. 
Urine Pregnancy 
Urine pregnancy testing will be performed locally at the visits specified in the Schedule of 
Assessments (Table 2), using the supplies provided by the Central Laboratory. 
7.1.8.7. 
Lipids / Lipoproteins 
Lipids and lipoproteins assessments are described in Section 7.2. 
7.1.8.8. 
Anti-drug Antibodies 
A serum sample for analysis of the induction of antibodies will be collected at the time points 
in the Schedule of Assessments (Table 2). Collection will be prior to and 4 hours after first 
investigational product administration (injection) and then as per the Schedule of 
Assessments. As presented in Section 6, serum samples for analysis are collected at every 
visit but assessment of ADA will only occur for samples collected at the following  visits: 
Randomization (prior to injection), Day 30, Day 150, Day 330, and Day 510. Samples will be 
stored for assessment (if needed) for samples collected at the following visits: Randomization 
(after injection), Day 90, Day 270, Day 450, End of Study Visit. 
7.1.9. 
Stored samples 
The central laboratory will take aliquots of serum and plasma samples from the received 
routine blood sampling noted above and will store these as frozen samples to permit future 
analysis of the effect of inclisiran on the expression of these exploratory biomarkers. 
Analyses may include markers of CV risk (eg, hsCRP, IL6, P-selectin, Lp-PLA2, 
adiponectin). 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 2). Parameters to be assessed will include:  
 Total cholesterol (TC), triglycerides, LDL-C, HDL-C, non-HDL-C, VLDL-C, Apo-
A1, ApoB, lipoprotein (a) [Lp(a)], hsCRP, and PCSK9. 
7.2.1. 
Change from Day 1 in LDL-C 
The primary efficacy endpoints are the percentage change in LDL-C from baseline to 
Day 510, and the time adjusted percent change in LDL-C from baseline after Day 90 and up 
to Day 540. 
In addition, this study will assess:  
 Absolute change in LDL-C from baseline to Day 510 
 Absolute change and percentage change in LDL-C from baseline to each assessment 
time up to Day 540 
 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 Day 510  
 Proportion of subjects in each group with greater or equal to 50% LDL-C reduction 
from baseline 
Blood samples for determination of LDL-C concentrations will be collected at the time 
points in the Schedule of Assessments (Table 2). 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, ApoB, Lp(a), hsCRP, and PCSK9.  
Additional aliquots of plasma and serum will be collected at each time point and stored for 
additional analyses, including future analysis of biomarkers of CV risk. 
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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7.4. 
Assessment of Pharmacogenetics 
All subjects will be invited to consent to pharmacogenetic analyses, unless underlying causal 
mutations of HeFH are well documented by a validated specialized laboratory. 
A blood sample will be collected, preferably during screening, only from subjects who sign a 
separate consent for pharmacogenetics. Samples will be processed as described in the 
Laboratory Manual and stored. Genetic assessment will be performed by an accredited 
laboratory. This assessment will determine if there is a different response for LDL-C 
lowering based on the type of mutation(s). 


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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 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. 


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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. 
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 
o wrong investigational product 
o wrong dose (including overdose, underdose, change in dosing regimen, strength, 
form concentration, amount) 


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o
wrong route of administration
o
wrong subject (ie, not administered to the intended subject)
o
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 (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 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 D).

Potential anaphylactic reactions assessed by Sampson criteria (APPENDIX E). 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: 
o
HbA1C becomes ≥6.5% and/or
o
Two consecutive values of fasting plasma glucose that are ≥126 mg/dL
o
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:
o
HbA1C increases from baseline > 0.5% and/or
o
New concomitant medication or increase in dose of current antidiabetic therapy is
initiated to improve the control of plasma glucose level.
8.4. 
Procedure for Adverse Event Reporting 
8.4.1. 
Serious Adverse Events (SAEs) 
All SAEs that occur during the designated study period from consent through EOS must be 
reported to MDCO GPV Department within 24 hours of awareness of the event using the 


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provided study specific SAE Report Form. 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. 
Non-Serious AEs 
All non-serious AEs that occur during the designated study period from consent 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 with or without an associated AE should be recorded as medication errors 
in the eCRF. 
Medication errors and an associated SAE should be recorded in the eCRF and also reported 
to MDCO GPV Department as described in Section 8.4.1. 
Medication errors and an associated non-serious AE should be recorded in the eCRF as 
described in Section 8.4.2. 
A mis-dosing protocol deviation (Section 12.3) should be reported as a medication error if 
it was an “unintended error”.
8.4.3.2. 
Pregnancy/Lactation Exposure 
Occurrences of pregnancy/lactation exposure in a study subject or study subject’s partner 
from the time of Day 1 through EOS must be reported to the Sponsor within 24 hours using 
the Pregnancy/Lactation 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/Lactation Exposure Report Form should 
be used to report the pregnancy/lactation exposure.  
When a pregnancy/lactation exposure occurs without any concurrent SAE, the 
Pregnancy/Lactation Exposure Report Form must be submitted alone.  


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8.5. 
Expectedness 
8.5.1. 
Expectedness Determination 
MDCO GPV 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 in making a 
recommendation to stop or modify the ORION-9 study for safety. 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 MDCO. In 
addition, MDCO retains the right to discontinue development of inclisiran at any time.  
If a study is prematurely terminated or discontinued, MDCO 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 MDCO, 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. 


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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 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. 


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10. STATISTICAL PLAN 
This study will be a Phase III, placebo-controlled, double-blind, randomized study in 
400 subjects with HeFH and elevated LDL-C despite maximum tolerated dose of LDL-C 
lowering therapies to evaluate the efficacy, safety, and tolerability of inclisiran injection(s). 
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 assumption (which was based on the 
observed results from a Phase II study) that the difference in change from baseline between 
the active dose group and the placebo group for LDL-C will be no less than 30 mg/dL, with a 
standard deviation of 20 mg/dL.  
Assuming about a 5% drop out rate, the sample size will be approximately 380 subjects that 
are evaluable for efficacy across the placebo and inclisiran dose groups. This sample size of 
at least 380 evaluable subjects, will provide more than 90% power to detect a 30% reduction 
of LDL-C levels in the inclisiran group compared to the placebo group at one-sided 
significance level of 0.025. Due to faster than expected enrollment, actual enrollment was 
482 subjects. This increased sample size will contribute additional safety data and not 
appreciably affect power calculations. 
10.2. 
RANDOMIZATION 
Subjects will be screened and approximately 400 eligible subjects will be randomized by the 
IRT system: 200 subjects will be randomized to inclisiran sodium 300 mg and 200 subjects 
randomized to placebo. Due to faster than expected enrollment, actual enrollment was 482 
subjects. Treatment allocation will be stratified by country and by current use of statins or 
other lipid-modifying therapies. Each subject will receive four subcutaneous (SC) injections 
of blinded inclisiran or placebo on Day 1, Day 90, Day 270, and Day 450. 
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. 


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10.3.2.1. 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 for analysis of the primary and secondary endpoints. 
10.3.2.2. Full Analysis Set (FAS) 
All subjects who are randomized into the study, take any study medication and have at least 
one post treatment lipid data measured. Treatment classification will be based on the 
randomized treatment. 
10.3.2.3. 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 510 day follow-up LDL-C assessment will comprise the modified 
intent-to-treat (mITT) population. Treatment classification will be based on the randomized 
treatment.  
10.3.2.4. 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 -14 to Day -1), the 
treatment period (Day 1 to Day 510), and the EOS visit (Day 540). 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. 
Analysis windows will be defined to maximize the amount of data that are included in the 
analysis models. Full details will be provided in the SAP. 
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 
Primary and key secondary efficacy endpoints will have missing data imputed using multiple 
imputation techniques (a primary method and sensitivity/exploratory methods). The primary 
imputation method will utilize a washout model for subjects in the inclisiran arm where it 
will be assumed that early terminating inclisiran sodium 300 mg subjects have missing data 
after their last observed assessment (monotone missing data) return to baseline values. The 
baseline values will be randomly sampled from a population estimated using baseline data 
from all subjects. One sensitivity technique includes control-based pattern mixture models 
which utilize placebo data for monotone missing inclisiran sodium 300 mg treatment data. 
Additional sensitivity data imputation techniques will be utilized. Retrieved data will be 


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utilized in all analyses where possible. Full details, including how intermittent missing data 
and missing placebo data will be handled, will be provided in the SAP. 
Unless otherwise specified, other missing data will not be imputed. 
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, FAS, mITT, and 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 
The ITT population will be the primary population for the efficacy analysis. Efficacy analysis 
will also be performed for the FAS and mITT populations as supportive analysis. 
10.4.3.1. Primary Efficacy Endpoints 
The primary efficacy endpoints are described in Section 3.3. 
The family-wise type I error rate is controlled at one-sided significance level of alpha=0.025 
by using a nested testing procedure. The percentage change in LDL-C from baseline to Day 
510 will be tested first. If the null hypothesis is rejected at one-sided significance level of 
alpha=0.025 and superiority of inclisiran over placebo is claimed, then the time adjusted 
percentage change in LDL-C from baseline after Day 90 and up to Day 540 will be tested, 
also at one-sided significance level of alpha=0.025. 
Mixed-effect models for repeated measures (MMRM) will be performed on the percent 
change in LDL-C from baseline to Day 510 to test the superiority of inclisiran over placebo. 
The model will include fixed effect for treatment, visits, baseline value, interaction between 
treatment and visits, and current use of statins or other lipid-modifying therapies. The 
Restricted Maximum Likelihood (REML) estimation approach will be used with covariance 
structure set as “Unstructured”. Missing data will be imputed using a multiple imputation 
washout model as noted in Section 10.3.4. A total of 100 imputed datasets will be created 
and results will be combined using Rubin’s method. Full details on the model and 
imputation will be provided in the SAP. 
The time adjusted percentage change in LDL-C from baseline after Day 90 and up to Day 
540 will be calculated from the MMRM with imputed data discussed above. Linear 
combinations of the estimated means after Day 90 and up to Day 540 will be used to 


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compare treatments. Results will be combined using Rubin’s method. Full details will be 
provided in the SAP. 
10.4.3.1.1. Sensitivity Analysis for Primary Efficacy Endpoints 
As noted in Section 10.3.4, additional methods to impute and analyze data will be utilized as 
sensitivity/exploratory analyses for the co-primary endpoints. A MMRM without any 
imputation (assuming data are missing at random) will also be performed. 
10.4.3.2. Secondary Efficacy Endpoints 
The secondary efficacy endpoints will not be tested if either one of the co-primary efficacy 
endpoints’ null hypothesis failed to be rejected.
Key secondary and other efficacy endpoints are described in Section 3.4. 
Key Secondary Endpoint Analysis: The Hochberg procedure will be applied to control the 
family-wise type I error rate at one-sided significance level of alpha=0.025 for the key 
secondary endpoints. The key secondary endpoints will be analyzed using the same methods 
as in the primary efficacy analysis. 
The two-sided 95% confidence interval for least squares means will be provided for 
continuous variables. Odds ratio and 95% confidence interval for the odds ratio will be 
provided for binary variables. Nominal p-values will be provided when applicable. 
Descriptive and graphical summaries by treatment group will also be presented. 
10.4.3.3. Exploratory Endpoints 
The exploratory objectives are described in Section 3.5. 
The analysis of the exploratory endpoints will be similar to that of the secondary endpoints. 
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. 


