Conditions: Atherosclerotic Cardiovascular Disease Symptomatic Atherosclerosis Type2 Diabetes Familial Hypercholesterolemia
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 382
Healthy volunteers: no

Brief summary:
This clinical study was designed to assess the efficacy, safety, and tolerability of long-term dosing of inclisiran and evolocumab given as subcutaneous injections in participants with high cardiovascular risk and elevated low-density lipoprotein cholesterol (LDL-C).

Detailed description:
MDCO-PCS-16-01 (ORION-3) was a Phase II, open-label, multicenter, non-randomized, active comparator long term extension study. Total study duration was 4 years from first participant enrolled to the last subject completed. The study consisted of three study periods:

Screening Period: Participants completing study MDCO-PCS-15-01 (ORION-1) were screened for all inclusion and exclusion criteria of study ORION-3.

Treatment Period: Participants fulfilling all eligibility criteria of ORION-3 were enrolled. Participants who received inclisiran in ORION-1 received inclisiran sodium throughout this study up to 4 years (Group 1; Inclisiran-only arm), and participants who received placebo in ORION-1 received evolocumab as open-label comparator up to Day 336, and then transitioned to inclisiran on Day 360 and every 180 days thereafter for up to 4 years (Group 2; Switching arm).

Safety follow up: Participants were followed up for safety during 4 weeks after the last dose of study treatment. Including the Screening Period, the total study duration for a participant was up to 4 years.

Arms:
arm 1: Participants received subcutaneous injections of inclisiran 300 milligrams (mg) on Day 1 and every 180 days thereafter for up to 4 years. arm 2: Participants received self-administered subcutaneous injections of evolocumab 140 mg on Day 1 and every 14 days thereafter until Day 336. Then, participants received subcutaneous injections of inclisiran 300 mg on Day 360 and every 180 days thereafter for up to 4 years.

Interventions: intervention 1: Inclisiran intervention 2: Evolocumab
Intervention descriptions: intervention 1: Inclisiran is a synthetic, chemically modified small interfering ribonucleic acid (siRNA) targeting proprotein convertase subtilisin kexin type 9 (PCSK9) messenger ribonucleic acid (mRNA) with a covalently attached triantennary N-acetylgalactosamine (GalNAc) ligand. intervention 2: Evolocumab is a fully human monoclonal antibody that inhibits PCSK9.

Protocol document:
Prot_000.pdf: 






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who have completed the EOS visit (90 days after last dosing) wish to continue treatment with inclisiran (and none 
of the mentioned decisions or recommendations to discontinue the trial are in place) they will be given the 
opportunity to enroll into ORION-8 (open-label extension trial) 
An interim analysis of lipids and PCSK9 will be conducted upon completion of Day 210 for subjects in Group 1 
(inclisiran only arm). A further interim analysis will be conducted when all subjects in Group 1 complete 24 month 
of treatment with inclisiran.   
 
Number of Subjects: Maximum 490 planned
Diagnosis and Main Criteria for Selection:
Subjects may be included if they meet all of the following inclusion criteria prior to entry into this study:
1.
Completion of study MDCO-PCS-15-01 (CKJX839A12201) and no contraindications to receiving inclisiran or 
evolocumab.
2.
Willing and able to give informed consent before initiation of any study-related procedures and willing to 
comply with all required study procedures.
3.
Willing to self-inject of evolucumab.
Subjects will be excluded from the study if any of the following exclusion criteria apply immediately prior to entry 
into the study:
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’s] 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.
Serious comorbid disease in which the life expectancy of the subject is shorter than the duration of the trial 
(eg, acute systemic infection, cancer, or other serious illnesses).
4.
Active liver disease defined as any known current infectious, neoplastic, or metabolic pathology of the liver or 
unexplained alanine aminotransferase (ALT), aspartate aminotransferase (AST), elevation >2x the upper 
limit of normal (ULN), or total bilirubin elevation >1.5x ULN at Study Entry visit,  confirmed by a repeat 
abnormal measurement at least 1 week apart.
5.
Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use at least two 
methods of contraception (eg, oral contraceptives, barrier methods, approved contraceptive implant, long-
term injectable contraception, intrauterine device) for the entire duration of the study. Exemptions from this 
criterion:
a.
Women >2 years postmenopausal (defined as 1 year or longer since their last menstrual period) AND 
more than 55 years of age
b.
Postmenopausal women (as defined above) and less than 55 years old with a negative pregnancy test 
within 24 hours of enrollment
c.
Women who are surgically sterilized at least 3 months prior to enrollment
d.
Males who are unwilling to use an acceptable method of birth control during the entire study period 
(ie, condom with spermicide).
e.
Treatment with investigational medicinal products other than inclisiran or devices within 30 days or 
five half˗lives, whichever is longer. 
6.
Planned use of other investigational medicinal products other than inclisiran or devices during the course of 
the study. 
7.
Subjects with a history of a serious hypersensitivity reaction to evolocumab or any of the excipients.
8.
Previous or current treatment (within 90 days of Study Entry) with monoclonal antibodies directed towards 
PCSK9.
9.
Any condition that according to the investigator could interfere with the conduct of the study, such as but not 
limited to:
a.
Inappropriate for this study, including 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). 








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4.4.1
Withdrawal from Study Medication......................................................29
4.4.2
Individual Subject Dosing Stopping Criteria ........................................29
5
Treatment of Subjects ........................................................................................................30
5.1
Study Medications..................................................................................................30
5.1.1
Inclisiran (also referred to as KJX839) .................................................30
5.1.2
Comparator Drug (evolocumab)............................................................31
5.1.3
Packaging and Labeling ........................................................................31
5.1.4
Storage...................................................................................................31
5.1.5
Accountability .......................................................................................32
5.1.6
Product Deficiencies Reporting.............................................................32
5.2
Concomitant Medications ......................................................................................33
5.2.1
Prohibited Concomitant Medications....................................................33
5.2.2
Permitted Concomitant Medications.....................................................33
5.3
Medical Management Guidelines ..........................................................................33
5.3.1
Adverse events.......................................................................................33
5.3.2
Pregnancy ..............................................................................................33
5.4
Restrictions.............................................................................................................34
5.5
Blinding..................................................................................................................34
6
SCHEDULE and Sequence of Procedures ........................................................................34
6.1
Schedule of Events/Assessments ...........................................................................34
6.2
General Conduct of the Study................................................................................42
6.3
Study Entry ............................................................................................................42
6.4
Observation Visit(s)...............................................................................................42
6.5
Day 1 of ORION-3.................................................................................................43
6.6
Treatment and Follow-Up Visits............................................................................43
6.6.1
Inclisiran Transition Visit - Day 360 (Group 2; Switching Arm) .........44
6.6.2
Treatment & Follow Up Visits After Day 360......................................45
6.7
Unscheduled Visit..................................................................................................45
6.8
End of Study Visit..................................................................................................45
7
Protocol assessments..........................................................................................................46
7.1
Assessment of Safety .............................................................................................46
7.1.1
Adverse Events......................................................................................46
7.1.2
Vital Signs .............................................................................................46
7.1.3
Physical Examination............................................................................46
7.1.4
Electrocardiograms................................................................................46
46
7.1.6
Clinical Laboratory Assessments ..........................................................46


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47
7.1.8
Stored samples.......................................................................................48
7.2
Assessment of Efficacy..........................................................................................48
7.3
Assessment of Patient Reported Outcomes ...........................................................48
7.3.1
Medication Adherence...........................................................................48
7.3.2
Treatment Satisfaction Questionnaire ...................................................48
8
Adverse Events ..................................................................................................................49
8.1
Definitions..............................................................................................................49
8.1.1
Adverse Event .......................................................................................49
8.1.2
Serious Adverse Event ..........................................................................49
8.1.3
Special Situations Events ......................................................................50
8.2
EVALUATING ADVERSE EVENTS..................................................................50
8.2.1
Pre-existing conditions..........................................................................50
8.2.2
AE Severity ...........................................................................................50
8.2.3
Relationship to Study Drug ...................................................................50
8.2.4
Requirements for Additional Safety Data Collection............................50
8.3
PROCEDURE FOR ADVERSE EVENT REPORTING......................................51
8.3.1
Serious Adverse Event Reporting .........................................................51
8.3.2
Nonserious Adverse Event Recording...................................................52
8.3.3
Medication Error Reporting ..................................................................52
8.3.4
Pregnancy Reporting .............................................................................52
8.3.5
Reporting the Special Situations Events................................................53
8.4
Study Stopping Criteria..........................................................................................53
8.4.1
Data Monitoring Committee Stopping Rules........................................53
8.4.2
Sponsor Discontinuation Stopping Criteria...........................................53
9
Data Collection ..................................................................................................................53
10 Statistical Plan....................................................................................................................54
10.1
Sample Size............................................................................................................54
10.2
General Statistical Considerations and Definitions ...............................................54
10.2.1
General Statistical Methods...................................................................54
10.2.2
Analysis Population...............................................................................54
10.2.3
Analysis Windows and Day 1 ...............................................................55
10.2.4
Missing Data Handling..........................................................................55
10.3
Statistical Analyses ................................................................................................55
10.3.1
Demographic and Background Characteristics .....................................55
10.3.2
Study Drug and Concomitant Medications ...........................................55
10.3.3
Efficacy Analysis...................................................................................55


