A Placebo-Controlled, Double-Blind, Randomized Trial to Evaluate the Effect of 300 mg of Inclisiran Sodium Given as Subcutaneous Injections in Subjects With Atherosclerotic Cardiovascular Disease (ASCVD) and Elevated Low-Density Lipoprotein Cholesterol (LDL-C)
Phase: PHASE3
Conditions: ASCVD, Elevated Cholesterol
Sponsor: The Medicines Company

Inclisiran 
 
 ORION-10 (MDCO-PCS-17-04) 
The Medicines Company 
 
 Clinical Study Protocol 
 
 
Protocol No.: MDCO-PCS-17-04 (ORION-10) 
A Placebo-Controlled, Double-Blind, Randomized Trial to Evaluate the Effect of 300 mg of 
Inclisiran Sodium Given as Subcutaneous Injections in Subjects with Atherosclerotic 
Cardiovascular Disease (ASCVD) and Elevated Low-Density Lipoprotein Cholesterol 
(LDL-C) 
 
CLINICAL STUDY PROTOCOL 
31 January 2019 
 
NCT03399370 

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 ATHEROSCLEROTIC 
CARDIOVASCULAR DISEASE (ASCVD) AND ELEVATED 
LOW-DENSITY LIPOPROTEIN CHOLESTEROL (LDL-C) 
ORION-10 
Protocol No.: MDCO-PCS-17-04 
U.S. IND No.: 127,589 
Development Phase: 
III 
Sponsor: 
The Medicines Company 
8 Sylvan Way 
Parsippany, NJ 07054 
Principal Investigator: 
Sponsor Representatives: 
Medical Director: 
Project Leader: 
Global  Safety Officer: 
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 
*MDCO = The Medicines Company 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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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 atherosclerotic cardiovascular 
disease (ASCVD) and elevated low-density lipoprotein cholesterol (LDL-C) 
Phase of Development: III 
Study Centers: Multicenter study in North America (approximately 175 sites); specific list is 
maintained by the Sponsor. 
Central Facilities: This list is maintained by the Sponsor 
Number of Subjects: Approximately 1500 eligible subjects will be randomized (750 subjects 
randomized to inclisiran sodium and 750 subjects randomized to placebo). Assuming about a 5% drop 
out rate, the sample size will be approximately 1425 subjects that are evaluable for efficacy across the 
placebo and inclisiran dose groups. Enrollment of statin intolerant subjects will be capped at 15% of 
total study enrollment. 
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) 
 

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Pharmacokinetics: 
The pharmacokinetic objectives are: 
 
To assess the effect of inclisiran on statin pharmacokinetics (at steady state for statins) using 
population analysis approach with sparse blood sampling  
 
To assess the effect of inclisiran on PCSK9 levels (at steady state for statins PK)  using 
population analysis approach with sparse blood sampling 
Methodology: This study is a Phase III, placebo-controlled, double-blind, randomized study in 
1500 subjects with ASCVD (coronary heart disease [CHD], cerebrovascular disease [CVD] or peripheral 
arterial disease [PAD]) 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 1500 eligible subjects will be randomized: 750 subjects 
will be randomized to inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) and 750 subjects will 
be randomized to placebo. Treatment allocation will be stratified 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).  
Pharmacokinetic biomarker samples will be collected and stored for up to 1 year following the 
completion of the last subject for research purposes to analyze the profile of rosuvastatin and atorvastatin 
in subjects taking these statins in combination with inclisiran (in terms of efficacy, safety and 
tolerability). 
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 subcutaneous (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 

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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 ASCVD (CHD, CVD or PAD) (APPENDIX A). 
3. Serum LDL-C ≥1.8 mmol/L (≥70 mg/dL). 
4. Fasting triglyceride <4.52 mmol/L (<400 mg/dL) at screening. 
5. No current or planned renal dialysis or renal transplantation. 
6. 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). 
7. Subjects not receiving statins must have documented evidence of intolerance to all doses of at 
least two different statins (APPENDIX B). 
8. 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. 
9. 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. 