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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 both potentially clinical 
significant (PCS)/clinically significant (CS) values for subjects without PCS/CS 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). 
10.5. 
Interim Analysis 
No interim analysis will be performed in this study. 
10.5.1. 
Interim Safety Reviews 
The independent Data Monitoring Committee (IDMC) will review safety data 90 days after 
the first 40 subjects receive the first injection of inclisiran or placebo. Thereafter the IDMC 
will review safety data every 3 months until the EOS unless requested otherwise by the 
IDMC. A recommendation may be taken to stop or amend the study at any of these reviews.  


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11. RECORDS RETENTION 
The US Food and Drug Administration (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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12. 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 
This study will be conducted as described in this protocol, except for an emergency situation 
in which the protection, safety, and well-being of the subject requires immediate 
intervention, based on the judgment of the investigator (or a responsible, appropriately 
trained professional designated by the investigator). In the event of a significant deviation 
from the protocol due to an emergency, accident, or mistake, the investigator or designee 
must contact the Sponsor, or their agent, at the earliest possible time by telephone. This will 
allow an early joint decision regarding the subject’s continuation in the study. The 
investigator and the Sponsor will document this decision. The IRB/EC will be informed of 
all protocol changes by the investigator in accordance with the IRB/EC established 
procedure. No deviations from the protocol of any type will be made without complying with 
all the IRB/EC established procedures. 
In an effort to minimize deviations and missing data, the investigator and pertinent study 
staff will be trained on the operational aspects of implementing the study protocol and all 
required procedure by the sponsor/sponsor representatives.  These trainings occur either as 
part of an Investigator Meeting or Site Initiation Visit.  Retraining will occur at subsequent 
interim site monitoring visits as needed. 


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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: 
 Inclusion criteria violation 
 Exclusion criteria violation 
 Laboratory assessments not drawn at Day 1, Day 510 or Day 540 (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 MDCO 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. 


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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 non-participation 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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14. 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.


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15. INVESTIGATOR AGREEMENT
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. 
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: Global 
Amendment 4 
Institution Name 


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potent gene silencing in vivo. Mol Ther. 2006;13(3):494-505. 
Khorova A. Oligonucleotide Therapeutics — A New Class of Cholesterol-Lowering Drugs. N Engl J 
Med. 2017;376;1:4-7. 
Kotowski IK, Pertsemlidis A, Luke A, Cooper RS, Vega GL, Cohen JC, Hobbs HH. A spectrum of 
PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am J Hum Genet. 
2006;78:410-22. 
Lakoski SG, Lagace TA, Cohen JC, Horton JD, Hobbs HH. Genetic and metabolic determinants of 
plasma PCSK9 levels. J Clin Endocrinol Metab. 2009;94:2537-43. 
Mann DM, Woodward M, Muntner P, Falzon L, and Kronish I. Mann Predictors of Nonadherence to 
Statins: A Systematic Review and Meta-Analysis. Ann Pharmacother. 2010;44:1410-21. 


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Milazzo L and Antinori S. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J 
Med. 2012;366(25):2425; author reply 2426. 
Morrissey DV, Lockridge JA, Shaw L, et al. Potent and persistent in vivo anti-HBV activity of 
chemically modified siRNAs. Nat Biotechnol. 2005;23(8):1002-7. 
Mousavi SA, Berge KE, and Leren TP. The unique role of proprotein convertase subtilisin/kexin 9 in 
cholesterol homeostasis. J Intern Med. 2009;266(6):507-19. 
Navarese EP, Kolodziejczak M, Schulze V, et al. Effects of proprotein convertase subtilisin/kexin 
type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis. Ann 
Intern Med. 2015;163:40-51. 
Poluzzi E, Strahinja P, Lanzoni M, et al. Adherence to statin therapy and patients’ cardiovascular risk: 
a pharmacoepidemiological study in Italy. Eur J Clin Pharmacol. 2008;64:425–432. 
Raal F, Scott R, Somaratne R, et al. 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 
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Trial. Circulation. 2012;126(20):2408-17. 
Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in patients at high cardiovascular risk with 
elevated LDL cholesterol. N Engl J Med. 2017;10:1056. 
Ridker PM, Tardif JC, Amarenco P, et al. Lipid-reduction variability and antidrug-antibody formation 
with bococizumab. N Engl J Med. 2017:Apr 20;376(16):1517-1526. doi: 10.1056/NEJMoa1614062. 
Epub 2017 Mar 17. 
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cardiovascular events. N Engl J Med. 2015;372:1489-99. 
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Sullivan D, Olsson AG, Scott R, et al. Effect of a Monoclonal Antibody to PCSK9 on Low-Density 
Lipoprotein Cholesterol Levels in Statin-Intolerant Patients: The GAUSS Randomized Trial. JAMA. 
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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 electronic case report form (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 non-statin 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: GENETIC INFORMED CONSENT 
Purpose and Selection of subjects: 
The purpose of the genetic test is to confirm the subject’s diagnosis of HeFH and to assess 
the response of inclisiran on LDL-C reduction by underlying causal mutations of HeFH. 
The genetic research analysis is an optional test that will be offered to all patients. 
Specimen collection: 
For subjects that agree to participate, a blood sample will be taken at any visit throughout the 
study and the Central lab will utilize a validated, next generation sequencing pipeline to 
analyze DNA for variants in four genes (LDLR, APOB, PCSK9, and LDLRAP1) that are 
associated with familial hypercholesterolemia to confirm the subject has HeFH.   
Blood samples taken for this optional research will not be used for any additional study or 
purpose and be destroyed one year after the main study is complete. A single-coded system 
will be used for all blood samples during the study and will be taken without using names of 
the subjects, medical record numbers, or other common identifiers that would allow for the 
linking of the code to the subject’s identity.  The blood sample for the genetic research
analysis will be labeled with the same code number.  
Results: 
Currently, the information obtained from the genetic testing does not contain clinical or 
therapeutic implications for the individual subject.  Results will only be reported to the 
attending physician, Sponsor, and patient (if requested). No additional follow up beyond 
what is required in the main study is required. 
Withdraw of consent: 
A subject can withdraw their consent for participation in this optional portion of the study at 
any time.  If consent is withdrawn when the blood sample has been taken but before it is sent 
for genetic research analysis, the study doctor will arrange to have it destroyed.  If consent is 
withdrawn after the blood sample has been sent for genetic research analysis, The Medicines 
Company and the study doctor will ensure that the blood sample and any DNA that has been 
extracted from it are destroyed.  If consent is withdrawn after the genetic research analysis 
has already been performed, The Medicines Company is not obliged to destroy the results of 
this research.  In this case only the blood sample and any DNA extracted will be destroyed. 


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APPENDIX D: 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.  


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Sensory Tests:  
A number of tests for lesions of the sensory cortex can be done. Examples include the 
following:  

Stereognosis: The ability to recognize an object by feel. Place a common object in
the persons hand and ask them to identify the object.

Graphesthesis: “Draw” a number in the palm of the person’s hand and ask them to 
identify the number.

Two-Point Discrimination: Simultaneously apply two pin pricks to the skin surface.
Continually repeat the test while bringing the two pins closer together, until the
individual can no longer identify two separate stimuli. The finger tips are the most
sensitive location for recognizing two point differences while the upper arms, thighs
and back are the least sensitive.

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+. 


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Biceps Reflex (C5 – C6):
Support the forearm on the examiners forearm. Place your thumb on the bicep tendon 
(located in the front of the bend of the elbow; midline to the anticubital fossa). Tap on your 
thumb to stimulate a response.  
Triceps Reflex (C7-C8): 
Have the individual bend their elbow while pointing their arm downward at 90 degrees. 
Support the upper arm so that the arm hangs loosely and “goes dead”. Tap on the triceps 
tendon located just above the elbow bend (funny bone).  
Brachioradialis Reflex (C5-C6): 
Hold the person’s thumb so that the forearm relaxes. Strike the forearm about 2-3 cm above 
the radial styloid process (located along the thumb side of the wrist, about 2-3 cm above the 
round bone at the bend of the wrist). Normally, the forearm with flex and supinate.  
Quadriceps Reflex (Knee jerk) L2 – L4:
Allow the lower legs to dangle freely. Place one hand on the quadriceps. Strike just below the 
knee cap. The lower leg normally will extend and the quadriceps will contract.  
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.