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10.3.4
Safety Analysis......................................................................................56
11 Records Retention..............................................................................................................57
12 Quality Control and Quality Assurance.............................................................................58
12.1
Monitoring .............................................................................................................58
12.2
Auditing .................................................................................................................58
12.3
Protocol Deviations................................................................................................58
13 Ethics and Responsibility...................................................................................................58
13.1
Informed Consent...................................................................................................59
13.2
Institutional Review Board/Ethics Committee ......................................................59
14 Confidentiality ...................................................................................................................59
15 Investigator Agreement......................................................................................................60
16 References..........................................................................................................................62
APPENDIX A
RECOMMENDED Neurological Examination ....................................65
APPENDIX B
Sampson Criteria for Diagnosing Anaphylaxis.....................................69


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List of tables
Table 5-1
Treatment assignments..........................................................................30
Table 5-2
Investigational Product..........................................................................30
Table 6-1
Study Design and Schedule of Assessments (Group 1; Inclisiran 
Only Arm) .............................................................................................35
Table 6-2
Study Design and Schedule of Assessments (Group 2; Switching 
Arm) ......................................................................................................38
List of figures
Figure 3-1
Study Design .........................................................................................26


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List of Abbreviations
AE
adverse event
AESIs
Adverse Events of Special Interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase 
Apo-A1
apolipoprotein A1
Apo-B
apolipoprotein B
aPTT
activated partial thromboplastin
ASCVD
atherosclerotic cardiovascular disease 
AST
aspartate aminotransferase
BUN
total protein urea
CHD
coronary heart disease
CK
creatine kinase
CRP
C-reactive protein
CTCAE
Common Terminology Criteria for Adverse Events
CV
cardiovascular
DCF
data clarification forms
dL
deciliter(s)
DMC
Data Monitoring Committee
EC
Ethics Committee
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
EOS
end of study
EU
European Union
FDA
Food and Drug Administration
FH
familial hypercholesterolemia
GalNAc
N-acetylgalactosamine
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
GPV
Global Pharmacovigilance Department
HbA1c
glycated hemoglobin A1C
HDL-C
high density lipoprotein cholesterol
HeFH
heterozygous familial hypercholesterolemia
hsCRP
high sensitivity C-reactive protein 
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation 
IDMC
Independent Data Monitoring Committee
IFN-γ
interferon-gamma
IL6
interleukin 6
INR
International normalized ratio
IRB
Institutional Review Board
ISR
injection site reaction
ITT
intent-to-treat


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IXRS                       Interactive Voice/ Web Response System
LDL-C
low density lipoprotein cholesterol
LDLR
low density lipoprotein receptor
LNP
lipid nanoparticles
Lp(a)
lipoprotein(a)
MCH
mean cell hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MD
multiple dose
MDCO
The Medicines Company
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
MI
myocardial infarction
mITT
Modified intent-to-treat
mL
milliliter(s)
mmHg
millimeters of mercury
mmol
millimole
mRNA
messenger ribonucleic acid
PCSK9
proprotein convertase subtilisin/kexin type 9
PEF
peak expiratory flow
PT
prothrombin time
RNA
ribonucleic acid
RNAi
ribonucleic acid interference
SAD
single ascending dose
SAE
serious adverse event
SAP
Statistical Analysis Plan
SC
subcutaneous
SD
standard deviation
siRNA
small interfering ribonucleic acid
TBIL
total bilirubin
TC
total cholesterol
TEAE
treatment emergent adverse event
TNF-α
tumor necrosis factor-alpha 
TSQM
Treatment Satisfaction Questionnaire for Medication
TTR
target transthyretin
ULN
upper limit of normal
USA
United States of America
VLDL-C
very low density lipoprotein cholesterol
WHO
World Health Organization


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Amendment 5 (07-Oct-2020)
Amendment rationale 
The first subject for this trial was randomized in March 2017 and enrollment was completed in 
Nov 2017 with 382 subjects enrolled. 
This amendment is written to address the sponsorship change from The Medicines Company to 
Novartis after acquisition of The Medicine Company by Novartis in Jan 2020. Administrative 
changes were made to the title page, the footer and headers and throughout the protocol to reflect 
the change in sponsorship and adding the Novartis study and IMP number. Additional minor 
changes to correct typos and provide clarifications were only incorporated directly into the 
protocol. 
Wording in consideration of the COVID-19 pandemic was implemented and additionally 
following changes were implemented in the protocol. 
-
Introduce Novartis protocol number and IMP code – CKJX839A12201E1 and KJX839
-
Contacts and process changes for NVS

Removal from protocol  specific contact information of employees of the The Medicine 
Company – provided to the sites outside of the protocol

Update of section 12.3 on handling of protocol deviations (including PDs for COVID-19 
related issues and any others considered relevant and not listed in the protocol)

Introduction of section 5.1.6 Reporting of product deficiencies (complaints) to ensure 
any deficiency observed to the product can be captured and reported within the trial.

Introduction of COVID-19 considerations – remote visits, extended visit windows

Update of Section 8.4.3.2 – Pregnancy, to include follow up on newborns for 12 months

Deletion of Secondary objective “Duration of lipid-lowering effect” in section 2.2 as this 
will no longer be evaluated. 

Deletion of Secondary endpoint  “Duration of lipid-lowering effect (LDL-C beta 
quantification over time)” in section 3.4 as this will no longer be evaluated. 

Update in the section 10.3.3.4 –Interim Analysis. A further interim analysis will be 
conducted when all subjects in Group 1 complete 24 month of treatment with inclisiran. 

Subjects in the trial who have completed the EOS will be given the opportunity to enroll 
into ORION-8 (open-label extension trial). 
Changes to specific sections of the protocol are shown in the track changes version of the protocol 
using strike through red font for deletions and red underlined for insertions.


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IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC and Health Authority approval 
according to local regulations prior to implementation. 
The changes herein affect the Informed Consent.  Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this protocol 
amendment. 


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1
Introduction
Inclisiran (also referred to as KJX839) is a novel synthetic ribonucleic acid (RNA) interference 
(RNAi) therapeutic, Inclisiran (CKJX839) for Injection (subcutaneous [SC] use), formerly 
referred to as ALN-PCSSC, for the treatment of hypercholesterolemia. This protocol describes a 
study to evaluate and compare the effect of inclisiran treatment on low density lipoprotein 
cholesterol (LDL-C) levels at Day 210 with evolocumab (REPATHA®). This study is sponsored 
by Novartis and  will be conducted in compliance with Good Clinical Practices (GCP) including 
the Declaration of Helsinki and all applicable regulatory requirements.
1.1
Background
1.1.1
Disease Overview
According to the World Health Organization (WHO), atherosclerotic cardiovascular disease 
(ASCVD), comprised mainly of coronary heart disease (CHD) and stroke, is the leading cause of 
death worldwide, resulting in 17 million deaths annually (WHO Cardiovascular Statistics, 2011). 
Data from the INTERHEART case-control study estimates that 45% of myocardial infarctions 
(MI) in Western Europe and 35% of myocardial infarctions in Central and Eastern Europe are 
due to abnormalities in blood lipids (Yusef et al, 2004). Hypercholesterolemia, specifically, 
elevated LDL-C, is one of the major risk factors for the development of CHD, the leading cause 
of death worldwide (Grundy et al, 2004; Go et al, 2014). The continuous and graded relationship 
between plasma LDL-C concentration and CHD risk is such, based upon data  a large body of 
epidemiological and clinical studies, for every 0.78 mmol/L (30 mg/dL) change in LDL-C, the 
relative risk for CHD changes by approximately 30% (Grundy et al, 2004). In addition, multiple 
clinical trials have demonstrated a decreased risk of cardiovascular mortality and morbidity in 
patients on statin therapy of around 5 to 6% for every 10 mg/dL reduction in LDL-C (Delahoy et 
al, 2009; Baigent et al, 2010). High dose statin treatment has also been shown to result in 
additional clinical benefit compared to low or moderate dose statin treatment (Cannon et al, 2004; 
Pedersen et al, 2005). Despite the extensive use of statins, current therapies for the management 
of elevated LDL-C remain inadequate in some patients. 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 aggressive management (Davidson et al, 2005). Among these 
high risk subjects, less than 50% achieved the target LDL-C goal of <2.6 mmol/L (100 mg/dL) 
following 6 months of statin treatment, despite close monitoring and drug regimen optimization 
(Foley et al, 2003; Baigent et al, 2005; Kearney et al, 2008; Foody et al, 2010). Thus, there is a 
clear unmet medical need for new drugs to lower LDL-C, especially in certain patient populations 
such as FH.
1.1.2
PCSK9 Biology and Target Rationale
Proprotein convertase subtilisin kexin type 9 (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   


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LDL-C levels (Zhao et al, 2006; Hooper et al, 2007; Horton et al, 2009). In one published study, 
heterozygous individuals (carrying a single copy of a loss of function PCSK9 mutation) had 
significantly lower LDL-C with median levels of approximately 70 mg/dL (1.81 mmol/L) (Cohen 
et al, 2006). Over a 15-year period of retrospective data analysis, this sustained lowering in       
LDL-C levels translated to an 88% lower risk of risk for CHD. Follow-up publications describe 
two adult individuals that are compound heterozygous for loss of function alleles of PCSK9. 
These individuals lack detectable plasma PCSK9 protein, have LDL-C levels ≤20 mg/dL, and yet 
are otherwise healthy (Zhao et al, 2006; Hooper et al, 2007). Additionally, recent human clinical 
trials with PCSK9 blocking antibodies have shown significant lowering of LDL-C in healthy 
volunteers and across a range of high cardiovascular (CV)-risk populations and with elevated 
LDL-C both with and without statins (Banerjee et al, 2012; Dias et al, 2012; Milazzo et al, 2012; 
Raal et al, 2012; Roth et al, 2012; Stein et al, 2012; Sullivan et al, 2012; Hooper et al, 2013). Thus, 
the overall scientific and clinical data suggests that PCSK9 is a well-validated drug target whose 
inhibition results in significant LDL-C lowering without otherwise negatively impacting overall 
health most recently culminating in the approval (in Europe and North America) of two 
monoclonal agents to inhibit PCSK9.
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).