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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. 
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 a subject’s participation in the study will be 
approximately 554 days which includes screening, investigational product administration, and the end of 
study (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 i.e., the 300 mg dose will be administered as 1.5 mL of placebo. 
 
 

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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. 
 
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 PCSK9, 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 ASCVD 
risk 
 
Exploratory Endpoints: 
 
Incidence of CV death, resuscitated cardiac arrest, non-fatal MI, and non-fatal stroke (ischemic 
and hemorrhagic) 
 
Pharmacokinetic Endpoint  
 
Steady state concentrations of statins (specifically, atorvastatin and rosuvastatin) at Day 1 
(baseline), Day 450, and Day 510 
 
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. 
 
 

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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 1425 subjects that are 
evaluable for efficacy across the placebo and inclisiran dose groups. This sample size of at least 
1425 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. This 
sample size will also contribute additional sufficient safety data. 
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. 
Missing data for the primary and key secondary endpoints will be imputed according to the algorithm 
specified in the Statistical Analysis Plan (SAP). 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 after missing data imputation. Missing data will be imputed using a multiple 
imputation washout model. Results will be combined using Rubin’s method. 
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 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....................................................................24 
1.4. 
Study Rationale ...........................................................................................................24 
1.4.1. 
Study Rationale ...........................................................................................................24 
1.4.2. 
Dose Rationale ............................................................................................................24 
1.5. 
Study Population .........................................................................................................24 
2. 
STUDY OBJECTIVES AND PURPOSE ..................................................................25 
2.1. 
Primary Objective .......................................................................................................25 
2.2. 
Secondary Objectives .................................................................................................25 
2.3. 
Exploratory Objectives ...............................................................................................25 
2.4. 
Pharmacokinetic Objectives .......................................................................................25 
3. 
STUDY DESIGN .......................................................................................................26 
3.1. 
Type/Design of Study .................................................................................................26 
3.2. 
Schematic Diagram of Study Design ..........................................................................26 
3.3. 
Primary Endpoints ......................................................................................................26 
3.4. 
Secondary Endpoints ..................................................................................................27 
3.5. 
Exploratory Endpoints ................................................................................................27 
3.6. 
Pharmacokinetic Endpoint ..........................................................................................27 
3.7. 
Measures to Minimize/Avoid Bias .............................................................................28 

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3.7.1. 
Blinded Study .............................................................................................................28 
4. 
SUBJECT POPULATION .........................................................................................29 
4.1. 
Number of Subjects ....................................................................................................29 
4.2. 
Inclusion Criteria ........................................................................................................29 
4.3. 
Exclusion Criteria .......................................................................................................30 
4.4. 
Withdrawal Criteria ....................................................................................................31 
4.4.1. 
Withdrawal from Study Medication ...........................................................................32 
4.5. 
Stopping Criteria .........................................................................................................32 
4.5.1. 
Individual Subject Dosing Stopping Criteria ..............................................................32 
5. 
TREATMENT OF SUBJECTS ..................................................................................34 
5.1. 
Study Medications ......................................................................................................34 
5.1.1. 
Inclisiran .....................................................................................................................34 
5.1.2. 
Placebo ........................................................................................................................34 
5.1.3. 
Packaging and Labeling ..............................................................................................34 
5.1.4. 
Storage ........................................................................................................................35 
5.1.5. 
Accountability .............................................................................................................35 
5.1.6. 
Product Complaints ....................................................................................................35 
5.2. 
Concomitant Medications ...........................................................................................36 
5.2.1. 
Prohibited Concomitant Medications .........................................................................36 
5.2.2. 
Permitted Concomitant Medications ..........................................................................36 
5.3. 
Medical Management Guidelines ...............................................................................37 
5.3.1. 
Adverse events ............................................................................................................37 
5.3.2. 
Pregnancy ...................................................................................................................37 
5.4. 
Restrictions .................................................................................................................37 
5.5. 
Blinding ......................................................................................................................37 
5.5.1. 
Blinding of study medications ....................................................................................37 
5.5.2. 
Method and Maintenance of Blinding ........................................................................37 
5.6. 
UNBLINDING ...........................................................................................................38 
5.6.1. 
In the Event of an Emergency: Unblinding a Code ....................................................38 
6. 
SCHEDULE AND SEQUENCE OF PROCEDURES ...............................................39 
6.1. 
Schedule of Assessments ............................................................................................39 
6.2. 
General Conduct of the Study .....................................................................................42 
6.3. 
Screening Period (Days –14 to –1) .............................................................................42 