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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 E: 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 BP 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: 
Inclisiran 
 
 ORION-9 (MDCO-PCS-17-03) 
The Medicines Company 
 
 Statistical Analysis Plan 
 
 
Protocol No.: MDCO-PCS-17-03 (ORION-9) 
A Placebo-Controlled, Double-Blind, Randomized Trial to Evaluate the Effect Of 300 mg 
of Inclisiran Sodium Given as Subcutaneous Injections in Subjects with Heterozygous 
Familial Hypercholesterolemia (HeFH) and Elevated Low-Density Lipoprotein Cholesterol 
(LDL-C) 
STATISTICAL ANALYSIS PLAN 
13 September 2019 
 
NCT03397121 


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Statistical Analysis Plan 
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2 
Protocol No.: MDCO-PCS-17-03 
(ORION-9) 
A PLACEBO-CONTROLLED, DOUBLE-BLIND, RANDOMIZED TRIAL 
TO EVALUATE THE EFFECT OF 300 MG OF INCLISIRAN SODIUM 
GIVEN AS SUBCUTANEOUS INJECTIONS IN SUBJECTS WITH 
HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA (HeFH) 
AND ELEVATED LOW-DENSITY LIPOPROTEIN CHOLESTEROL 
(LDL-C) 
U.S. IND NO.: 127,589 
EudraCT No.: 2017-002472-30 
PROTOCOL VERSION: GLOBAL AMENDMENT #4 
SAP VERSION: v3.0 13 Sep 2019 
3


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Statistical Analysis Plan 
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TABLE OF CONTENTS 
1.
INTRODUCTION ........................................................................................................7 
2.
TRIAL DESIGN ...........................................................................................................8 
2.1. 
Type/Design of Trial .....................................................................................................8 
2.2. 
Objectives of Trial ........................................................................................................9 
2.3. 
Schematic Diagram of Trial Design .............................................................................9 
2.4. 
Schedule and Sequence of Procedures .......................................................................10 
3.
GENERAL CONDUCT OF TRIAL ..........................................................................13 
3.1. 
Screening Period (Days –14 to –1) .............................................................................13 
3.2. 
Randomization ............................................................................................................14 
3.3. 
Day 30 Visit ................................................................................................................15 
3.4. 
Additional Dosing Visits (Days 90, 270, and 450) .....................................................15 
3.5. 
Additional NON DOSING Clinic Visits (Days 150, 330, and 510) ...........................15 
3.5.1. 
Day 150 .......................................................................................................................15 
3.5.2. 
Day 330 .......................................................................................................................16 
3.5.3. 
Day 510 .......................................................................................................................16 
3.6. 
End of Study (EOS) Visit (Day 540 – 90 days post last dose) ...................................16 
3.7. 
Interim Analysis ..........................................................................................................17 
3.7.1. 
Interim Safety Reviews ...............................................................................................17 
3.8. 
Assessment of Safety ..................................................................................................17 
3.8.1. 
Adverse Events ...........................................................................................................17 
3.8.2. 
Demographics and Medical History ...........................................................................17 
3.8.3. 
Vital Signs ..................................................................................................................17 
3.8.4. 
Physical Examination .................................................................................................17 
3.8.5. 
Neurological Evaluation .............................................................................................18 
3.8.6. 
Electrocardiograms .....................................................................................................18 
3.8.7. 
Cardiovascular Events ................................................................................................18 
3.8.8. 
Clinical Laboratory Assessments ...............................................................................18 
3.8.8.1. 
Hematology .................................................................................................................18 
3.8.8.2. 
Coagulation .................................................................................................................18 
3.8.8.3. 
Chemistry ....................................................................................................................18 
3.8.8.4. 
Inflammatory markers (IL6, IFN-γ, and TNF-α, hsCRP) ...........................................19 
4


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4 
3.8.8.5. 
Urinalysis ....................................................................................................................19 
3.8.8.6. 
Urine Pregnancy .........................................................................................................19 
3.8.8.7. 
Anti-drug Antibodies ..................................................................................................19 
3.8.9. 
Stored samples ............................................................................................................19 
3.9. 
Assessment of Efficacy ...............................................................................................20 
3.10. 
Assessment of Pharmacodynamics .............................................................................20 
3.11. 
Assessment of Pharmacogenetics ...............................................................................20 
4. 
ADVERSE EVENTS..................................................................................................21 
4.1. 
Adverse Event .............................................................................................................21 
4.2. 
AE Severity .................................................................................................................21 
4.3. 
Study Drug Causality ..................................................................................................21 
4.4. 
Serious Adverse Event ................................................................................................21 
4.5. 
Additional collection of safety data: Special Situations .............................................22 
4.5.1. 
Special Situations ........................................................................................................22 
4.5.2. 
Other safety related information .................................................................................22 
5. 
MEASURES TO MINIMIZE/AVOID BIAS .............................................................24 
5.1.1. 
Blinded Study .............................................................................................................24 
6. 
STATISTICAL PLAN................................................................................................25 
6.1. 
Sample Size ................................................................................................................25 
6.2. 
Randomization ............................................................................................................25 
6.3. 
General Statistical Considerations and Definitions ....................................................25 
6.3.1. 
General Statistical Methods ........................................................................................25 
6.3.2. 
Analysis Populations ..................................................................................................26 
6.3.2.1. 
Intent-to-Treat (ITT) Population .................................................................................26 
6.3.2.2. 
Full Analysis Set (FAS) ..............................................................................................26 
6.3.2.3. 
Modified Intent-to-Treat (mITT) Population ..............................................................26 
6.3.2.4. 
Safety Population ........................................................................................................26 
6.3.3. 
Analysis Windows and Baseline ................................................................................26 
6.3.4. 
Missing data handling .................................................................................................27 
6.3.4.1  
Efficacy .......................................................................................................................27 
6.3.4.2 
 Safety .........................................................................................................................27 
6.4. 
Statistical Analyses .....................................................................................................28 
6.4.1. 
Subject Disposition .....................................................................................................28 
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6.4.2. 
Protocol Deviations ....................................................................................................28 
6.4.3. 
Demographic and Background Characteristics ..........................................................29 
6.4.4. 
Study Drug Exposure ..................................................................................................29 
6.4.5. 
Concomitant Medications ...........................................................................................29 
6.4.6. 
Efficacy Analysis ........................................................................................................29 
6.4.6.1. 
Primary Efficacy Endpoints ........................................................................................29 
6.4.6.2. 
Secondary Efficacy Endpoints ....................................................................................33 
6.4.6.3. 
Exploratory Endpoints ................................................................................................34 
6.4.7. 
Subgroup Analysis ......................................................................................................34 
6.4.8. 
Safety Analysis ...........................................................................................................36 
6.4.8.1. 
Adverse Events ...........................................................................................................36 
6.4.8.2. 
Laboratory Tests .........................................................................................................38 
6.4.8.3. 
Diabetes Assessment ..................................................................................................39 
6.4.8.4. 
Anti-Drug Antibody ....................................................................................................42 
6.4.8.5. 
Vital Signs ..................................................................................................................42 
6.4.8.6. 
Electrocardiograms .....................................................................................................43 
6.4.8.7. 
Neurological Examinations ........................................................................................43 
7. 
COMPUTER METHODS ..........................................................................................44 
8. 
CHANGES TO ANALYSES SPECIFIED IN THE PROTOCOL ............................45 
9. 
REFERENCES ...........................................................................................................46 
APPENDIX 1. DETAILS OF MMRM USED FOR EFFICACY ANALYSES.........................47 
APPENDIX 2. MULTIPLE IMPUTATION WASHOUT MODEL ..........................................48 
APPENDIX 3. CONTROL-BASED PATTERN MIXTURE MODEL .....................................51 
APPENDIX 4. CRITERIA FOR POTENTIALLY CLINICALLY SIGNIFICANT 
AND CLINICALLY SIGNIFICANT ABNORMAL LABORATORY 
TESTS.........................................................................................................................53 
APPENDIX 5. ADDITIONAL ADVERSE EVENT INVESTIGATIONS................................54 
APPENDIX 6. CLINICALLY RELEVANT ADVERSE EVENTS AT THE 
INJECTION SITE PREFERRED TERMS ................................................................56 
LIST OF TABLES 
Table 1: 
Study Design and Schedule of Assessments ..............................................................11 
Table 2: 
Analysis Windows for Each Scheduled Visit .............................................................26 
Table 3: 
Subgroups for Analysis...............................................................................................35 
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LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................10 
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1. 
INTRODUCTION 
The Medicines Company is developing a novel synthetic ribonucleic acid (RNA) interference 
(RNAi) therapeutic, Inclisiran for Injection (subcutaneous [SC] use), formerly referred to as 
ALN-PCSSC, for the treatment of hypercholesterolemia. This document presents a statistical 
analysis plan (SAP) for The Medicines Company. Protocol MDCO-PCS-17-03, Global 
Amendment 4 (31 Jan 2019), A placebo-controlled, double-blind, randomized trial to evaluate 
the effect of 300 mg of inclisiran sodium given as subcutaneous injections in subjects with 
heterozygous familial hypercholesterolemia (HeFH) and elevated low density lipoprotein 
cholesterol (LDL-C). 
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2. 
TRIAL DESIGN 
2.1. 
Type/Design of Trial 
This study is a Phase III, placebo-controlled, double-blind, randomized study in 400 subjects 
with HeFH and elevated LDL-C despite maximum tolerated dose of LDL-C lowering therapies 
to evaluate the efficacy, safety, and tolerability of subcutaneous inclisiran injection(s). 
Subjects will be screened and approximately 400 eligible subjects will be randomized: 200 
subjects will be randomized to inclisiran sodium 300 mg and 200 subjects randomized to 
placebo. Due to faster than expected enrollment, actual enrollment was 482 subjects. Treatment 
allocation will be stratified by country and by current use of statins or other lipid-modifying 
therapies. Each subject will receive four subcutaneous injections of blinded inclisiran or placebo 
on Day 1, Day 90, Day 270, and Day 450.  
On Day 1, all eligible subjects will be randomized and will receive the first SC injection of 
investigational product (inclisiran or placebo). After the first SC injection, the subject will be 
observed in the clinic for at least 4 hours post injection in order to have additional laboratory 
assessments and vital signs completed before being discharged. Subjects will return on Day 90, 
Day 270, and Day 450 to receive additional investigational product. During these subsequent 
dosing visits, subjects will be observed in the clinic for at least 30 minutes after administration of 
each injection and have additional laboratory assessments completed if needed. Subjects will 
also have in clinic visits on Day 30, Day 150, Day 330, and Day 510 for follow-up and limited 
laboratory assessments. The end of study (EOS) visit will be conducted on Day 540. 
Pharmacodynamic assessments will be collected at various visits and include LDL-C levels as 
well as other lipids and lipoproteins (eg, total cholesterol, triglycerides, HDL-C, non HDL-C, 
very low-density lipoprotein cholesterol [VLDL-C], apolipoprotein A1 [Apo-A1], apolipoprotein 
B [ApoB], lipoprotein(a) [Lp(a)], high sensitivity C-reactive protein [hsCRP], and PCSK9). 
All subjects will be invited to consent to pharmacogenetic analyses, unless underlying causal 
mutations of HeFH are well documented by a validated specialized laboratory. A blood sample 
will be collected, preferably during screening, only from subjects who sign a separate consent for 
pharmacogenetics. 
Safety assessments including adverse events (AEs), serious adverse events (SAEs), 
electrocardiograms (ECGs), concomitant medications, and safety laboratory parameters will also 
be collected during the study. In addition, formation of anti-drug antibodies (ADA) and further 
characterization of ADA will be evaluated. 
End of study evaluations will be conducted at the Day 540 visit. 
Subjects who have completed the study to Day 540 will be given the opportunity to enroll in a 
separate open label long-term extension study to collect long-term safety and efficacy data for 
inclisiran.  
The independent Data Monitoring Committee (IDMC) will review safety data after the first 40 
subjects receive the first SC injection of inclisiran or placebo and have completed 1 month 
follow-up. Thereafter the IDMC will review safety data every 3 months until the end of study 
(EOS) unless requested otherwise by the IDMC. A recommendation may be taken to stop or 
amend the study at any of these reviews. 
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2.2. 
Objectives of Trial 
Primary Objectives: 
The primary objectives of this study are to evaluate the effect of inclisiran treatment on: 
 LDL-C levels at Day 510 
 Time adjusted percent change in LDL-C levels from baseline after Day 90 and up to Day 
540 levels 
Secondary Objectives: 
The secondary objectives of this study are to evaluate the effect of inclisiran on: 
 PCSK9, total cholesterol, ApoB and non-HDL-C at Day 510 
 LDL-C and PCSK9 levels over time to Day 540 
 Mean maximum reduction in LDL-C levels 
 LDL-C and PCSK9 levels over time in individual subjects 
 Other lipids, lipoproteins, apolipoproteins 
 Proportion of subjects achieving prespecified LDL-C targets  
 Safety and tolerability profile of inclisiran 
Exploratory Objectives: 
The exploratory objectives of this study are to collect/evaluate the effect of inclisiran on the 
following: 
 Cardiovascular (CV) events such as CV death, resuscitated cardiac arrest, non-fatal 
myocardial infarction (MI), and non-fatal stroke (ischemic and hemorrhagic) 
 Response of LDL-C reduction by underlying causal mutations of HeFH 
2.3. 
Schematic Diagram of Trial Design 
The study design is presented in Figure 1: 
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Figure 1: 
Study Design 
 