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1.2
Inclisiran , an RNAi Therapeutic for Hypercholesterolemia
Inclisiran for Injection (SC use) is comprised of the PCSK9 siRNA, ALN-60212, formulated in 
phosphate buffer. The PCSK9 siRNA is a chemically synthesized double stranded 
oligonucleotide covalently linked to a ligand containing GalNAc residues. This synthetic 
investigational RNAi therapeutic has been designed to suppress the liver production of PCSK9 
when administered via SC injection. Inhibition of PCSK9 synthesis through an RNAi mechanism 
has the potential to lower tissue and circulating plasma PCSK9 protein levels, resulting in higher 
expression of LDLR in the liver, and consequently lower LDL-C levels in the blood stream. The 
initial proposed indication for inclisiran is the treatment of subjects with hypercholesterolemia 
who are not achieving therapeutic LDL-C goals despite maximally tolerated lipid-lowering 
therapy, or for subjects who are intolerant of statins.
1.2.1
Preclinical Studies
The pharmacology, metabolism, pharmacokinetics (PK), and toxicology of inclisiran were 
evaluated in a series of in vitro and in vivo nonclinical studies. Development and reproductive 
toxicology studies have not been conducted.
The results of the pharmacology studies show that inclisiran exhibited dose-dependent sustainable 
suppression of PCSK9 protein that was paralleled by lowering of serum LDL-C with the same 
kinetics. The time to reach PCSK9 nadir was approximately 20 days and the mean maximal 
PCSK9 and LDL-C inhibition was 93% and 74%, respectively.
Off-target analysis encompassing bioinformatics and tissue culture assays indicate a very low 
likelihood of inclisiran affecting heterologous gene transcription, thereby decreasing the potential 
of untoward side effects. In a cardiovascular and respiratory study in telemetered conscious 
cynomolgus monkeys, inclisiran had no immediate or delayed effects on clinical observations, 
qualitative or quantitative electrocardiogram (ECG) parameters, hemodynamic parameters, 
respiration rate, or body temperature at any dose level.
Pharmacokinetic studies showed that inclisiran is very well absorbed following SC administration. 
Inclisiran has a short plasma half-life (range: 1 to 4 hours) and preferentially distributes to the 
liver, its target organ, achieving Tmax levels within 8 hours of administration. With the exception 
of the kidney which is the main route of elimination, liver concentrations of inclisiran are many 
fold higher than other tissues examined, thereby reducing the potential for off-target toxicity. In 
addition, studies with heart tissue showed that very low levels of inclisiran are internalized and it 
does not associate with the ribonucleic acid-induced silencing complex indicating a low 
likelihood of activity in heterologous tissues.
The results of repeat dose toxicology studies in rats and monkeys show that inclisiran was well 
tolerated. The most consistent findings were the presence of vacuolation in hepatocytes of rats 
and lymph node macrophages of monkeys and basophilic granules in hepatocytes of monkeys 
and renal tubule epithelium of rats. The presence of vacuolation, particularly in the liver, and 
basophilic granules in the kidney are not associated with changes in clinical pathology parameters 
including liver function enzymes and urinalysis parameters signifying that the vacuolation and 
basophilic granules are not adverse toxicological findings. In addition, there are indications that 
these findings are reversible.


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Inclisiran was tested in a series of in vitro and in vivo genetic toxicology studies, including a 
bacterial mutagenicity assay, an in vitro chromosome aberration assay using human peripheral 
lymphocytes, and an in vivo bone marrow micronucleus assays in rats. There were no gene 
mutations or chromosomal damage observed in any study. Therefore, inclisiran is not genotoxic.
Further information is in the Investigator’s Brochure (IB).
1.2.2
Clinical Studies
One Phase I study has been conducted to date (Study ALN-PCSSC-001). This was a randomized, 
single-blind, placebo-controlled, single-dose escalation and multiple-dose study of inclisiran 
administered SC to subjects with elevated LDL-C. The study was conducted in two phases: a 
single ascending dose (SAD) phase and a multiple dose (MD) phase. During the SAD phase, 
24 subjects were assigned to either receive placebo or one of five doses of inclisiran ranging from 
25 mg to 800 mg. Those who received doses of at least 100 mg saw their LDL-C drop at least 
40%; at the 500 mg dose, LDL-C levels dropped as much as 78%. At 140 days after the treatment 
was given, subjects still had an average LDL-C reduction of about 40%.
In the MD phase, 45 subjects received multiple doses of either inclisiran (125mg weekly x4, 
250 mg biweekly x2, 300 mg and 500 mg twice given 1 month apart) or placebo. These subjects 
had maximal LDL-C reductions of 80% and average LDL-C reductions of 50% to 60%. To date, 
the drug appears to be generally safe and well tolerated. One subject on statin comedication had 
elevated liver enzymes with alanine aminotransferase (ALT) >4x the upper limit of normal (ULN), 
which resolved on stopping the statin.
One Phase II dose finding study CKJX839A12201 (MDCO-PCS-15-01; ORION-1) was 
conducted and is complete. This study was a placebo-controlled, double-blind, randomized trial 
to compare the effect of inclisiran administered SC as either a single dose (200 mg, 300 mg, or 
500 mg) on Day 1 or as two doses (100 mg, 200 mg, or 300 mg) on Day 1 and Day 90 in subjects 
with high cardiovascular risk and elevated LDL-C. A total of 501 subjects were randomized 
(placebo=127 and inclisiran=374) and 497 received at least one dose of study drug (placebo=127 
and inclisiran=370). After administration of dosing, all subjects were followed until Day 210. 
Subjects whose LDL-C values had not returned to within 20% of the change from their baseline 
value were followed up to Day 360. Regular reviews of safety were performed by an independent 
Data Monitoring Committee and no safety concerns were reported and no changes to the protocol 
were requested during conduct of the study.
An interim analysis was performed after all subjects had completed the Day 90 visit in order to 
select the dose for subsequent studies. Inclisiran was generally well tolerated following single and 
multiple dosing. There was no imbalance observed in the incidence or type of AEs and serious 
adverse events (SAEs) across the dose range of inclisiran groups with a similar incidence to 
placebo. The majority of adverse events (AEs) were mild or moderate in severity. The most 
common AEs observed after the first injection until Day 90 were myalgia, back pain, fatigue, 
headache, dizziness, nasopharyngitis, diarrhea and hypertension. A low incidence of mild, 
localized, injection site reactions (ISRs) was reported with no clear dose dependent or cumulative 
effect observed following first or second injection. No subjects developed treatment emergent 
liver findings that met the laboratory definition of Hy's Law. One subject developed clinically 
significant changes in liver function tests reported as an SAE which was attributed to concomitant 
statin therapy and a recent statin dose increase and resolved on discontinuation of statin. All doses 


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of inclisiran inhibited PCSK9 synthesis and lowered LDL-C significantly. One dose of 300 mg 
inclisiran achieved a mean 51% LDL-C reduction. Two doses of 300 mg inclisiran achieved a 
mean 57% LDL-C reduction in LDL-C. The LDL-C reduction was significant and durable out 
to 180 days following either one or two injections of inclisiran. No additional LDL-C reduction 
was observed with 500 mg as a single dose. Potentially favorable changes were also observed in 
the overall atherogenic lipid profile. 
The end of trial evaluation confirmed the data observed at the interim analysis. Inclisiran, at all 
tested doses, was safe and well-tolerated in subjects at high cardiovascular risk who had elevated 
LDL-C levels. A single dose of 300 mg inclisiran sodium achieved a maximum mean LDL-C 
reduction of 50.9% at Day 60. Two 300 mg inclisiran sodium doses administered at Day 1 and 
Day 90 achieved a maximum mean LDL-C reduction of 55.5% at Day 150. The LDL-C reduction 
was clinically significant and durable out to 360 days following either one or two injections of 
inclisiran. Maximum PCSK9 reduction was observed at the 300 mg dose level. A similar 
reduction observed in LDL-C at Day 270 compared to Day 90 along with the time adjusted mean 
LDL-C reduction of 50.5% over this time interval further support a dose regimen of 300 mg 
inclisiran sodium given at Day 1, Day 90, and every 6 months thereafter as the optimal dose and 
dose regimen to investigate further in subsequent Phase III clinical studies. Modeling and 
simulation analyses provide further support for the proposed 6 monthly maintenance regimen.
No persistent and clinically relevant treatment related abnormalities were reported in any 
laboratory parameter. A low incidence of AST, ALT and CK rises were reported, although some 
of these subjects also had elevated baseline value or underlying medical conditions contributing 
to these elevations. There were no treatment emergent increases in bilirubin from a normal 
baseline and no case met the definition of Hy’s Law. One subject had a rise in ALT on Day 104 
following the second injection of 300 mg inclisiran sodium as reported in the interim analysis. 
This was considered related to a recent increase in the dose of statin and resolved immediately on 
stopping the statin. There were no clinically relevant or persistent changes in the inclisiran dose 
groups observed in any other laboratory parameters including renal function, hemoglobin, 
platelets, HbA1c and coagulation parameters and no clinically relevant differences from placebo.
Subjects participating in MDCO-PCS-15-01 (CKJX839A12201) were asked to consent to the 
ORION-3 trial described in this protocol (MDCO-PCS-16-01 (CKJX839A12201E1)) once their 
lipid levels have returned to within 20% of the baseline levels or after they reached the Day 360 
visit in study MDCO-PCS-15-01, whichever occured first.
1.2.3
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 comparator. 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. Evolocumab is an approved drug 
with a good safety profile, but may cause allergic reactions.
An expanded risk-benefit summary is provided in the current/approved version of the 
Investigator’s Brochure.