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6.4. 
Randomization ............................................................................................................43 
6.5. 
Day 30 Visit ................................................................................................................44 
6.6. 
Additional Dosing Visits (Days 90, 270, and 450) .....................................................44 
6.7. 
Additional NON DOSING Clinic Visits (Days 150, 330, and 510) ...........................44 
6.7.1. 
Day 150 .......................................................................................................................45 
6.7.2. 
Day 330 .......................................................................................................................45 
6.7.3. 
Day 510 .......................................................................................................................45 
6.8. 
End of Study (EOS) Visit (Day 540 – 90 days post last dose) ...................................45 
7. 
PROTOCOL ASSESSMENTS ..................................................................................47 
7.1. 
Assessment of Safety ..................................................................................................47 
7.1.1. 
Adverse Events ...........................................................................................................47 
7.1.2. 
Demographics and Medical History ...........................................................................47 
7.1.3. 
Vital Signs ..................................................................................................................47 
7.1.4. 
Physical Examination .................................................................................................47 
7.1.5. 
Neurological Evaluation .............................................................................................47 
7.1.6. 
Electrocardiograms .....................................................................................................47 
7.1.7. 
Cardiovascular Events ................................................................................................47 
7.1.8. 
Clinical Laboratory Assessments ...............................................................................47 
7.1.8.1. 
Hematology .................................................................................................................48 
7.1.8.2. 
Coagulation .................................................................................................................48 
7.1.8.3. 
Chemistry ....................................................................................................................48 
7.1.8.4. 
Inflammatory markers (IL6, IFN-γ, and TNF-α, hsCRP) ...........................................48 
7.1.8.5. 
Urinalysis ....................................................................................................................49 
7.1.8.6. 
Urine Pregnancy .........................................................................................................49 
7.1.8.7. 
Lipids / Lipoproteins ...................................................................................................49 
7.1.8.8. 
Anti-drug Antibodies ..................................................................................................49 
7.1.9. 
Stored samples ............................................................................................................49 
7.2. 
Assessment of Efficacy ...............................................................................................50 
7.2.1. 
Change from Day 1 in LDL-C ....................................................................................50 
7.2.2. 
Change from Day 1 in Lipids/Lipoproteins ................................................................50 
7.3. 
Assessment of Pharmacodynamics .............................................................................50 
7.4. 
Assessment of Pharmacokinetics ................................................................................51 
8. 
ADVERSE EVENTS..................................................................................................52 