FUP=follow-up; V=visit 
2.4. 
Schedule and Sequence of Procedures 
The Schedule of Assessments (Table 1) summarizes the study assessments by time point. 
This study consists of four periods: Screening, Randomization, Treatment, and End of Study. 
 Screening period (Days -14 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. 
 Treatment period (Day 1 through Day 510): occurs from the start of investigational 
product administration through the final clinic visit. 
o Dosing: Day 1, Day 90, Day 270, and Day 450 (final dose) 
o Additional clinic visits: Day 30, Day 150, Day 330, and Day 510 
 End of study (EOS) visit: Day 540 (90 days past last dose) 
For subjects who decided to prematurely and permanently discontinue from study 
treatment and who decline further follow-up visits, 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. 
The expected duration of the subjects’ involvement in the study will be approximately 554 days 
which includes screening, investigational product administration, and the EOS period to Day 
540. 
 
 
 
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Schedule of Assessments 
Table 1: 
Study Design and Schedule of Assessments 
 
Screen-
ing 
Random-
ization 
Treatment 
 
EOS1 
Visits 
 
V1 
(baseline) 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 (90 
days post 
last dose) 
Timelines 
Day -14 to 
-1 
Day 1 
Day 30 
Day 90 
Day 150 
Day 270 
Day 330 
Day 450 
Day 510 
Day 540 
Visit windows (± days) 
 
 
±2 
±30 
±30 
±30 
±30 
±30 
±14 
±14 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Assessment of eligibility 
X 
X2 
 
 
 
 
 
 
 
 
Demographics and 
medical history 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X3 
X3 
 
X3 
 
X3 
 
X3 
X3 
X3 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Investigational product 
administration 
 
X4,5 
 
X4,5 
 
X4,5 
 
X4,5 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
X 
Neurological examination 
 
X 
 
 
 
 
 
 
 
X 
Weight/height/waist 
circumference 
X6 
 
 
 
 
 
 
 
 
X 
Vital signs7 
X 
X 
 
X 
 
X 
 
X 
 
X 
12-lead ECG 
X 
X 
 
 
 
 
 
 
 
X 
Fasted lipid 
profile/biomarkers8 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
ADA 
 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
Full Serum chemistry10 
 
X 
 
 
 
 
 
 
 
X 
Limited serum 
chemistry10 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Urinalysis (local)11 
X 
X 
 
 
 
 
 
 
 
X 
Hematology and 
coagulation12 
X 
X 
 
 
X 
 
 
 
 
X 
Pharmacogenetic sample13 
X 
 
 
 
 
 
 
 
 
 
Previous/concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs/SAE reporting 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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ADA=anti-drug antibodies; AE=adverse event; ECG=electrocardiogram; EOS=end of study; SAE=serious adverse event; V=visit 
1. For subjects who decided to prematurely and permanently discontinue from study treatment and who decline further follow-up visits, 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.  
2. Assessment of laboratory eligibility criteria will be based on central laboratory values obtained within timeframes defined in the inclusion and exclusion criteria. 
3. Only in women of childbearing potential (performed locally, prior to any dosing, using central laboratory kit supplies; urine pregnancy test) 
4. Subjects will be observed in the clinic for at least 4 hours following the first injection only (Randomization visit) and 30 minutes for each subsequent visit in order to have 
additional vital and/or laboratory assessments completed if needed.  
5. For any suspected episode of anaphylaxis, the investigator will need to collect a blood sample for tryptase within 30 minutes of an onset of anaphylaxis (or as soon as logically 
possible). 
6. Height will be measured at baseline only and used to calculate body mass index. 
7. On Day 1 vital signs will be measured prior to injection and 4 hours post injection; all other visits, vital signs are measured only prior to injection.  When available, an 
automated BP device is recommended for collection of blood pressure (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 (heart rate (HR), BP) is required per applicable visit. 
8. See Section 3.9 for details of specific tests to be analyzed. 
9. ADA serum samples will be collected on Day 1 prior to injection and 4 hours after injection. At all other visits, ADA serum samples will be collected prior to injection only if an 
injection is scheduled for that visit. As presented in Section 6, serum samples for analysis are collected at every visit but assessment of ADA will only occur for samples 
collected at the following visits: Randomization (prior to injection), Day 30, Day 150, Day 330, and Day 510. Samples will be stored for assessment (if needed) for samples 
collected at the following visits: Randomization (after injection), Day 90, Day 270, Day 450, End of Study Visit. 
10. See Section 3.8.8.3 for details of specific tests to be analyzed. 
11. See Section 3.8.8.5 for details of specific tests to be analyzed. 
12. See Section 3.8.8.1 and Section 3.8.8.2 for details of specific tests to be analyzed.  
13. Sample may be taken during screening or anytime during study to be processed and stored, but only after separate consent has been signed. 
 