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MDCO-PCS-15-01. In countries where applicable, on signing consent and being entered into this 
study, the investigator will be informed by the IXRS regarding the treatment allocation, and 
therefore, whether placebo or inclisiran was administered in study MDCO-PCS-15-01 
(CKJX839A12201) and the subject will be informed accordingly. Those subjects who received 
inclisiran in MDCO-PCS-15-01 will receive inclisiran sodium throughout this study (Group 1; 
inclisiran only arm), and those subjects who received placebo in MDCO-PCS-15-01 
(CKJX839A12201) will receive evolocumab as comparator for 1 year, and then transition to 
inclisiran for the remainder of the study (Group 2; switching arm). Until study drug is available, 
subjects will have monthly observation visits until study drug administration commences.
Day 1 of ORION-3 is the day when eligible subjects will receive the first SC administration of 
inclisiran or evolocumab.
Group 1 (Inclisiran Only Arm):
After first study drug administration of inclisiran, all subjects will be observed in the clinic for at 
least 4 hours post injection before being discharged.
The subsequent visit schedule is as follows:

Dosing visits: Every 180 days until Day 720, an additional dose on Day 810, then back to
every 180 day dosing until EOS. Therefore, dosing after Day 1 (ORION-3) will occur on 
Days 180, 360, 540, 720, 810*, 990, 1170 and 1350.
*Day 810 dose added to assess the effect of giving 2 doses 90 days apart (at Days 720 and 
810).

Safety follow-up visits: Days 30, 90, 210, 270, 390, 450, 570, 630, 870, 1080, 1260, and 
EOS (Day 1440).
Group 2 (Switching Arm):
Subjects receiving evolocumab will receive the first dose on Day 1 (ORION-3), administered by 
the investigator, and will then self administer evolocumab at home every 14 days until Day 336.  
Sites will then be assigned to have their evolocumab treated patients placed into one of two 
transition groups.

Transition 1 (staged): Day 336 will be the final dose of evolocumab therapy and the first 
dose of inclisiran will be administered at the Day 360 visit.

Transition 2 (concurrent): Day 336 will be the final dose of evolocumab therapy at home. At 
the Day 360 visit subjects will receive an additional dose of evolocumab and their first dose 
of inclisiran, both administered by the investigator.
After first study drug administration of inclisiran on Day 360, all subjects in Group 2 (switching 
arm) will be observed in the clinic for at least 4 hours post injection before being discharged.
The subsequent visit schedule is as follows:

Dosing visits: Day 450 (2nd dose), then every 180 days until end of study (Days 630, 810, 
990, 1170 and 1350).

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2. Willing and able to give written and informed consent before initiation of any study-related 
procedures and willing to comply with all required study procedures. 
3. Willing to self-inject.
4.3
Exclusion Criteria
Subjects will be excluded from the study if any of the following exclusion criteria apply 
immediately prior to entry into the study:
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’s] 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. Serious comorbid disease in which the life expectancy of the subject is shorter than the 
duration of the trial (eg, acute systemic infection, cancer, or other serious illnesses).
4. Active liver disease defined as any known current infectious, neoplastic, or metabolic 
pathology of the liver or unexplained ALT, aspartate aminotransferase (AST), 
elevation >2x ULN or total bilirubin elevation >1.5x ULN at Study Entry visit, 
confirmed by a repeat abnormal measurement at least 1 week apart.
5. Females who are pregnant or nursing, or who are of childbearing potential and unwilling 
to use at least two methods of contraception (eg, oral contraceptives, barrier methods, 
approved contraceptive implant, long-term injectable contraception, intrauterine device) 
for the entire duration of the study. Exemptions from this criterion: 
a.
Women >2 years postmenopausal (defined as 1 year or longer since their last menstrual 
period) AND more than 55 years of age
b. Postmenopausal women (as defined above) and less than 55 years old with a negative 
pregnancy test within 24 hours of enrollment
c.
Women who are surgically sterilized at least 3 months prior to enrollment 
6. Males who are unwilling to use an acceptable method of birth control during the entire study 
period (ie, condom with spermicide).
7. Treatment with investigational medicinal products other than inclisiran or devices within 30 
days or five half˗lives, whichever is longer.
8.
Planned use of investigational medicinal products other than inclisiran or devices during the 
course of the study.
9.
Subjects with a history of a serious hypersensitivity reaction to evolocumab or any of the 
excipients.
10. Previous or current treatment (within 90 days of Study Entry) with monoclonal antibodies 
directed towards PCSK9. 
11. Any condition that according to the investigator could interfere with the conduct of the 
study, such as but not limited to:
a.
Inappropriate for this study, including subjects who are unable to communicate or to 
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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. Involved with, or a relative of, someone directly involved in the conduct of the study.
e.
Any known cognitive impairment (eg, Alzheimer Disease).
4.4
Withdrawal Criteria
All subjects have the right to withdraw 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 for any subject study treatment or 
observations were discontinued, the reason will be recorded and the Sponsor should be notified 
promptly. Reasons that a subject may discontinue participation in a clinical study are considered 
to constitute one of the following:

AE

Death

Subject withdrew consent

Physician decision

Lost to follow-up
It is especially important that all subjects be contacted to attend the Day 210 visit, as it is the 
primary endpoint of the study. .Subjects discontinuing participation in this trial should be 
encouraged to complete the EOS visit except for those subjects who specifically withdraw consent. 
All data collected up until the time of subject withdrawal is to be entered into the electronic case 
report form (eCRF).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, the investigator will 
inform the Medical Monitor and the Sponsor immediately. If there is a medical reason for 
withdrawal, the subject will remain under the supervision of the investigator for protocol-
specified safety follow up procedures.  
4.4.2
Individual Subject Dosing Stopping Criteria
Subjects will have clinic visits at regular intervals. The following individual dosing stopping 
criteria will be followed:
1. Dosing with study medication (inclisiran or evolocumab) may be temporarily discontinued 
or stopped for intolerable AEs, 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. Subjects with persistent and unexplained increases in transaminases (ALT or AST) >3x 
ULN or with bilirubin increases >2x ULN from a normal baseline on two consecutive 
occasions at least 4-7 days apart by repeat test must be discontinued from study treatment 


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and asked to complete the remainder of the scheduled visits without receiving study 
medication (inclisiran or evolocumab).
3. Subjects with unexplained creatine kinase (CK) values >5 x ULN confirmed by repeat test, 
for whom the CK elevation is associated with muscle pain, muscle tenderness and/or muscle 
weakness, or new onset renal dysfunction, must be discontinued from study treatment and 
asked to complete the remainder of the scheduled visits without receiving study medication 
(inclisiran or evolocumab).
5
Treatment of Subjects
5.1
Study Medications
Treatments will be assigned based on the treatment the subjects received in Study MDCO-PCS-
15-01, as outlined in Table 5-1.
Table 5-1
Treatment assignments
Study MDCO-PCS-15-01 
(ORION-1)
Study MDCO-PCS-16-01
(ORION-3)
Inclisiran 
Inclisiran sodium 300 mg (equivalent to 284 mg 
inclisiran)/ 1.5 mL
Placebo
Evolocumab 140 mg every 2 weeks, as per the 
prescribing information of the approved therapy, 
until Day 336 or Day 360 (at Day 360, subjects will 
be transitioned to Inclisiran)
5.1.1
Inclisiran (also referred to as KJX839)
Study drug (inclisiran) information is described in Table 5-2.
Table 5-2
Investigational Product
Investigational Product
Product Name
Inclisiran for Injection
Dosage Form:
Solution for Injection
Unit Dose
300 mg (equivalent to 284 mg inclisiran) /1.5 mL 
vial 
Route of Administration
SC use
Physical Description
Clear, colorless to pale yellow solution essentially 
free of particulates
Manufacturer
Alcami Corporation, Charleston, South Carolina, 
USA.
Study drug preparation: The pharmacist or qualified designee will prepare the study drug under 
aseptic conditions to be administered to the subject on that day.
The procedure for preparing study drug is provided in the Pharmacy Manual.
Study drug administration: Subjects will be administered a single SC injection of 300 mg 
(equivalent to 284 mg inclisiran)/ 1.5 mL Inclisiran for Injection at predefined time points as 
described in the Schedule of Assessments (Section 6.1). Study drug injection will be administered 