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8.1. 
Definitions ..................................................................................................................52 
8.1.1. 
Adverse Event .............................................................................................................52 
8.1.2. 
Serious Adverse Event ................................................................................................52 
8.1.3. 
Special Situations ........................................................................................................53 
8.2. 
Collection and Assessment of Adverse Events ..........................................................53 
8.2.1. 
Pre-existing Conditions ..............................................................................................53 
8.2.2. 
Adverse Event Severity ..............................................................................................53 
8.2.3. 
Relationship to Investigational Product ......................................................................53 
8.3. 
Requirements For Additional Safety Data Collection ................................................53 
8.3.1. 
Special Situations ........................................................................................................53 
8.3.2. 
Other safety related information .................................................................................54 
8.4. 
Procedure for Adverse Event Reporting .....................................................................54 
8.4.1. 
Serious Adverse Events (SAEs) .................................................................................54 
8.4.2. 
Non-Serious AEs ........................................................................................................55 
8.4.3. 
Special situations ........................................................................................................55 
8.4.3.1. 
Medication Errors .......................................................................................................55 
8.4.3.2. 
Pregnancy/Lactation Exposure ...................................................................................55 
8.5. 
Expectedness ...............................................................................................................56 
8.5.1. 
Expectedness Determination ......................................................................................56 
8.6. 
Study Stopping Criteria ..............................................................................................56 
8.6.1. 
Independent Data Monitoring Committee (IDMC) Stopping Rules ..........................56 
8.6.2. 
Sponsor Discontinuation Stopping Criteria ................................................................56 
9. 
DATA COLLECTION ...............................................................................................57 
10. 
STATISTICAL PLAN................................................................................................58 
10.1. 
Sample Size ................................................................................................................58 
10.2. 
Randomization ............................................................................................................58 
10.3. 
General Statistical Considerations and Definitions ....................................................58 
10.3.1. 
General Statistical Methods ........................................................................................58 
10.3.2. 
Analysis Population ....................................................................................................58 
10.3.2.1. 
Intent-to-Treat (ITT) Population .................................................................................58 
10.3.2.2. 
Full Analysis Set (FAS) ..............................................................................................59 
10.3.2.3. 
Modified Intent-to-Treat (mITT) Population ..............................................................59 
10.3.2.4. 
Safety Population ........................................................................................................59 

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10.3.3. 
Analysis Windows and Baseline ................................................................................59 
10.3.4. 
Missing Data Handling ...............................................................................................59 
10.4. 
Statistical Analyses .....................................................................................................60 
10.4.1. 
Demographic and Background Characteristics ..........................................................60 
10.4.2. 
Investigational Product and Concomitant Medications ..............................................60 
10.4.3. 
Efficacy Analysis ........................................................................................................60 
10.4.3.1. 
Primary Efficacy Endpoints ........................................................................................60 
10.4.3.1.1. Sensitivity Analysis for Primary Efficacy Endpoints .................................................61 
10.4.3.2. 
Secondary Efficacy Endpoints ....................................................................................61 
10.4.3.3. 
Exploratory Endpoints ................................................................................................61 
10.4.4. 
Safety Analysis ...........................................................................................................61 
10.4.4.1. 
Adverse Events ...........................................................................................................61 
10.4.4.2. 
Laboratory Tests .........................................................................................................62 
10.4.4.3. 
Vital Signs ..................................................................................................................62 
10.4.4.4. 
Neurological Examinations ........................................................................................62 
10.4.4.5. 
Pharmacodynamic Parameters ....................................................................................62 
10.4.4.6. 
Pharmacokinetic Parameters .......................................................................................62 
10.5. 
Interim Analysis ..........................................................................................................62 
10.5.1. 
Interim Safety Reviews ...............................................................................................62 
11. 
RECORDS RETENTION ..........................................................................................63 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................64 
12.1. 
Monitoring ..................................................................................................................64 
12.2. 
Auditing ......................................................................................................................64 
12.3. 
Protocol Deviations ....................................................................................................64 
13. 
ETHICS AND RESPONSIBILITY ............................................................................66 
13.1. 
Informed Consent .......................................................................................................66 
13.2. 
Institutional Review Board/Ethics Committee ...........................................................66 
14. 
CONFIDENTIALITY ................................................................................................67 
15. 
INVESTIGATOR AGREEMENT .............................................................................68 
16. 
REFERENCES ...........................................................................................................69 
APPENDIX A: PATIENTS WITH ESTABLISHED ASCVD .....................................................73 
APPENDIX B: REQUIREMENTS FOR BACKGROUND LIPID LOWERING 
TREATMENT ............................................................................................................74 

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APPENDIX C: RECOMMENDED NEUROLOGICAL EXAMINATION .................................76 
APPENDIX D: SAMPSON CRITERIA FOR DIAGNOSING ANAPHYLAXIS .......................81 
 