 
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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 1) for a detailed schedule. 
3.1. 
Screening Period (Days –14 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 14 days prior to randomization: 
 Informed consent 
 Assessment of inclusion and exclusion criteria 
 Demographics and medical history 
 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 3.8.3) 
 12-lead ECG 
 Fasting lipid profile/biomarkers (Section 3.9) 
 Central clinical laboratory (limited serum chemistry, hematology and coagulation) 
(Section 3.8.8) 
 Urinalysis (performed locally, using central laboratory supplies) 
 Previous and concomitant medications 
 AE/SAE reporting (beginning from time of consent) 
 Pharmacogenetics (stored samples, only if separate consent has been signed) (Protocol 
Appendix C) 
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 (Protocol Section 4.2 and 4.3). Please refer to 
Section 3.8.8 and Section 3.9 for details of laboratory tests performed during the screening 
period. 
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3.2. 
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 investigational product. 
All treatment groups will be studied concurrently. A total of 400 randomized subjects are 
planned for inclusion in the study: 200 subjects per group. Due to faster than expected 
enrollment, actual enrollment was 482 subjects. 
The following procedures will be performed prior to the injection:  
 Assessment of inclusion and exclusion criteria 
 Pregnancy test (performed locally, using central laboratory supplies) (women of 
childbearing potential only) 
 Randomization 
 Neurological examination (Protocol Appendix D) 
 Vital signs: blood pressure and heart rate (Section 3.8.3) 
 12-lead ECG 
 Fasting lipid profile/biomarkers (Section 3.9) 
 Central clinical laboratory (full serum chemistry, hematology and coagulation) 
(Section 3.8.8) 
 Urinalysis (performed locally, using central laboratory supplies) 
 Assessment of ADA (Section 3.8.8.7) 
The following procedures will be performed after the injection:  
 Vital signs: blood pressure and heart rate (4 hours after injection) (Section 3.8.3) 
 Collection and storage of serum samples for possible future use to detect the formation of 
ADA (4 hours after injection)  
 Concomitant medications 
 AE/SAE reporting  
Investigational product 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 4 hours 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 patient 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. Photographs should be submitted to the study inbox of global safety office 
at The Medicines Company. 
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Detailed instructions for investigational product administration are found in the Pharmacy 
Manual.  
3.3. 
Day 30 Visit 
Subjects will return to the clinic for a follow-up visit 30 days following the first dose of 
investigational product. The following assessment will be completed during this visit: 
 Assessment of ADA (Section 3.8.8.7) 
 Concomitant medications 
 AE/SAE reporting 
3.4. 
Additional Dosing Visits (Days 90, 270, and 450) 
Subjects will return on Day 90 for a second investigational product injection. Subsequent 
investigational product injections will be administered on Day 270 and Day 450.  
The following assessments will be completed during these visits prior to investigational product 
administration: 
 Pregnancy test (performed locally, using central laboratory supplies, if applicable) 
(women of childbearing potential only) 
 Vital signs: blood pressure and heart rate (Section 3.8.3) 
 Fasting lipid profile/biomarkers (Section 3.9) 
 Collection and storage of serum samples for possible future use to detect the formation of 
ADA (Section 3.8.8.7) 
 Central clinical laboratory (limited serum chemistry) (Section 3.8.8) 
 Concomitant medication 
 AE/SAE reporting 
Administration of the investigational product is identical to Day 1 and is per Section 5.1.1 of the 
protocol 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 150, 330, and 510) 
Subjects will return to the clinic for dosing follow-up visits 60 days following each dose of 
investigational product. The following assessments will be completed during these visits: 
3.5.1. 
Day 150 
 Fasting lipid profile/biomarkers (Section 3.9) 
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 Assessment of ADA (Section 3.8.8.7) 
 Central clinical laboratory (limited serum chemistry and hematology and coagulation) 
(Section 3.8.8) 
 Concomitant medications 
 AE/SAE reporting 
3.5.2. 
Day 330 
 Fasting lipid profile/biomarkers (Section 3.9) 
 Assessment of ADA (Section 3.8.8.7) 
 Central clinical laboratory (limited serum chemistry) (Section 3.8.8) 
 Concomitant medications 
 AE/SAE reporting 
3.5.3. 
Day 510 
 Pregnancy test (performed locally, using central laboratory supplies, if applicable) 
(women of childbearing potential only) 
 Fasting lipid profile/biomarkers (Section 3.9) 
 Assessment of ADA (Section 3.8.8.7) 
 Central clinical laboratory (limited serum chemistry) (Section 3.8.8) 
 Concomitant medications 
 AE/SAE reporting 
3.6. 
End of Study (EOS) Visit (Day 540 – 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 D) 
 Vital signs: blood pressure and heart rate (Section 3.8.3) 
 12-lead ECG 
 Fasting lipid profile/biomarkers (Section 3.9) 
 Collection and storage of serum samples for possible future use to detect the formation of 
ADA (Section 3.8.8.7) 
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 Central clinical laboratory (full serum chemistry, hematology and coagulation) 
(Section 3.8.8) 
 Urinalysis (performed locally, using central laboratory supplies) 
 Concomitant medication 
 AE/SAE reporting 
 All ongoing SAEs have been followed to resolution  
3.7. 
Interim Analysis 
No interim analysis will be performed in this study. 
3.7.1. 
Interim Safety Reviews 
The IDMC will review safety data after the first 40 subjects receive the first SC injection of 
inclisiran or placebo and have completed one month follow-up. Thereafter the IDMC will review 
safety data every 3 months until the EOS unless requested otherwise by the IDMC. A 
recommendation may be taken to stop or amend the study at any of these reviews. 
3.8. 
Assessment of Safety 
3.8.1. 
Adverse Events 
Subjects will be carefully monitored for 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 and blood pressure) is required per applicable visit. 
3.8.4. 
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 and EOS visit only). Significant changes from baseline 
will be collected as AE data. 
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3.8.5. 
Neurological Evaluation 
A full neurological examination (Protocol Appendix D) will be performed as per the Schedule of 
Assessments (Table 1).   
3.8.6. 
Electrocardiograms 
Twelve lead ECGs will be collected at the time points in the Schedule of Assessments (Table 1) 
only, unless clinically indicated. Significant changes from baseline will be collected as AE data. 
3.8.7. 
Cardiovascular Events 
Information on CV events such as CV death, resuscitated cardiac arrest, non-fatal MI, and non-
fatal stroke (ischemic and hemorrhagic) will be collected as AE data. 
3.8.8. 
Clinical Laboratory Assessments 
Specimens will be obtained at the time points in the Schedule of Assessments (Table 1). 
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 1). 
Analysis will vary based on visit day as follows: 
 Full serum chemistry - Baseline (Day 1) and EOS (Day 540)  
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase 
(ALP), gamma glutamyl transferase (GGT), total bilirubin (TBIL), direct and indirect 
bilirubin, creatine phosphokinase (CPK), lactate, bicarbonate, uric acid, creatinine, blood 
urea nitrogen (BUN), estimated glomerular filtration rate (eGFR), sodium, potassium, 
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calcium, inorganic phosphate, chloride, albumin, total protein, glucose (fasting), glycated 
hemoglobin A1C (HbA1c), and tryptase (as required). 
 Limited serum chemistry - Screening, Days 90, 150, 270, 330, 450 and 510  
ONLY: AST, ALT, ALP, GGT, TBIL, CPK, creatinine, eGFR, fasting glucose, HbA1c 
(not at Day 150, 330, and 510) and tryptase (as required). 
3.8.8.4. 
Inflammatory markers (IL6, IFN-γ, and TNF-α, hsCRP) 
The hsCRP 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 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 1), using the supplies provided by the Central Laboratory. 
3.8.8.7. 
Anti-drug Antibodies 
A serum sample for analysis of the induction of antibodies will be collected at the time points in 
the Schedule of Assessments (Table 1). Collection will be prior to and 4 hours after first 
investigational product administration (injection) and then as per the Schedule of Assessments. 
As presented in Section 3, serum samples for analysis are collected at every visit but assessment 
of ADA will only occur for samples collected at the following visits: Randomization (prior to 
injection), Day 30, Day 150, Day 330, and Day 510. Samples will be stored for assessment (if 
needed) for samples collected at the following visits: Randomization (after injection), Day 90, 
Day 270, Day 450, and the End of Study Visit. 
3.8.9. 
Stored samples 
The central laboratory will take aliquots of serum and plasma samples from the received routine 
blood sampling noted above and will store these as frozen samples to permit future analysis of 
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the effect of inclisiran on the expression of these exploratory biomarkers. Analyses may include 
markers of CV risk (eg, hsCRP, IL6, P-selectin, Lp-PLA2, adiponectin). 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. 
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 1). Pharmacodynamic parameters to be assessed will include:  
 Total cholesterol (TC), triglycerides, LDL-C, HDL-C, non-HDL-C, VLDL-C, Apo-A1, 
ApoB, lipoprotein (a) [Lp(a)], hsCRP, and PCSK9. 
LDL-C using ultracentrifugation will be done additionally at baseline and at Day 510. 
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. 
Blood samples for determination of LDL-C concentrations will be collected at the time points in 
the Schedule of Assessments (Table 1). Details regarding the collection, processing, shipping, 
and storage of the samples will be provided in a Laboratory Manual. 
Additional aliquots of plasma and serum will be collected at each time point and stored for 
additional analyses, including future analysis of biomarkers of CV risk. 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. 
3.11. 
Assessment of Pharmacogenetics 
All subjects will be invited to consent to pharmacogenetic analyses, unless underlying causal 
mutations of HeFH are well documented by a validated specialized laboratory. 
A blood sample will be collected, preferably during screening, only from subjects who sign a 
separate consent for pharmacogenetics. Samples will be processed as described in the Laboratory 
Manual and stored. Genetic assessment will be performed by an accredited laboratory. This 
assessment will determine if there is a different response for LDL-C lowering based on the type 
of mutation(s). 
 
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4. 
ADVERSE EVENTS 
This section will describe how the 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 (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. 
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, 
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 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 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 
myocardial infarction (MI) that may be considered minor could be an SAE if it prolonged 
hospitalization. 
4.5. 
Additional collection of safety data: Special Situations 
4.5.1. 
Special Situations 
Special Situations designated for this study include: 
 Medication errors that fall into the following categories 
o wrong investigational product 
o wrong dose (including overdose, underdose, change in dosing regimen, strength, form 
concentration, amount) 
o wrong route of administration 
o wrong subject (i.e., not administered to the intended subject) 
o 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 
electronic case report form (eCRF) pages. Photographs of ISR, if they were obtained during the 
study visits, should be forwarded to the study inbox. 
Other safety related information that should be reported as adverse events in accordance with the 
process described in Protocol Section 8.4 are: 
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 Abnormal neurological examination, e.g., peripheral sensory and motor evaluation, an 
assessment of gait, pain, position, strength and reflexes (Protocol Appendix D). 
 Potential anaphylactic reactions assessed by Sampson criteria (Protocol Appendix E). 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: 
o HbA1c becomes ≥6.5% and/or 
o Two consecutive values of fasting plasma glucose that are ≥126 mg/dL 
o 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: 
o HbA1c increases from baseline > 0.5% and/or 
o 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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5. 
MEASURES TO MINIMIZE/AVOID BIAS 
5.1.1. 
Blinded Study 
This study will employ a double-blind technique with a placebo control. Randomization via 
automated interactive response technology (IRT) will be used to assign a 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. 
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6. 
STATISTICAL PLAN 
6.1. 
Sample Size 
The sample size calculation is performed with the assumption (which is based on the observed 
results from a Phase II study) that the difference in change from baseline between the active dose 
group and the placebo group for LDL-C will be no less than 30 mg/dL, with a standard deviation 
of 20 mg/dL. 
Assuming about a 5% drop out rate, the sample size will be approximately 380 subjects that are 
evaluable for efficacy across the placebo and inclisiran dose groups. This sample size of at least 
380 evaluable subjects, will provide more than 90% power to detect a 30% reduction of LDL-C 
levels in the inclisiran group compared to the placebo group at one-sided significance level of 
0.025. Due to faster than expected enrollment, actual enrollment was 482 subjects. This 
increased sample size will contribute additional safety data and not appreciably affect power 
calculations. 
6.2. 
Randomization 
Subjects will be screened and approximately 400 eligible subjects will be randomized by the IRT 
system: 200 subjects will be randomized to inclisiran sodium 300 mg and 200 subjects 
randomized to placebo. Due to faster than expected enrollment, actual enrollment was 482 
subjects. Treatment allocation will be stratified by country and by current use of statins or other 
lipid-modifying therapies. Each subject will receive four subcutaneous (SC) injections of blinded 
inclisiran or placebo on Day 1, Day 90, Day 270, and Day 450. 
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). 
All p-values will be two-sided. 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 ‘<0.001’ 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%. 
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6.3.2. 
Analysis Populations 
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 for analysis of the primary and secondary endpoints. 
6.3.2.2. 
Full Analysis Set (FAS) 
All subjects who are randomized into the study, take any study medication and have at least one 
post treatment lipid data measured will comprise the full analysis set (FAS) population. 
Treatment classification will be based on the randomized treatment. 
6.3.2.3. 
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 Day 510 follow-up LDL-C assessment will comprise the modified intent-to-
treat (mITT) population. Treatment classification will be based on the randomized treatment. 
6.3.2.4. 
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. 
6.3.3. 
Analysis Windows and Baseline 
The analysis windows around each visit day are provided in Table 2:  below. 
Table 2: 
Analysis Windows for Each Scheduled Visit 
Scheduled Visit 
Analysis Window 
         From 
 To 
Baseline 
Before randomization/First 
Study Treatment 
Day 30 
Day 1 
Day 60 
Day 90 
Day 61 
Day 120 
Day 150 
Day 121 
Day 210 
Day 270 
Day 211 
Day 300 
Day 330 
Day 301 
Day 390 
Day 450 
Day 391 
Day 480 
Day 510 
Day 481 
Day 525 
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Day 540 
Day 526 
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.  
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 with each subject during the study through Day 540 ±14 
days on all efficacy laboratory assessments of lipids/lipoproteins/biomarkers to keep missing 
data to a minimum regardless of whether the subject is on study treatment, uses ancillary 
therapies, experiences an adverse event, or adheres to the protocol (these data points are referred 
to as retrieved data). However, if missing data, defined as data not available from either 
scheduled (within the protocol defined visit window) or unscheduled visits, occurs for the 
primary or any of key secondary efficacy endpoints then that data will be imputed. 
The primary method to impute missing data for the first co-primary efficacy endpoint 
(percentage change in LDL-C from baseline to Day 510) 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 co-primary 
and key secondary efficacy endpoints to assess the impact of missing values. Note that the 
control-based PMM will be the primary method for imputing data for the second co-primary 
efficacy endpoint (time adjusted percentage change in LDL-C from baseline after Day 90 and up 
to Day 540). 
Unless otherwise specified, missing data for all parameters not listed in the primary and key 
secondary 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.  
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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: 
 