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by qualified clinical study site staff under the supervision of the investigator or designee. The site 
of injection is the abdomen. Do not inject into areas of active skin disease or injury such as 
sunburns, skin rashes, inflammation, tattoos or skin infections.
If a local reaction around the injection site occurs, photographs of the injection site should be 
obtained, if possible, at first presentation and at each of the follow-up visits until the injection site 
reaction resolves. Detailed instructions for study drug administration are found in the Pharmacy 
Manual.
5.1.2
Comparator Drug (evolocumab)
Evolocumab will be administered as a single SC injection at a dose and frequency as per the label 
of the approved therapy. Training for self administration will be provided by site personnel 
according to the label, and the first dose will be injected under supervision of the Investigator or 
designee. Subjects will be required to self administer evolocumab every 14 days until Day 336. 
For subjects in Transition 2, an additional dose of evolocumab, the final dose, will be administered 
at the Day 360 visit by the investigator and these subjects will also receive their first inclisiran 
injection at the same visit. The investigator (or designee) should use different sites of injection 
when administering these two products (evolocumab and inclisiran) at the same time. Do not 
inject into the same area of the skin.
Evolocumab, a monoclonal antibody directed towards PCSK9, is a sterile, clear to opalescent, 
colorless to pale yellow solution available as a 140 mg/mL solution in a single-use prefilled 
syringe or SureClick® autoinjector. Evolocumab is indicated as an adjunct to diet and maximally 
tolerated statin therapy for the treatment of adults with heterozygous familial 
hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (CVD), who 
require additional lowering of low density lipoprotein cholesterol (LDL-C). The recommended 
subcutaneous dosage of evolocumab in patients with HeFH or patients with primary 
hyperlipidemia with established clinical atherosclerotic CVD is 140 mg every 2 weeks.
5.1.3
Packaging and Labeling
Inclisiran for Injection will be provided by the sponsor. Medication labels will comply with 
regulatory requirements. The storage conditions for each medication provided will be described 
on the medication label.
The Inclisiran for Injection (subcutaneous use) is packaged in a glass vial containing 300 mg 
(equivalent to 284 mg inclisiran) per 1.5 mL. The container closure system consists of a Type I 
glass vial, a Teflon-faced bromobutyl 13 millimeter stopper, and a flip off Truedge aluminum 
seal.
Evolocumab will be provided as prefilled pens, as locally approved.
5.1.4
Storage
Inclisiran for Injection will be stored at room temperature [up to 25°C (77°F)] as specified in the 
Pharmacy Manual. Access should be strictly limited to the investigator, pharmacists, and their 
designees. No special procedures are required for the safe handling of Inclisiran for Injection.
Evolocumab will be used according to its approved label. Evolocumab should be kept in the 
refrigerator and allowed to warm to room temperature for at least 30 minutes before use. 


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Alternatively, evolocumab can be kept at room temperature [up to 25°C (77°F)] in the original 
carton, but under these conditions, it must be used within 30 days.
5.1.5
Accountability
The investigator or designee must maintain an inventory record of study drugs received and 
administered to assure the regulatory authorities and the Sponsor that the investigational new drug 
will not be dispensed to any person who is not a subject under the terms and conditions set forth 
in this protocol. Drug accountability forms and/or specific instructions can be found in the 
Pharmacy and Comparator Manuals.
The study drug supplied for use in this study is to be prescribed only by the principal investigator 
or designated subinvestigators and may not be used for any purpose other than that outlined in 
this protocol.
During the study, all used study drug containers (eg, empty vials/bottles) will be kept until the 
monitor has reviewed the accountability records.
All unused study drug will be destroyed on site (or returned to the packaging and labeling facility 
for destruction if destruction on site is not possible) once the study drug has been inventoried and 
the monitor has reviewed the accountability records. In the event that study drug(s) needs to be 
returned for any other reason, the site will receive a written request listing the drug lot number(s) 
to be returned and the reason for the return request.
5.1.6
Product Deficiencies Reporting
Sites are required to report any product deficiency observed for the study medications (inclisiran) 
to sponsor immediately but no later than 24 hours from the time of awareness.
In addition, any product deficiency observed for inclisiran,is required to be recorded in the eCRF.
In case the drug deficiency is leading to an Adverse Event or Serious Adverse Event these have 
to be recorded and reported as specified in Section 8, Section 4, Section 2 and relationship to the 
drug deficiency must be indicated.
Product Deficiencies reporting: 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 Complaints: A report of dissatisfaction with the product with regard to its 
efficacy, strength, integrity, purity, or quality; thus a potential failure to meet product 
specifications. Examples include: 

An indication that there is an unexpected physical change in the drug product such as 
discoloration, change in shape of the drug product, presence of particulates or any other 
physical change that might indicate contamination, a manufacturing defect or any other 
event that might indicate a compromise in product quality. 

An indication that the content does not meet its labeled volume, count, etc. 

An indication that there is an unexpected physical change in any part of the container (this 
includes the bottle, any part of the seal, the cap or the label). 

An indication that the product is mislabeled. 


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
An indication that there is an unexpected physical change of the product or container once 
the product is diluted or reconstituted (the container includes the unit dose, bag, intravenous 
line, syringe or any other item that is in contact with the product). 

An indication that the product is falsified, tampered with, or adulterated. 

An indication that the product did not meet its pharmacologic effect, ie, lack of efficacy. 
5.2
Concomitant Medications
5.2.1
Prohibited Concomitant Medications
Background lipid-lowering treatment should remain stable throughout the study duration. As a 
result, the following medications/treatments are not permitted to be added or changed during the 
study:

Medications prescribed to lower LDL-C (eg, statins, ezetimibe, lomitapide, mipomersen, 
niacin, colesevelam, bile acid absorption inhibitors, monoclonal antibodies directed towards 
PCSK9 (with the exception of evolocumab for Group 2 during the first year). 

Any medication taken for the purpose of lipid lowering, including over-the-counter or 
herbal therapies.

Any other investigational medicinal product(s) other than inclisiran during the course of the 
study.
5.2.2
Permitted Concomitant Medications
The following medications/treatments are permitted during the study:

Hormone replacement therapy 

Lipid-lowering medications; subjects already on lipid-lowering medications (such as statins 
and/or ezetimibe) should remain on the dose that they have received at time of study entry.

Prescription medications prescribed to treat preexisting medical conditions such as diabetes 
and hypertension

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 study drug administration must be discontinued and 
the pregnancy should be followed through to outcome. The pregnancy should be followed up to 
determine outcome, including spontaneous or voluntary termination, details of the birth, and the 
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complications. Newborns should be followed for 12 months.  Reporting of pregnancy and any 
associated AEs are specified in Section 8.3.4.
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
Not applicable, this is an open-label study.
6
SCHEDULE and Sequence of Procedures
The Schedule of Events/Assessments (Table 6-1 and Table 6-2) summarizes the study 
assessments by time point. 
This study consists of three study periods:

Observation Period: Consent/Study Entry until first dose on Day 1 (ORION-3)

Treatment Period: Day 1 (ORION-3) to Day 360
-
Group 1 (inclisiran only arm)
-
Group 2 (evolocumab treatment; switching arm)