LIST OF TABLES 
Table 1: 
Investigational Product ...............................................................................................34 
Table 2: 
Schedule of Assessments ............................................................................................40 
 
LIST OF FIGURES 
Figure 1: 
Schematic Diagram of Study Design ..........................................................................26 

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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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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 
PK 
pharmacokinetics 
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 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.  
A single 300 mg SC dose of inclisiran sodium was observed to increase Cmax and AUC up to 
approximately two-fold in subjects with mild and moderate renal impairment, and increased 
Cmax up to four-fold and AUC up to three-fold in subjects with severe renal impairment 
compared to subjects with normal renal function. However, by 48 hours plasma levels of 
inclisiran were below the level of quantification in all groups.  
Despite the differences observed in PK parameters over the first 48 hours following injection 
of inclisiran, there were generally no relevant differences between the groups with respect to 
PCSK9 reduction and LDL-C reduction. In addition, there was no difference in the overall 
safety profile between subjects with normal renal function and those with mild, moderate, or 
severe renal impairment. 
This finding is consistent with that observed in the previous Phase I (ALN-PCSSC-001) 
study where doses above 300 mg led to a dose related increase in PK parameters. A single 
500 mg dose increased AUC 2-3 fold and Cmax 4-5 fold compared to a single 300 mg dose, 
which is similar to the increase observed in subjects with severe renal impairment compared 
to those with normal renal function in this study. In both the Phase I (ALN-PCSSC-001) and 
Phase II (ORION-1) studies single doses above 300 mg did not lead to greater reductions in 
PCSK9 or LDL-C levels over time or differences in the safety profile. 
These data support the administration of inclisiran to subjects with mild, moderate, or severe 
renal impairment in future and ongoing clinical studies with inclisiran. 
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 

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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 generally well tolerated. 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 approximately 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.  
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. 

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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 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 ASCVD 
(CHD, CVD or PAD) 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) 
2.4. 
Pharmacokinetic Objectives 
The pharmacokinetic objective of this study are:  
 To assess the effect of inclisiran on statin pharmacokinetics (at steady state for 
statins) using population analysis approach with sparse blood sampling  
 To assess the effect of inclisiran on PCSK9 levels (at steady state for statins PK)  
using population analysis approach with sparse blood sampling 

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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 
1500 subjects with ASCVD (CHD, CVD or PAD) 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 study in North 
America. Informed consent will be obtained from subjects before the initiation of any study-
specific procedures. 
Subjects will be screened and approximately 1500 eligible subjects will be randomized: 
750 subjects will be randomized to inclisiran sodium 300 mg and 750 subjects will be 
randomized to placebo. Treatment allocation will be stratified 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) 
3.6. 
Pharmacokinetic Endpoint 
The pharmacokinetic endpoint of this study is:  
 Steady state concentrations of statins (specifically, atorvastatin and rosuvastatin) at 
Day 1 (baseline), Day 450, and Day 510 