 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 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 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 treatment group for each 
analysis 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 treatment for 
each analysis population. 
 The number of subjects who are screened, screen failures, and randomized will be 
summarized by country and site for all screened subjects. 
 The number of subjects in each treatment group will be summarized by country and site 
for each analysis population. 
Completers are defined as a subject who completes the Day 540 visit. 
A summary of inclusion/exclusion criteria will be provided by treatment group for all screened 
subjects and for the ITT population. 
A summary of the number of subjects by visit will be provided by 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 
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 510 or Day 540 (EOS) visits                                           
 Mis-dosing for any reason other than subject safety or withdrawal  
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 Prohibited concomitant medication / Change in baseline statin or other lipid-lowering 
therapy dose                                                     
 SAE form not reported to MDCO 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 years), race, gender, ethnicity, country, and 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 
baseline diabetes status based on HbA1c and fasting glucose will be summarized by treatment 
group using the ITT, FAS, mITT, and Safety populations. 
Medical history (targeted medical history, other medical history, and medical history of statin 
intolerance) will be summarized by treatment group using the ITT, FAS, mITT and Safety 
populations. 
6.4.4. 
Study Drug Exposure 
Study drug administration will be summarized overall by treatment group and by dosing visits 
(including, missed doses, and injection site location) for safety population. 
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 ITT, FAS, mITT, and safety population. 
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 
2017). 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. The high intensity group will include simvastatin 40 mg. A shift table for lipid 
modifying therapy statin intensity from baseline to Day 540 (EOS) will also be provided.  The 
statin intensity of the last statin taken on or prior to Day 540 (EOS) will be used for the post-
baseline statin. 
6.4.6. 
Efficacy Analysis 
The ITT population will be the primary population for the efficacy analysis. Efficacy analyses 
will also be performed for the FAS and mITT populations as supportive analyses. 
6.4.6.1. 
Primary Efficacy Endpoints 
The co-primary endpoints for this study are:  
 Percentage change in LDL-C from baseline to Day 510 
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 Time adjusted percentage change in LDL-C from baseline after Day 90 and up to Day 
540. This is the average percentage change in LDL-C from baseline over the period after 
Day 90 and up to Day 540.  
Note: The time adjusted percentage change in LDL-C from Baseline after Day 90 and up to 
Day 540 analysis reflects LDL-C effect at a steady state. As such, this analysis assesses the effect 
on LDL-C levels seen with a more chronic dosing regimen. The Day 90 dose is the start of the 6 
monthly dosing regimen. 
The statistical hypotheses for the co-primary endpoint of the percentage change in LDL-C from 
baseline to Day 510 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 510 = 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 510 < 0. 
The statistical hypotheses for the co-primary endpoint of the time adjusted percentage change 
from baseline after Day 90 and up to Day 540 are as follows: 
H02: The difference (inclisiran minus placebo), between subjects treated with inclisiran 
300mg and placebo in the least squares mean time adjusted percentage change in LDL-C 
from baseline after Day 90 and up to Day 540 = 0. 
HA2: The difference (inclisiran minus placebo), between subjects treated with inclisiran 
300mg and placebo in the least squares mean time adjusted percentage change in LDL-C 
from baseline after Day 90 and up to Day 540 < 0. 
The family-wise type I error rate is controlled at a two-sided significance level of alpha=0.05 by 
using a nested testing procedure. The percentage change in LDL-C from baseline to Day 510 will 
be tested first. If the null hypothesis is rejected at a two-sided significance level of alpha=0.05 
and superiority of inclisiran over placebo is claimed, then the time adjusted percentage change in 
LDL-C from baseline after Day 90 and up to Day 540 will be tested, also at a two-sided 
significance level of alpha=0.05.  
The primary endpoints 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.   
Percentage change in LDL-C from baseline to Day 510 
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 510 on each multiply imputed dataset 
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(100 total). The model will include the fixed effect of treatment group 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 for hypothesis testing. 
See Appendix 2 for more details on this analysis. 
Time adjusted percentage change in LDL-C from baseline after Day 90 and up to Day 540. 
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 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. 
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 
over all visits on each multiply imputed dataset (100 total). The model will include fixed effects 
for treatment, visit, 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). 
The time adjusted percentage change in LDL-C from baseline after Day 90 and up to Day 540 
will be calculated from the MMRM. Linear combinations of the estimated means after Day 90 
and up to Day 540 will be used to compare treatment effects.  Note that Day 90 will be excluded 
from the MMRM. 
Treatment effects 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. 
6.4.6.1.1. Sensitivity Analysis for Primary Efficacy Endpoints 
In order to support the robustness of the conclusions drawn from the co-primary efficacy 
analyses, we will perform the following sensitivity analyses for the co-primary efficacy 
endpoints.  
Percentage change in LDL-C from baseline to Day 510 
 A control-based pattern-mixture model (PMM), using the same imputed datasets and 
MMRM model that was used for the second co-primary efficacy endpoint primary 
analysis will be used to compare treatments at Day 510. Multiple imputations will be 
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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 treatment, visit, 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 510 will be used to compare treatment groups. This will be the 
same model that is used as a sensitivity analysis for the second co-primary endpoint. 
 The impact of country and current use of statins or other lipid-modifying therapies will be 
assessed by including country (possibly pooled into a region), the treatment-by-country 
interaction, and current use of statins or other lipid-modifying therapies (yes or no) as 
fixed effects into the primary efficacy analysis ANCOVA (using multiple imputation 
washout model data).   
 An ANCOVA model without multiple imputation will be performed using the mITT 
population.  The model will include the fixed effect of treatment group and baseline 
LDL-C as a covariate. 
 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 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 co-primary efficacy endpoint becomes 
statistically insignificant.  
Time adjusted percentage change in LDL-C from baseline after Day 90 and up to Day 540. 
 A mixed model for repeated measurements (MMRM) analysis without multiple 
imputation, that assumes missing data are MAR, will be performed. The model will 
include fixed effects for treatment, visit, 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 combination of 
the estimated means after Day 90 and up to Day 540 will be used to compare treatment 
groups. This will be the same model that is used as a sensitivity analysis for the first co-
primary endpoint. 
 The impact of country and current use of statins or other lipid-modifying therapies will be 
assessed by including country (possibly pooled into a region),  the treatment-by-country 
interaction, and current use of statins or other lipid-modifying therapies (yes or no) as 
fixed effects into the primary efficacy analysis MMRM (using multiple imputation 
control-based PMM data).   
 The time adjusted percentage change will also be calculated by taking the arithmetic 
mean of calculated percent change in LDL-C from baseline at each visit after Day 90 
through Day 540. This analysis will be based on the control-based PMM imputed datasets 
(100 multiple imputation datasets). The two sample t-test will be performed to test the 
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treatment difference between inclisiran and placebo.  Results will be combined and 
summarized using Rubin’s method. 
 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 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 co-primary efficacy endpoint becomes 
statistically insignificant.  
Other sensitivity analysis may be performed. 
6.4.6.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints will not be tested if either one of the co-primary efficacy 
endpoints’ null hypothesis fails to be rejected. 
The key secondary endpoints of this study are: 
 Absolute change in LDL-C from baseline to Day 510. 
 Time adjusted absolute change in LDL-C from baseline after Day 90 and up to Day 
540. 
 Percentage change from baseline to Day 510 in PCSK9, total cholesterol, ApoB, and 
non-HDL-C. 
The Hochberg procedure [Hochberg, 1988] will be applied to control the family-wise type I error 
rate at a two-sided significance level of alpha=0.05 for the key secondary endpoints. 
Missing values will be imputed using the control-based PMM (see Appendix 2 for more details) 
on LDL-C, PCSK9, total cholesterol, ApoB, and non-HDL-C, absolute change or percent change 
from baseline will be calculated based on imputed data before any analysis is performed.  
The absolute change in LDL-C from baseline to Day 510 and percentage change from baseline to 
Day 510 in PCSK9, total cholesterol, ApoB, and non-HDL-C will be analyzed using a MMRM 
with covariates as specified in Appendix 1 and Appendix 3. Time adjusted absolute change in 
LDL-C from baseline after Day 90 and up to Day 540 will be analyzed similarly to that of time 
adjusted percentage change in LDL-C from baseline after Day 90 and up to Day 540. 
MMRM without multiple imputation (see Appendix 1) will be used as sensitivity analyses for the 
key secondary endpoints.  
The other secondary endpoints of this study are: 
 Maximum percentage change in LDL-C. This is calculated by finding the smallest 
LDL-C value across all post baseline visits for each individual subject. This value 
will be used to compare with each subject’s baseline value and calculate the percent 
change from baseline to the lowest LDL-C value. 
 Absolute change from baseline to Day 510 in PCSK9, total cholesterol, ApoB and 
non-HDL-C.  
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 Absolute change and percentage change in LDL-C from baseline to each assessment 
time up to Day 540. 
 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 Day 510. 
 Proportion of subjects in each group with greater or equal to 50% LDL-C reduction 
from baseline.  
 Absolute change and percentage change in other lipids, lipoproteins, apolipoproteins, 
and PCSK9 from baseline at each subsequent visit to Day 540. 
 Proportion of subjects in each group who attain global lipid targets for their level of 
ASCVD risk. 
The two-sided 95% confidence interval for least squares means will be provided for continuous 
variables at a single point using an analysis of covariance model or using MMRM methods for 
variables measured over time (see Appendix 1 for more details). The odds ratio and 95% 
confidence interval for the odds ratio will be provided for binary variables using logistic 
regression models. Nominal p-values will be provided when applicable. 
Descriptive and graphical summaries by treatment group will also be presented. 
6.4.6.3. 
Exploratory Endpoints 
The exploratory endpoints of this study are: 
 Incidence of CV death, resuscitated cardiac arrest, non-fatal MI, and stroke (ischemic and 
hemorrhagic) 
A major cardiovascular event (MACE) is defined as the composite of CV death, 
resuscitated cardiac arrest, non-fatal MI, and stroke (ischemic or hemorrhagic).  Refer to 
Appendix 5 for details on the search terms used.  The number and percentage of subjects 
with MACE or any of the individual events will be presented by treatment group. 
 Proportion of subjects in each group with any LDL-C reduction from baseline at any visit 
(responders). 
The number and percentage of subjects with any LDL-C reduction at any visit will be 
presented by treatment group.  The odds ratio and 95% confidence interval for the odds 
ratio will be provided using a logistic regression model.  The number and percentage of 
subjects with any LDL-C reduction will also be summarized at each visit.  
 