Follow-up Treatment Period: Day 360 to EOS
-
all subjects on inclisiran
The expected duration of the subjects’ involvement in the study will be approximately 4 years, 
which includes consent, study drug administration, and follow-up through the EOS visit (final 
visit which occurs 90 days following the final administration of study drug, or at least 30 days 
following the final administration of study drug if the study ends early or if the subject 
discontinues the study early).
At each visit, LDL-C levels, AEs, SAEs, concomitant medications, vital signs, and safety 
laboratory assessments will be collected.
6.1
Schedule of Events/Assessments
If the COVID-19 pandemic limits or prevents on-site study visits, alternative methods of 
providing continuing care may be implemented. Phone calls or remote/virtual contacts (e.g. 
teleconsult) can replace on-site study visits, for the duration of the pandemic until it is safe for 
the participant to visit the site again.  Also, the visits window has been extended to +/-2 months 
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Table 6-1
Study Design and Schedule of Assessments (Group 1; Inclisiran Only Arm)
Stud
y 
Entry
m
Obser-
vation 
Visits a
First 
Dose
q
Treatment & Follow-Up
(first 2 years) f
FU Visits 
(dosing) f
FU Visits 
(regular) f
EO
Sp
Study Day  
every 
30 
days
(± 7)
Day 1
FU1
30
(± 
2)
FU2
90
(± 
7)
FU3
180
(± 7)
FU4
210
(± 
7)
FU5
270
(± 
7)
FU6
360
(± 7)
FU7
390
(± 
7)
FU8
450
(± 
7)
FU9
540
(± 
7)
FU10
570
(± 7)
FU1
1
630
(± 7)
FU1
2
720
(± 7)
FU13, 810
FU15, 990
FU17, 
1170
FU19, 
1350
FU14, 870
FU16, 
1080
FU18, 
1260
*COVID 19 visit window 
(months)
(± 2)
(± 2)
(± 2)
Informed consent
X
Inclusion / Exclusion Criteria
X
Physical Examination (including 
full neurological examination & 
weight)
X
X
X
X(D1080) e
X
Vital Signs b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12 Lead ECGc
X
X
X
X(D1080) e
X
HbA1c n and serum glucose
X
X
X
X
X (D810 
and 1350)
X (D1080)
X
Hematology d
X
X
X
X
X
X (D1080)
X
Coagulation d
X
X
X
X 
(S)
X 
(S)
X 
(S)
X 
(S)
X
X 
(S)
X 
(S)
X (S)
X
X (S)
X (S) / X 
(D1080)
X
Full Chemistry d
X
X
X
X
X
X (D1080)
X
Limited Chemistry
X
X
X
X
X
X
X
X
X
X
X (D 870, 
1260)
Urinalysis (local) g
X
X
X g
X
X
X
X
X
X
X
X
X 
X 
X 
Pregnancy test (local)  i
X
X
X h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Stored samples k
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Efficacy parameters 
(LDL-C, lipids, PCSK9) l
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Protocol No. MDCO-PCS-16-01 (CKJX839A12201E1)
Stud
y 
Entry
m
Obser-
vation 
Visits a
First 
Dose
q
Treatment & Follow-Up
(first 2 years) f
FU Visits 
(dosing) f
FU Visits 
(regular) f
EO
Sp
Study Day  
every 
30 
days
(± 7)
Day 1
FU1
30
(± 
2)
FU2
90
(± 
7)
FU3
180
(± 7)
FU4
210
(± 
7)
FU5
270
(± 
7)
FU6
360
(± 7)
FU7
390
(± 
7)
FU8
450
(± 
7)
FU9
540
(± 
7)
FU10
570
(± 7)
FU1
1
630
(± 7)
FU1
2
720
(± 7)
FU13, 810
FU15, 990
FU17, 
1170
FU19, 
1350
FU14, 870
FU16, 
1080
FU18, 
1260
*COVID 19 visit window 
(months)
(± 2)
(± 2)
(± 2)
Lipoproteins l
[Lp(a), ApoB]
X
X
X
X
X
X
X
X
Study drug administration: 
     inclisiran 
Xo,q
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE/SAE reporting
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Product  deficiencies (including 
AE/SAEs related to the drug or 
device deficiency
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 AE = adverse event; ECG = electrocardiogram; FU=follow-up; EOS = end of study; HbA1c= glycated hemoglobin 
A1C; hsCRP=high sensitivity C-reactive protein; IL6=interleukin 6; IFN-γ=interferon gamma; LDL-C = low-density lipoprotein cholesterol; PCSK9 = proprotein 
convertase subtilisin/kexin type 9; S = Stored sample; SAE = serious adverse event; TNF-α=tumor necrosis factor alpha.
*: The visit window is extended to +/- 2 months (in addition to existing visit window) during the COVID-19 pandemic, to allow on-site visits (rather than remote 
visits) to occur as much as possible. a Observation visits every 30 days (±7 days) until study drug is available. 
b Vital signs: blood pressure and heart rate will be measured prior to injection. On Day 1 (vital signs will also be measured at 4 hours after injection).
c ECG should be performed prior to the injection.
d Hematology, chemistry (including glucose, liver and renal function, hsCRP, IL6, IFN-γ, and TNF-α), and coagulation testing (of which some will be collected and 
stored for future analyses).. Blood samples for determination of laboratory values will be performed prior to study drug injection. All laboratory testing will be 
performed with subjects in a fasted state. See Section 7.1.6 for a list of laboratory parameters. Lab tests performed by study’s designated Central Lab facility from 
entry into the study to EOS. On days when inclisiran is injected, if indicated, the investigator will need to collect a blood sample for tryptase within 30 minutes of the 
onset of anaphylaxis (or as soon as logistically possible). 
e Physical and neurological  examinations, weight, and ECG performed once yearly.
f Visit windows are ± 2 days for the Day 30 visit, and ± 7 days from Day 90 onwards.
g Urinalysis collection is prior to the injection on Day 1; supplies from the Central Lab must be used to perform the urinalysis.
h Urine pregnancy test performed and results available prior to the injection on Day 1; supplies from the Central Lab must be used to perform the test. 


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Amended Protocol Version No.05 Clean
Protocol No. MDCO-PCS-16-01 (CKJX839A12201E1)
i Women of childbearing potential will have a pregnancy test at each visit.
 
k Plasma glucose and lactate will be collected at intervals throughout the study and stored for future analyses. See Section 7.1.8 for details. Additional blood 
samples will be collected every 180 days and aliquots of plasma and serum stored for future analyses.
l Efficacy parameters will include LDL-C, total cholesterol, triglycerides, HDL-C, non-HDL-C, very low-density lipoprotein (VLDL-C), C-reactive protein (CRP), and 
PCSK9. A standard lipid panel will be done at all visits (Day 1 to EOS) however some PCSK9 samples will be stored for future analyses and ultracentrifugation is 
to be done only at Day 1, Day 210, Day 360, Day 570, Day 720 and EOS.
m Until study drug is available, subjects will attend a basic observation visit at 30 day intervals. These visits will include safety labs (hematology, chemistry, 
coagulation) and recording of AEs, SAEs, and concomitant medications.
n  HbA1c assessed every 270 days. Therefore, HbA1C to be assess at follow-up visits on Days 270, 540, 810, 1080, and 1350.
o  Subjects will be observed in the clinic for at least 4 hours post their first inclisiran injection before being discharged (Day 1 for subjects in Group 1; inclisiran only 
arm)
p EOS will occur 90 days following the final administration of study drug. However, if the study ends early or if the subject discontinues the study, the EOS visit 
should occur at least 30 days following the final administration of study drug.
q There should be a minimum of 7 days between Study Entry or last observation visit and Day 1.




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Amended Protocol Version No.05 Clean
Protocol No. MDCO-PCS-16-01 (CKJX839A12201E1)
Study 
Entryo
Obser-
vation 
Visits a
First 
Doset
Treatment & Follow-Up
(first 2 years) f
FU 
Visits 
(dosing) 
f
FU Visits 
(regular) f
EOSs
Study Day  
every 
30 
days
(± 7)
Day 
1
FU1
30
(± 
2)
FU2
90
(± 
7)
FU3
180
(± 
7)
FU4
210
(± 
7)
FU5
270
(± 
7)
FU6
360
(± 
7)
FU7
390
(± 
7)
FU8
450
(± 
7)
FU9
510
(± 
7)
FU10
540
(± 7)
FU11
630
(± 7)
FU12
720
(± 7)
FU13, 
810
FU15, 
990
FU17, 
1170
FU19, 
1350
FU14, 
900
FU16, 
1080
FU18, 
1260
*COVID 19 
visit window 
(months)
(± 2)
(± 2)
(± 2)
HbA1c q and 
serum glucose
X
X
X
X
X 
(D810 
and 
1350)
X 
(D1080)
X
Hematology d
X
X
X
X
X
X 
(D1080)
X
Coagulation d
X
X
X
X 
(S)
X 
(S)
X 
(S)
X 
(S)
X
X 
(S)
X 
(S)
X (S)
X
X (S)
X (S) / X 
(D1080)
X
Full Chemistry
d
X
X
X
X
X
X 
(D1080)
X
Limited 
Chemistry
X
X
X
X
X
X
X
X
X
X
X (D 900, 
1260)
Urinalysis 
(local) g
X
X
X g
X
X
X
X
X
X
X
X
X 
X 
X 
Pregnancy
test (local)  i
X
X
X h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Amended Protocol Version No.05 Clean
Protocol No. MDCO-PCS-16-01 (CKJX839A12201E1)
Study 
Entryo
Obser-
vation 
Visits a
First 
Doset
Treatment & Follow-Up
(first 2 years) f
FU 
Visits 
(dosing) 
f
FU Visits 
(regular) f
EOSs
Study Day  
every 
30 
days
(± 7)
Day 
1
FU1
30
(± 
2)
FU2
90
(± 
7)
FU3
180
(± 
7)
FU4
210
(± 
7)
FU5
270
(± 
7)
FU6
360
(± 
7)
FU7
390
(± 
7)
FU8
450
(± 
7)
FU9
510
(± 
7)
FU10
540
(± 7)
FU11
630
(± 7)
FU12
720
(± 7)
FU13, 
810
FU15, 
990
FU17, 
1170
FU19, 
1350
FU14, 
900
FU16, 
1080
FU18, 
1260
*COVID 19 
visit window 
(months)
(± 2)
(± 2)
(± 2)
Stored 
samples k
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Efficacy 
parameters 
(LDL-C, lipids, 
PCSK9) m
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lipoproteins m
[Lp(a), ApoB]
X
X
X
X
X
X
X
X
Study drug 
administration: 
     
evolocumab l,n
Xt
Every 14 days through Day 336   X p
    Inclisiran
Xr
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE/SAE 
reporting
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 AE = adverse event; ECG = electrocardiogram; FU=follow-up; EOS = end of study; HbA1c= glycated hemoglobin A1C; hsCRP=high 
sensitivity C-reactive protein; IL6=interleukin 6; IFN-γ=interferon gamma; LDL-C = low-density lipoprotein cholesterol; PCSK9 = proprotein convertase 
subtilisin/kexin type 9; S = Stored sample; SAE = serious adverse event; TNF-α=tumor necrosis factor alpha.