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3.7. Measures to Minimize/Avoid Bias 
3.7.1. 
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 study in North America in subjects with ASCVD (CHD, CVD or 
PAD) and elevated LDL-C despite maximum tolerated dose of LDL-C lowering therapies. 
4.1. Number of Subjects  
Approximately 1500 subjects (at least 1425 evaluable) will be randomized. 
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 ASCVD (CHD, CVD or PAD (see APPENDIX A).
3. Serum LDL-C ≥1.8 mmol/L (≥70 mg/dL).
4. Fasting triglyceride <4.52 mmol/L (<400 mg/dL) at screening.
5. No current or planned renal dialysis or renal transplantation.
6. 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).
7. Subjects not receiving statin must have documented evidence of intolerance to all
doses of at least two different statins (see APPENDIX B).
8. 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.
9. 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 ALT, aspartate aminotransferase
(AST), >3x the 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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These applicable reasons above will be recorded in the e-CRF.  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 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 for Injection) 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 in vial or pre-filled syringe 
(equivalent to 284 mg inclisiran) for injection 
Route of 
Administration 
SC use 
Physical Description 
Clear, colorless to pale yellow solution essentially free of particulates 
Manufacturer 
Investigational product preparation: The procedure for preparing investigational product 
is provided in the Pharmacy Manual.  
Investigational product administration: Subjects will be administered a single SC injection 
of 300 mg Inclisiran for Injection at predefined time points as described in the Schedule of 
Assessments (Table 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 and 
placebo pre-filled syringes will be blinded and look identical to the corresponding inclisiran 
vials and pre-filled syringes. Placebo will be administered as a 1.5 mL SC injection to match 
the dose in the 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 and pre-filled syringes, 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 container closure system for the vial consists of a Type I glass vial, a Teflon-faced 
bromobutyl 13 millimeter stopper, and a flip off Truedge aluminum seal.   
The container closure system for the pre-filled syringe consists of a Type I glass syringe with 
a stainless steel 27G ½” staked needle covered by a removable rigid needle shield and 
Fluorotech coated bromobutyl plunger.   
Each vial and pre-filled syringe will have a yellow shroud to maintain the blind. 
5.1.4. 
Storage 
Investigational product (vial and pre-filled syringes) will be stored at controlled room 
temperature (20°C to 25°C [68°F to 77°F] with allowable excursions between 15°C and 30°C 
[59°F and 86°F]) as specified in the Pharmacy Manual. Access should be strictly limited to 
the investigator, pharmacists, and their designees. No special procedures are required for the 
safe handling of Inclisiran for Injection.  
5.1.5. 
Accountability 
The investigator or designee must maintain an inventory record of investigational product 
(inclisiran/placebo) received and all administered to assure the regulatory authorities and the 
Sponsor that the new investigational product will not be dispensed to any person who is not a 
subject under the terms and conditions set forth in this protocol. Investigational product 
accountability forms and/or specific instructions can be found in the Pharmacy Manual. 
The investigational product supplied for use in this study is to be prescribed only by the 
Principal Investigator or designated sub-investigators and may not be used for any purpose 
other than that outlined in this protocol. 
During the study, all used vials of investigational product will be kept until the monitor has 
reviewed the accountability records. Since used syringes must be discarded, the box that the 
pre-filled syringes came in 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: 

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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). 
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 vial, any part of the seal, the cap, the pre-filled syringe or the label).

An indication that the product is mislabeled.

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 unit dose of investigational product will contain a yellow shroud 
to maintain the blind.  
Randomization via an automated IRT will be used to assign subjects to blinded 
investigational product. The clinical study site pharmacist will maintain the double blind 
according to site-specific procedures and the Pharmacy Manual. It should be noted that 
inclisiran may be visually distinguishable from placebo; therefore, blinded syringes will be 
provided to all study sites and used to maintain the blind. 
5.5.2. 
Method and Maintenance of Blinding 
Investigational product will be blinded prior to distribution to sites. All unit doses of 
investigational product (inclisiran/placebo) will be covered by a yellow shroud to maintain 
the blind. In addition, all study sites will be provided a bulk supply of single use syringes 

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similarly covered by a yellow shroud to be used to withdraw investigational product from the 
vial only 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 
 
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 
PK (statin levels) 
 
X13 
 
 
 
 
 
X13 
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; PK=pharmacokinetic; SAE=serious adverse event; V=visit  

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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) 
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. Blood draws for PK analysis will be drawn prior to dosing on Day 1 and Day 450. 

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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) 
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 1500 randomized subjects are planned for inclusion in the 
study: 750 subjects per group.  
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 C) 
 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)  
 PK sampling 
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) 
 PK sampling (Day 450 only) 
 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: 

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6.7.1. 
Day 150 

Fasting lipid profile/biomarkers (Section 7.2)

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)

PK sampling

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 C)

Vital signs: blood pressure and heart rate (Section 7.1.3)

12-lead ECG

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 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 (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 will be performed as per the Schedule of Assessment 
(APPENDIX C). 
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 Pharmacokinetics 
In a subset of subjects who receive background treatment with highly effective statins (i.e., 
atorvastatin or rosuvastatin), at any dose, steady state concentrations will be measured to 
determine the effect of inclisiran on these steady state statin concentrations, PCSK9 levels, 
and absolute and percentage change in PCSK9 levels from baseline at Day 450 and Day 510. 