 Response of LDL-C reduction by underlying causal mutations of HeFH 
 
The absolute change and percentage change in LDL-C and PCSK9 from baseline to Day 
510 will be summarized by HeFH mutation type and treatment group. 
6.4.7. 
Subgroup Analysis  
Analysis of efficacy and safety will also be performed for subgroups of interest including: 
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Table 3: 
Subgroups for Analysis 
Table # [1] 
  
Categories and comments 
1 
Gender 
Male 
Female 
 
 
2 
Age #1 
< 65 vs ≥ 65 years 
 
 
 
3 
Age #2 
< 75 vs ≥ 75 years 
 
 
 
4 
Body mass index #1 
≤ vs > median 
 
 
 
5 
Body mass index #2 
Quartiles 
 
 
 
6 
Race 
White 
Black 
Other 
 
7 
Baseline statin use 
Yes 
No 
 
 
8 
Baseline statin intensity 
High intensity 
Not high 
intensity 
 
 
9 
Other lipid management therapy 
Any statin with other 
lipid management 
therapy 
No statin but 
other lipid 
management 
therapy 
No lipid 
management 
therapy 
 
10 
Baseline triglyceride level #1 
<200 mg/dL vs ≥200 
mg/dL 
 
 
 
11 
Baseline triglyceride level #2 
≤ vs > median 
 
 
 
12 
Metabolic disease [2] 
Diabetes 
Metabolic 
syndrome 
without diabetes 
Neither 
 
13 
ASCVD status [3] 
ASCVD 
ASCVD risk 
equivalents 
 
 
14 
Renal impairment by eGFR categories 
- mL/min/1.73m2 [4] 
≥15 to <30 
≥30 to <60 
≥60 to <90 
≥90 
15 
History of allergy [5] 
Yes 
No 
 
 
16 
Baseline LDL-C #1 
≤ vs > median 
 
 
 
17 
Baseline LDL-C #2 
Quartiles 
 
 
 
18 
Study center region  
North America 
Europe 
South Africa 
 
19 
Post baseline LDL-C [6] 
≤25 at any time point 
vs >25 mg/dL at all 
time points 
 
 
 
20 
Phenotype [7] 
FH 
Non-FH 
 
 
21 
Baseline ezetimibe use 
Yes 
No 
 
 
[1] Numbers provide the order that the subgroups will be presented. 
[2] Metabolic syndrome is not based on medical history but will be defined according to the American Heart 
Association (AHA) definition (see Reference 1). 
[3] Derived from the targeted medical history page: CHD=Yes or CVD=Yes or PAD=Yes then the subject is 
ASCVD; all other subjects are ASCVD risk equivalent 
[4] Creatinine clearance (CrCl) values using the Cockroft and Gault estimation: 
CrCl = {((l40–age) x weight)/(72xSerum Creatinine)}x 0.85 (if female) 
[5] A history of allergy was identified using the following high-level group term (HLGT): allergic conditions.  
[6] For descriptive summary of PCSK9 data only. 
[7] Phenotype is defined using Simon Broome diagnostic criteria (see Appendix A in protocol). Definite Familial 
Hypercholesterolemia (FH) and Possible Familial Hypercholesterolemia will be included as FH. 
 
Baseline variables to be analyzed by subgroup: 
Disposition 
Protocol Deviations 
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Demographics and Baseline Characteristics 
Targeted Medical History 
Other Medical History 
Medical History of Partial or Complete Statin Intolerance 
Study Drug Administration 
Day 1 Concomitant Medications 
New or Changed Concomitant Medications 
Prior Medications 
Prior Lipid Modifying Therapies 
Day 1 Lipid Modifying Therapy Usage 
New or Changed Lipid Modifying Therapy Usage 
Shift from Baseline in Statin Intensity 
 
Safety variables to be analyzed by subgroup: 
Treatment Emergent Adverse Events  
Treatment Emergent Serious Adverse Events 
Treatment Emergent Adverse Events at the Injection Site  
Withdrawals due to TEAEs 
 
Efficacy variables to be analyzed by subgroup: 
Co-Primary #1: Percentage change in LDL-C from baseline to Day 510 – ANCOVA – Washout 
Imputation 
Co-Primary #2: Time adjusted percentage change in LDL-C from baseline after Day 90 and up to Day 
540. This is the average percentage change in LDL-C from baseline over the period after Day 90 and up 
to Day 540 – MMRM – control-based PMM 
Key Secondary #1: Absolute change in LDL-C from baseline to Day 510 – MMRM – control-based 
PMM 
Key Secondary #2: Time adjusted absolute change in LDL-C from baseline after Day 90 and up to Day 
540 – MMRM – control-based PMM  
Key Secondary #3: Percentage change from baseline to Day 510 in PCSK9, total cholesterol, ApoB, and 
non-HDL-C – MMRM – control-based PMM  
Other Secondary #3: Actual value, absolute change and percentage change in LDL-C from baseline to 
each assessment time up to Day 540 – Descriptive Stats 
Other Secondary #6: Actual value, absolute change and percentage change in other lipids, lipoproteins, 
apolipoproteins, and PCSK9 from baseline at each subsequent visit to Day 540 – MMRM 
Other Secondary #6: Actual value, absolute change and percentage change in other lipids, lipoproteins, 
apolipoproteins, and PCSK9 from baseline at each subsequent visit to Day 540 – Descriptive Stats* 
* Post baseline LDL-C subgroup included for PCSK9 summary table only. 
6.4.8. 
Safety Analysis 
The safety objectives of this study are to evaluate the safety and tolerability profile of inclisiran. 
6.4.8.1. 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) dictionary (v20.1) 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:  
 
 
Overall Summary of TEAEs 
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 
TEAEs by SOC and PT 
 
TEAEs by PT 
 
Common (2% 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 
 
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  
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% 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, Additional Adverse Events 
Investigations) 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.  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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6.4.8.2. 
Laboratory Tests 
Laboratory values will be summarized by treatment group, 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.  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:  
o Non HbA1c: >1 and ≤3x ULN at baseline and >1 and ≤3x ULN at final visit 
o HbA1c: ≥6.5% at baseline and ≥6.5% and ≥0.5% change from baseline at final 
visit 
 
 Elevated further:  
o Non HbA1c: >1 and ≤3x ULN at baseline or post baseline and becoming > 3x 
ULN post baseline 
 
 Final visit:  
o Non HbA1c: >1 and ≤3x ULN at final visit only but not at baseline or previous 
visits 
o  HbA1c: ≥6.5% and ≥0.5% change from baseline at final visit only but not at 
baseline or previous visits 
 
 Persistently elevated:  
o Non HbA1c: >1 and ≤3x ULN at a post baseline visit and remains >1 and ≤3x 
ULN until final visit 
o 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 
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 Resolved:  
o Non HbA1c: >1 and ≤3x ULN at baseline or post baseline, resolved to < ULN at 
any post baseline visit, and remaining < ULN at final visit 
o 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 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.  
 
6.4.8.3. 
Diabetes Assessment 
Diabetes will be assessed by the analysis of: 
 TEAEs 
 change in glucose-related laboratory values over time 
 shifts from baseline in glucose control category and, 
 incidence of post-baseline new onset of diabetes. 
Note that diabetes related tables dealing with the fasting 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%.   
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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* 
 
Fasting Glucose 
Normal 
<100 mg/dL 
Impaired  
≥100 to <126 mg/dL 
Diabetes  
≥126 mg/dL 
 
HbA1c 
Normal 
<5.7% 
Impaired 
≥5.7 to <6.5% 
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. 
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 
Fasting glucose ≥126 mg/dL on 
two consecutive occasions 
OR 
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HbA1c <5.7% 
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. 
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 
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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.   
1. Diabetic TEAEs identified by the SMQ search (see Appendix 5), or 
2. Post-baseline fasting glucose ≥126 mg/dL on two consecutive occasions, or 
3. Initiation of anti-diabetic medication at any time post-baseline, or 
4. 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.  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.  
The change from baseline to EOS will also be summarized by the following categories: 
 Systolic blood pressure (mmHg):  
o ≤ -20  
o > -20 to ≤ -10  
o > -10 to ≤ -5 
o > -5 to < 5 
o ≥ 5 to < 10 
o ≥ 10 to < 20 
o ≥ 20 
 Diastolic blood pressure (mmHg):  
o ≤ -10 
o > -10 to ≤ -5 
o > -5 to ≤ -3 
o > -3 to < 3 
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o ≥ 3 to < 5 
o ≥ 5 to < 10 
o ≥ 10 
6.4.8.6. 
Electrocardiograms 
The percentage of subjects with abnormal ECG findings reported as AEs will be summarized by 
treatment group 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. 
 
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7. 
COMPUTER METHODS 
Statistical analyses will be performed using SAS (version 9.4 or later version). 
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8. 
CHANGES TO ANALYSES SPECIFIED IN THE PROTOCOL 
The following items were changed between the final version of the protocol and the final SAP. 
 Primary efficacy endpoint analyses were modified per FDA feedback. 
 Due to the distribution of the data, current use of statins or other lipid-modifying 
therapies at baseline (yes or no) was removed from the primary analyses and included as 
factors in the models of the sensitivity analyses. 
 Imputation methods were modified per FDA feedback. 
 Subgroup analyses were added for select variables. 
 A secondary efficacy endpoint was renamed from mean maximum percent change to 
maximum percent change. 
 The exploratory endpoint, proportion of subjects in each group with any LDL-C 
reduction from baseline at any visit (responders), was added 
 Identification of PCS/CS laboratory values were modified. 
 
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9. 
REFERENCES 
1. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, 
Krauss RM, Savage PJ, Smith SC, Spertus JA, Costa F (October 2005): Diagnosis and 
management of the metabolic syndrome: an American Heart Association/National Heart, 
Lung, and Blood Institute Scientific Statement. Circulation. 112 (17): 2735–52. 
2. Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. 
Biometrika. 1988;75:800-2.Protocol MDCO-PCS-17-08 Amendment 2  
3. Ratitch B, O’Kelly M: Imputation of Pattern-Mixture Models Using Standard SAS/STAT 
Procedures, PharmaSUG2011 - Paper SP04. 
4. Rubin, D.B. (1987), Multiple Imputation for Nonresponse in Surveys, New York: John 
Wiley & Sons, Inc. 
 