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Amended Protocol Version No.05 Clean
Protocol No. MDCO-PCS-16-01 (CKJX839A12201E1)
*: The visit window is extended to +/- 2 months (in addition to existing visit window) during the COVID-19 pandemic, to allow on-site visits (rather than remote 
visits) to occur as much as possible.
a Observation visits every 30 days (±7 days) until study drug is available. 
b Vital signs: blood pressure and heart rate will be measured prior to injection. On Day 360 (transition visit), vital signs will also be measured at 4 hours after 
injection.
c ECG should be performed prior to the injection.
d Hematology, chemistry (including glucose, liver and renal function, hsCRP, IL6, IFN-γ, and TNF-α), and coagulation testing (of which some will be collected and 
stored for future analyses). Blood samples for determination of laboratory values will be performed prior to study drug injection. All laboratory testing will be 
performed with subjects in a fasted state. See Section 7.1.6 for a list of laboratory parameters. Lab tests performed by study’s designated Central Lab facility from 
entry into the study to EOS. On days when inclisiran is injected, if indicated, the investigator will need to collect a blood sample for tryptase within 30 minutes of the 
onset of anaphylaxis (or as soon as logistically possible). 
e Physical and neurological  examinations, weight, and ECG performed once yearly.
f Visit windows are ± 2 days for the Day 30 visit, and ± 7 days from Day 90 onward.
g Urinalysis collection is prior to the injection on Day 1; supplies from the Central Lab must be used to perform the urinalysis.
h Urine pregnancy test performed and results available prior to the injection on Day 1; supplies from the Central Lab must be used to perform the test. 
i Women of childbearing potential will have a pregnancy test at each visit.
 
k Plasma glucose and lactate will be collected at intervals throughout the study and stored for future analyses. See Section 7.1.8 for details. Additional blood 
samples will be collected every 180 days and aliquots of plasma and serum stored for future analyses.
l  Diary cards should be turned in to study site coordinator at follow-up visits on Day 30, 90, 180, 270 and 360.
m Efficacy parameters will include LDL-C, total cholesterol, triglycerides, HDL-C, non-HDL-C, very low-density lipoprotein (VLDL-C), C-reactive protein (CRP), and 
PCSK9.  A standard lipid panel will be done at all visits (Day 1 to EOS) however some PCSK9 samples will be stored for future analyses and ultracentrifugation is 
to be done only at Day 1, Day 210, Day 360, Day 510, Day 720 and EOS.
n Day 1 in clinic; Days 14 through 336 to be self-injected according to label; for subjects in Transition 2; at Visit Day 360 in the clinic.
o Until study drug is available, subjects will attend a basic observation visit at 30 day intervals. These visits will include safety labs (hematology, chemistry, 
coagulation) and recording of AEs, SAEs, and concomitant medications.
p Only subjects in Transition 2 will receive a final dose of evolocumab at Visit Day 360 with the first dose of inclisiran.
q  HbA1c assessed every 270 days. Therefore, HbA1C to be assess at follow-up visits on Days 270, 540, 810, 1080, and 1350.
r Subjects will be observed in the clinic for at least 4 hours post their first inclisiran injection before being discharged 
s EOS will occur 90 days following the final administration of study drug. However, if the study ends early or if the subject discontinues the study, the EOS visit 
should occur at least 30 days following the final administration of study drug.
t There should be a minimum of 7 days between Study Entry or last observation visit and Day 1.


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Protocol No. MDCO-PCS16-01(CKJX839A12201E1)
6.2
General Conduct of the Study
On completion of study MDCO-PCS-15-01 (ORION-1), eligible subjects will be consented for 
this 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. 
In countries where applicable, on signing consent and being entered into this study, the investigator 
will be informed by the IXRS regarding the treatment allocation, and therefore, whether placebo 
or inclisiran was administered in study MDCO-PCS-15-01 and the subject will be informed 
accordingly.
Until study drug is available subjects will attend a basic visit for safety and concomitant 
medications at 30 day intervals. Once study drug is available, eligible subjects will receive a single 
injection of study drug on Day 1 (ORION-3).
Note: Data on medical history and concomitant medications will be reported from Baseline of 
ORION-1. Details will be described in the Statistical Analysis Plan (SAP).
6.3
Study Entry

Sign Informed Consent

Assessment of inclusion/exclusion criteria

Vital signs: blood pressure and heart rate will be measured prior to injection

Central laboratory assessments (hematology, chemistry [including HbA1c], and coagulation) 

Urinalysis (local, using supplies provided)

Pregnancy test (local, using supplies provided)

Collection of additional blood samples

Assessment of lipids/lipoproteins

Concomitant medications recording

AE/SAE collection
Entry into the study should only occur once subject eligibility is confirmed.
6.4
Observation Visit(s)
Until study drug is available subjects will attend a basic visit at 30 day intervals (±7 days), where 
the following procedures will be performed: 

Central laboratory assessments (hematology, chemistry, coagulation and lipids)

Urinalysis (local, using supplies provided)

Pregnancy test (local, using supplies provided)

Assessment of lipids/lipoproteins

Concomitant medications recording 

AE/SAE collection
Once study drug is available, eligible subjects will receive study drug on Day 1 (ORION-3).


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Amended Protocol Version No. 05 Clean
Protocol No. MDCO-PCS16-01(CKJX839A12201E1)
6.5
Day 1 of ORION-3
The following procedures will be performed prior to the injection:

Vital signs: blood pressure and heart rate will be measured prior to injection 

12-lead ECG

Central laboratory assessments (hematology, chemistry [including HbA1c], and coagulation)

Physical examination including full neurological examination (see APPENDICX A)

Urinalysis (local, using supplies provided)

Pregnancy test (local, using supplies provided); results must be available prior to dosing

Assessment of lipids/lipoproteins

Concomitant medications

AE/SAE collection
Study drug administration will occur at this visit for all subjects. Inclisiran will be given by the 
investigator. Subjects receiving evolocumab will receive training in self-injection technique and 
the first injection will be supervised by the investigator or designee.
After first study drug administration of inclisiran only, subjects will be observed in the clinic for 
at least 4 hours post injection before being discharged. The following procedures will be performed 
4 hours after the injection, only for those subjects receiving inclisiran:

Vital signs: blood pressure and heart rate

Concomitant medications

AE/SAE collection
6.6
Treatment and Follow-Up Visits
All subjects will return to the study center 30 days (± 2 days) after first study drug administration 
for Follow-Up Visit 1 and after 90 days (± 7 days) for Follow-Up Visit 2.
Group 1 (inclisiran only arm) subjects will return at Day 180 (± 7 days) for their second study 
drug administration of inclisiran, and then at 30 and 90 days after each subsequent study drug 
administration of inclisiran.

Dosing visits will take place on Days 180, 360, 540, 720, 810, 990, 1170 and 1350.

Safety follow-up visits will occur on Days 30, 90, 210, 270, 390, 450, 570, 630, 870, 1080, 
1260, and EOS (Day 1440).
Group 2 (switching arm) subjects will return to the study center at Days 180, 210, 270 for study 
related procedures. At Day 360 visit, subjects in Group 2 (switching arm) are assigned to either 
Transition 1 (staged) or Transition 2 (concurrent) (see Section 3.1).
Study drug administration of inclisiran and safety follow-up visits for both Transition 1 (staged) 
and Transition 2 (concurrent) will occur as follows:

Dosing visits will take place on Day 360 (first dose of inclisiran), Day 450, Day 630, 810, 
990, 1170, and 1350.




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Protocol No. MDCO-PCS16-01(CKJX839A12201E1)

AE/SAE collection

Study drug administration

First dose of inclisiran

For subjects in Transition 2, their first inclisiran administration should occur prior to the 
final administration of evolocumab (to be given up to 30 minutes after inclisiran 
administration using a separate injection site)
The following procedures will be performed 4 hours after the first inclisiran injection: 

Vital signs: blood pressure and heart rate 

Concomitant medications

AE/SAE collection 
6.6.2
Treatment & Follow Up Visits After Day 360
Refer to Section 6.6 for the schedule of follow-up visits and the assessments to be completed 
following the Day 360 transition visit to inclisiran.
6.7
Unscheduled Visit
If deemed necessary by the Investigator, subjects may attend an unscheduled visit at the clinic. 
These visits are not part of the protocol per se and will not be recorded in the eCRF but should be 
noted in the subject’s medical notes.
6.8
End of Study Visit
Subjects will receive study drug for approximately 4 years (or until the investigator's 
recommendation of discontinuation, sponsor's recommendation of discontinuation, the subject's 
decision to discontinue for any reason, or until an administrative decision is made to end the study). 
Regardless of treatment arm (inclisiran or evolocumab), the EOS visit will be the final safety 
follow-up visit which occurs 90 days (at Day 1440) following the final administration of study 
drug. However, if the study ends early or if the subject discontinues the study, the EOS visit should 
occur at least 30 days following the final administration of study drug.
If subjects, who have completed the EOS (90 days after last dosing), wish to continue treatment 
with inclisiran (and no decision or recommendation was made to discontinue the trial) they will be 
given the opportunity to enroll into ORION-8 (open-label extension trial) 
A subject’s participation in the study is complete when:

All ongoing SAEs have been followed to resolution or stabilization (Section 5.3.1) and 

The following procedures/assessments have been completed: 
-
Vital signs: blood pressure and heart rate 
-
Physical examination (including weight and full neurological examination as described in 
(APPENDICX A)
-
12-lead ECG
-
Central laboratory assessments (hematology, chemistry and coagulation testing)
-
Urinalysis (local, using supplies provided)