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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 are: 

Abnormal neurological examination, eg, peripheral sensory and motor evaluation, an
assessment of gait, pain, position, strength and reflexes (APPENDIX C).

Potential anaphylactic reactions assessed by Sampson criteria (APPENDIX D). If
Sampson criteria are positive, confirm by elevation of tryptase in blood plasma
measured within 30 minutes of symptoms.

Hyperglycemia-related AEs:
Report ‘New onset of diabetes’ in subjects with no medical history of diabetes when:
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 
provided study specific SAE Report Form. Each SAE must also be recorded on the source 
documents and on the appropriate page of the eCRF.  

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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-10 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 
1500 subjects with ASCVD 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 study in North America. 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 1425 subjects that 
are evaluable for efficacy across the placebo and inclisiran dose groups. This sample size of 
at least 1425 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. This sample size will also contribute additional 
sufficient safety data. 
10.2. 
Randomization 
Subjects will be screened and approximately 1500 eligible subjects will be randomized by 
the IRT system: 750 subjects will be randomized to inclisiran sodium 300 mg and 
750 subjects will be randomized to placebo. Treatment allocation will be stratified 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. 
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. This will be the primary 
population for analysis of the primary and key secondary efficacy endpoints. 

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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 
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. 

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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 population 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. 
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’s available.
Missing values will be imputed for LDL-C after reflexive approach at each visit using the 
method specified in the final SAP. Analysis on both primary efficacy endpoints will be 
performed after imputation. 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. 
Missing values will be imputed according to the method specified in the final SAP on LDL-
C, PCSK9, total cholesterol, ApoB, and non-HDL-C before any analysis is performed. 
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). 
10.4.4.6. Pharmacokinetic Parameters  
Pharmacokinetic biomarker samples will be collected and stored for up to 1 year following 
the completion of the last subject for research purposes to analyze the profile of rosuvastatin 
and atorvastatin in subjects taking these statins in combination with inclisiran (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: Amendment 4 
Institution Name 

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APPENDIX A: PATIENTS WITH ESTABLISHED ASCVD  
 
Coronary heart disease (CHD): 
 Prior myocardial infarction  
 Prior coronary revascularization (PCI or CABG)  
 Angiographic or CT-imaging (eg, MDCT/CTA) evidence of coronary atherosclerosis 
(>70% stenosis in at least one major epicardial coronary artery) 
 
Cerebrovascular disease (CVD): 
 Prior ischemic stroke confirmed by a brain imaging study – CT or MRI; thought not 
to be caused by atrial fibrillation, valvular heart disease or mural thrombus  
 Carotid artery stenosis >70% on prior angiography or ultrasound 
 History of prior percutaneous or surgical carotid artery revascularization 
 
Peripheral arterial disease (PAD): 
 Prior documentation of a resting ankle-brachial index    0.85  
 History of prior percutaneous or surgical revascularization of an iliac, femoral, or 
popliteal artery 
 Prior non-traumatic amputation of a lower extremity due to peripheral artery disease 
 
 

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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: 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 D: SAMPSON CRITERIA FOR DIAGNOSING 
ANAPHYLAXIS 
Anaphylaxis is highly likely when any one of the following three criteria is fulfilled: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin,
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-
tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING:
a.
Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced
peak expiratory flow [PEF], hypoxemia)
b. Reduced blood pressure or associated symptoms of end-organ dysfunction (eg,
hypotonia [collapse], syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for
that patient (minutes to several hours):
a.
Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen
lips-tongue-uvula)
b. Respiratory compromise (eg, dyspnea, wheeze, bronchospasm, stridor, reduced
PEF, hypoxemia)
c.
Reduced 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.