 
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APPENDIX 1. DETAILS OF MMRM USED FOR EFFICACY ANALYSES 
A number of efficacy analyses will utilize a mixed-effects model for repeated measures 
(MMRM).  This includes the co-primary efficacy endpoints (in the case of the first co-primary 
efficacy endpoint, it will be used as a sensitivity analysis), the key secondary efficacy endpoints, 
and other secondary efficacy endpoints.  
The models will generally include fixed effects for treatment, visit, baseline value, and the 
interaction between treatment and visit.  The current use of statins or other lipid-modifying 
therapies will also be included as a fixed effect for some sensitivity analyses. The visits will 
include Days 90, 150, 270, 330, 450, and 510, with Day 510 as the primary time-point. Linear 
combinations of the estimated means will be created for the various hypothesis tests. Note that 
for time adjusted percentage change analyses (second co-primary efficacy endpoint) Day 90 will 
be excluded from the models.  
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' '510’); 
run; 
 
(where ('0' '510') is the value of the placebo [‘0’] at day 510 [‘510’] 
in interaction term treatment*visit_day) 
 
 
 
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APPENDIX 2. MULTIPLE IMPUTATION WASHOUT MODEL  
A multiple imputation washout model will be utilized for the primary efficacy analysis of the 
percentage change in LDL-C from baseline to Day 510 endpoint.  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 510 
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. 
The covariates and baseline characteristics which can be predictive of the response for the 
subjects in the inclisiran group who completed all 4 doses and have data present at Day 540 
(considered to have completed the study) 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 510 from the inclisiran group 
(continuous) 
 Current use of statins or other lipid-modifying therapies (categorical) 
The covariates and baseline characteristics which can be predictive of the response for the 
remaining subjects in the inclisiran group 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 510 from the placebo group (continuous) 
 Current use of statins or other lipid-modifying therapies (categorical) 
The covariates and baseline characteristics which can be predictive of the response for the 
placebo group will be included in a multiple imputation procedure (SAS PROC MI) and will 
include the following: 
 Baseline value of efficacy measurement (continuous) 
 Observed value of efficacy measurement at Day 90 (continuous) 
 Observed value of efficacy measurement at Day 150 (continuous) 
 Observed value of efficacy measurement at Day 270 (continuous) 
 Observed value of efficacy measurement at Day 330 (continuous) 
 Observed value of efficacy measurement at Day 450 (continuous) 
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 Observed value of efficacy measurement at Day 510 (continuous) 
 Observed value of efficacy measurement at Day 540 (continuous) 
 Current use of statins or other lipid-modifying therapies (categorical) 
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 
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 for the placebo treatment 
group.  These datasets will be utilized in Step #3. 
3. Subjects in the inclisiran group who received all 4 doses of study medication, have the Day 
510 value missing, and have evaluable data at Day 540 will be included in this step.  Missing 
values at Day 510 will be imputed assuming data are MAR.  Only subjects in the inclisiran 
group will be included in this step.  Observed Baseline and Day 510 data will be utilized to 
impute missing Day 510 data utilizing SAS PROC MI.  This will be performed 100 times to 
create 100 datasets that are fully imputed at Day 510. 
4. The remaining missing values at Day 510 in the inclisiran group will be imputed in this step. 
Note that the subjects with imputed inclisiran Day 510 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 510.  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 510 primary efficacy endpoint. 
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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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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 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 (see 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 270 (continuous) 
 Observed value of efficacy measurement at Day 330 (continuous) 
 Observed value of efficacy measurement at Day 450 (continuous) 
 Observed value of efficacy measurement at Day 510 (continuous) 
 Observed value of efficacy measurement at Day 540 (continuous) 
 Current use of statins or other lipid-modifying therapies (categorical) 
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. 
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4. After the missing data imputation is completed using the above steps, absolute 
change/percentage change values will be calculated in each of the imputed datasets at each 
visit. 
5. These 100 datasets will be analyzed using the MMRM described in Appendix 1 for the co-
primary efficacy endpoints and key secondary efficacy endpoints. 
6. Treatment effects (difference in LS means between treatments) from these 100 analyses will 
then be combined using Rubin’s Method via SAS PROC MIANALYZE procedure for each 
endpoint. 
 
 
 
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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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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) 
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 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) 
 
8) Major cardiovascular events (MACE) 
 
Cardiac death 
 
 Fatal SAEs in Cardiac disorders SOC   
 Fatal SAEs in General disorder SOC:  PTs ‘Death’, ‘Sudden cardiac death’, 
‘Cardiac death’, ‘Apparent death’  
 
Cardiac arrest 
 
 PT ‘Cardiac arrest’ 
 
Non-fatal MI 
 
 Myocardial infarction (SMQ, broad and narrow), nonfatal events only 
 
Stroke 
 
 Central Nervous System hemorrhages and cerebrovascular accidents (HLT), fatal 
and non-fatal events 
 
 
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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 
 
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STATISTICAL ANALYSIS PLAN ADDENDUM 
 
 
 
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Protocol No.: MDCO-PCS-17-03 
(ORION-9) 
 
A PLACEBO-CONTROLLED, DOUBLE-BLIND, RANDOMIZED TRIAL 
TO EVALUATE THE EFFECT OF 300 MG OF INCLISIRAN SODIUM 
GIVEN AS SUBCUTANEOUS INJECTIONS IN SUBJECTS WITH 
HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA (HeFH) 
AND ELEVATED LOW-DENSITY LIPOPROTEIN CHOLESTEROL 
(LDL-C) 
 
U.S. IND NO.: 127,589 
EudraCT No.: 2017-002472-30 
PROTOCOL VERSION: GLOBAL AMENDMENT #4 
SAP VERSION: v3.0 13 Sep 2019 
 
 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ........................................................................................................4 
2. 
CHANGES TO ANALYSES .......................................................................................5 
2.1. 
Concomitant Medications .............................................................................................5 
2.2. 
Subgroups .....................................................................................................................5 
2.3. 
Laboratory Tests ...........................................................................................................5 
2.4. 
Statin/LMT Use at Baseline ..........................................................................................5 
2.5. 
Appendix 2: Multiple Imputation Washout Model ......................................................5 
 
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1. 
INTRODUCTION 
The following Statistical Analysis Plan Addendum summarizes changes to the SAP that were 
requested by the FDA after the SAP was finalized, the database was locked, and the study was 
unblinded.  An update to the effects used in the imputation model and a clarification of the steps 
used for the multiple imputation washout model found in Appendix 2 of the SAP are also 
included. 
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2. 
CHANGES TO ANALYSES 
2.1. 
Concomitant Medications 
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. Two types of summaries will be presented for the analysis of statins. For the first 
summary, simvastatin 40 mg will be included in the high intensity group (as originally presented 
in the SAP). For the second summary, simvastatin 40 mg will be included in the moderate 
intensity group based on the FDA feedback received on September 13, 2019. 
2.2. 
Subgroups 
Select baseline, efficacy, and safety variables will be summarized by subgroup. One of the 
subgroups will be baseline statin intensity. For this subgroup classification, simvastatin 40 mg 
will be considered as moderate intensity. 
2.3. 
Laboratory Tests 
 
The number and percentage of subjects satisfying Hy’s Law will also be tabulated by treatment 
group based on the following lab findings: 
• 
Any elevated post-baseline aminotransferases defined as:  
 ALT > 3 x ULN or  
 AST > 3 x ULN 
• 
Elevated post-baseline serum total bilirubin (TBL) > 2 x ULN and serum alkaline 
phosphatase (ALP) levels < 2 x ULN 
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. Per FDA feedback, 
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 (ALT, AST, TBL) 
results. 
2.4. 
Statin/LMT Use at Baseline 
The small number of subjects who were not currently using statins or other lipid-modifying 
therapies (LMT) at baseline caused convergence issues with the imputation models.  As such, the 
statin/LMT use at baseline effect was removed from the multiple imputation washout model and 
Control Based - Pattern Mixture Model imputation steps. Note that the statin/LMT use at 
baseline effects were already removed from the analysis models. 
2.5. 
Appendix 2: Multiple Imputation Washout Model 
 
Minor changes were made to the description of the multiple imputation washout model to aid in 
the understanding of the method.  The changes did not alter the way the method was 
implemented.  The final wording is provided below. 
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A multiple imputation washout model will be utilized for the primary efficacy analysis of the 
percentage change in LDL-C from baseline to Day 510 endpoint. 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 510 
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 placebo group the following variables will be included in a multiple imputation 
procedure (SAS PROC MI), this assumes missing data are MAR: 
 Baseline value of efficacy measurement (continuous) 
 Observed value of efficacy measurement at Day 90 (continuous) 
 Observed value of efficacy measurement at Day 150 (continuous) 
 Observed value of efficacy measurement at Day 270 (continuous) 
 Observed value of efficacy measurement at Day 330 (continuous) 
 Observed value of efficacy measurement at Day 450 (continuous) 
 Observed value of efficacy measurement at Day 510 (continuous) 
 Observed value of efficacy measurement at Day 540 (continuous) 
For the subjects in the inclisiran group who completed all 4 doses and have data present at Day 
540 (considered to have completed 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 510 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 510 from the placebo group (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. 
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2. The remaining missing values in the placebo group with a monotone missing data pattern 
will be imputed in this step.  Missing data will be imputed assuming data are MAR.  Only 
subjects in the placebo group will be utilized in this step.  SAS PROC MI will be used to 
impute missing values utilizing the monotone reg option. This will be performed for the 100 
datasets.  After this step, the 100 datasets will be fully imputed for the placebo treatment 
group.  These datasets will be utilized in Step #4. 
3. Subjects in the inclisiran group who received all 4 doses of study medication, have the Day 
510 value missing, and have evaluable data at Day 540 will be included in this step.  Missing 
values at Day 510 will be imputed assuming data are MAR.  Only subjects in the inclisiran 
group will be included in this step.  Observed Baseline and Day 510 data will be utilized to 
impute missing Day 510 data utilizing SAS PROC MI.  This will be performed 100 times to 
create 100 datasets that are fully imputed at Day 510. 
4. The remaining missing values at Day 510 in the inclisiran group will be imputed in this step. 
Note that the subjects with imputed inclisiran Day 510 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 510.  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 510 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. 
 
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