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Amended Protocol Version No. 05 Clean
Protocol No. MDCO-PCS16-01(CKJX839A12201E1)
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, an MI that may be considered minor could also be an SAE if it 
prolonged hospitalization.
8.1.3
Special Situations Events
Information that is not necessarily considered an adverse event but which can possibly contribute 
to the overall knowledge concerning the safety of the compound will be considered a special 
situation event (Section 8.2.4).
8.2
EVALUATING 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 are not to be reported as AEs.
8.2.2
AE Severity
The severity of every AE must be assessed by the investigator using a three-point grading system.
1 = Mild: Discomfort noticed, but no disruption to daily activity. Requires minimal or no treatment.
2 = Moderate: Discomfort sufficient to reduce or affect normal daily activity. Requires therapeutic 
measures.
3 = Severe: Inability to work or perform normal daily activity. May require systemic drug therapy 
or other treatment.
8.2.3
Relationship to Study Drug
The relationship of an AE to study treatment will be assessed by using a binary assessment. The 
investigator should determine whether there is a ‘Reasonable possibility’ or ‘No reasonable 
possibility’ that the study product caused the event based on the definitions below.
Reasonable possibility - There is a reasonable possibility that the administration of the study 
product caused the AE. There is evidence to suggest a causal relationship between the study 
product and the AE. 
No reasonable possibility - There is no reasonable possibility that the administration of the study 
product caused the AE. There is no temporal relationship between the study product and event 
onset, or an alternative etiology has been established.
8.2.4
Requirements for Additional Safety Data Collection
8.2.4.1
Special Situations
Special Situations designated for this study are the following:

Medication errors that fall into the following categories:


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Amended Protocol Version No. 05 Clean
Protocol No. MDCO-PCS16-01(CKJX839A12201E1)

wrong subject (ie, not administered to the intended patient)/wrong study product 
(inclisiran vs evolocumab)

wrong dose (including overdose, underdose, change in dosing regimen, strength, form, 
concentration, amount);

wrong route of administration

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 
8.2.4.2
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 requires collection, evaluation and reporting safety 
information in this study are:

Abnormal neurological examination, eg, peripheral sensory and motor evaluation, an 
assessment of gait, pain, position, strength and reflexes (APPENDICX A).

Potential anaphylactic reactions assessed by Sampson criteria (APPENDIX B). If Sampson 
criteria are positive, confirm by elevation of tryptase in blood plasma measured within 
30 minutes of symptoms.
Hyperglycemia-related AEs and medications initiated to control hyperglycemia will be collected 
at each follow-up visit. New onset of diabetes in subjects with no medical history of diabetes will 
be reported when:

HbA1C becomes ≥6.5% and/or

Two consecutive values of fasting plasma glucose that are ≥126 mg/dL
In the case that a new concomitant medication is added for control of plasma glucose, further 
information regarding the subject will be collected to assess for a diagnosis of new onset diabetes.
Report ‘Worsening of the glycemic control’ or ‘diabetic complications’ in subjects with a medical 
history of disease (HbA1C ≥6.5% at baseline) when:

HbA1C increases from Baseline (Day 1 of ORION-3) >0.5% and/or

New concomitant medication or increase in dose of current antidiabetic therapy is initiated to 
improve the control of plasma glucose level.
8.3
PROCEDURE FOR ADVERSE EVENT REPORTING
8.3.1
Serious Adverse Event Reporting
All SAEs that occur in subjects between Study Entry and Day 1, as well as in subjects assigned to 
inclisiran or evolocumab treatment from study Day 1 through the EOS visit must be reported to 


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the Sponsor’s Global Pharmacovigilance Department (GPV) within 24 hours of awareness of the 
event using the SAE/AESI Report Form designated to the ORION-3 study.
The completion and processing of the SAE/AESI Report Form should be per the instructions in 
the provided SAE/AESI Report Form completion guidelines. Each SAE/AESI must be recorded 
on the sources documents and entered on the appropriate page of the eCRF.
The investigator should provide any follow-up information for the event to the Sponsor on an 
updated SAE/AESI 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.
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.
8.3.2
Nonserious Adverse Event Recording
All nonserious AEs that occur in subjects between Study Entry and Day 1, as well as in subjects 
assigned to inclisiran or evolocumab treatment from study Day 1 up to EOS must be assessed and 
recorded on the source documents and eCRFs, regardless of causal relationship to the study drug.
8.3.3
Medication Error Reporting
Medication errors (with or without an associated AE) need to be recorded as medication errors in 
the eCRF.
Medication errors and an associated SAE need to be recorded in the eCRF and reported to the 
Novartis Safety department using SAE/SS Report Form as described in Section 8.3.1.
Medication errors and an associated nonserious AE need to be recorded in the eCRF as described 
in Section 8.3.2.
A mis-dosing protocol deviation (refer to Section 12.3) would need to be reported as a medication 
error if it was an “unintended error” as defined in Section 8.3.1.
8.3.4
Pregnancy Reporting
Occurrences of pregnancy in a study subject or study subject’s partner from study Day 1 through 
the EOS visit must be reported within 24 hours using the Pregnancy/Lactation Exposure Report 
Form.
In cases where a pregnancy occurs with a SAE, the SAE Report Form must be used to report the 
SAE and the Pregnancy Report Form must be used to report the pregnancy. When a pregnancy 
occurs without any concurrent SAE, the Pregnancy Report Form should be submitted alone. 
The pregnancy should be followed up to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. Newborns should be followed for 12 
months.


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8.3.5
Reporting the Special Situations Events
The occurrence of the special situation events that are listed in Section 8.2.4 must be reported to 
the Novartis safety department using SAE/SS Report Form for the ORION-3 study. The SAE/SS 
Report Form should indicate that the reported event is the event of Special Situation.
The Special Situation events do not need to be serious to be reported.
8.4
Study Stopping Criteria
8.4.1
Data Monitoring Committee Stopping Rules
The DMC will use all available evidence and its collective judgment in making a recommendation 
to stop or modify the ORION-3 study for safety. Any statistical considerations are not a substitute 
for the committee’s medical, scientific, or statistical expertise.
8.4.2
Sponsor Discontinuation Stopping Criteria
The Sponsor will review data on an ongoing basis and may, on discussion with the DMC, 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 Sponsor . In addition, 
Sponsor retains the right to discontinue development of inclisiran at any time.
If a study is prematurely terminated or discontinued, Sponsor will promptly notify the investigator. 
After notification, the investigator must contact all participating subjects and the hospital 
pharmacy (if applicable) within 30 days of the notification. Final study visits should occur within 
30 days of subject contact. As directed by Sponsor , all study materials must be collected and all 
care report forms (CRFs) completed to the greatest extent possible.
The Sponsor will inform the health authorities and the IRBs/EC that the study has been stopped 
and the reasons for doing so, within the locally applicable timelines.
9
Data Collection
An electronic data capture (EDC) system 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 MDCO and documented in the site files.
This study will utilize the same EDC system used in the ORION-1 study to collect the data defined 
by this protocol, 
. Data already collected for medical history, 
ongoing concomitant medications, and ongoing adverse events will be retained and utilized in
analysis as defined by the SAP.
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 


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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 End of Study will be defined as the last visit of the last subject.
10
Statistical Plan
This study will be an open label, long term extension study with an active comparator 
(evolocumab), in approximately 490 subjects who have completed study MDCO-PCS-15-01 
(CKJX839A12201) (ORION-1), to evaluate the efficacy, safety, and tolerability of long-term 
Inclisiran injections.  The primary objective of this study is to evaluate the effect of inclisiran 
treatment on LDL-C levels at Day 210 compared to Baseline of ORION-1 in Group 1 (inclisiran 
only arm). A separate SAP document will provide more detailed specifications in data analysis 
and presentation.
10.1
Sample Size
This is an extension of the MDCO-PCS-15-01 (CKJX839A12201) (ORION-1) study. All eligible 
and willing subjects who have completed the ORION-1 study to at least Day 210 and whose     
LDL-C has returned to within 20% of the Baseline of ORION-1 value or who have reached Day 
360 can be enrolled into the ORION-3 study. Subjects withdrawn from the ORION-1 study at any 
time are not eligible for the ORION-3 study.
10.2
General Statistical Considerations and Definitions
10.2.1
General Statistical Methods
All study-collected data will be summarized by treatment group using descriptive statistics, graphs, 
and/or raw data listings. Categorical variables will be summarized using counts and percentages. 
Percentages are based on the number of subjects in the analysis set for whom there are nonmissing 
data, unless otherwise specified. Continuous variables, including changes from Baseline of 
ORION-1 or changes from Baseline (Day 1 of ORION-3), will be summarized using descriptive 
statistics (n, mean, standard deviation [SD], median and interquartile range [first and third 
quartiles], minimum and maximum).
A SAP will be written after finalizing of the eCRF and before database lock. The specifications in 
this document will detail the implementation of all the planned statistical analyses in accordance 
with the principal features stated in the protocol.
Note: Data on medical history and concomitant medications will be reported from Baseline of 
ORION-1. Details will be described in the Statistical Analysis Plan (SAP).
Statistical analyses will be carried out using SAS® statistical analysis software version 9.2 or 
higher (SAS® Institute, Inc., Cary, North Carolina, USA).
10.2.2
Analysis Population
The following populations will be used for data analyses and/or presentation.


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10.2.2.1 Intent-to-Treat (ITT) Population
The ITT Population will include all subjects who entered into the study. Treatment classification 
will be based on the allocated treatment.
10.2.2.2 Modified Intent-to-Treat (mITT) Population
The mITT Population will include all subjects who receive at least one dose of study drug and 
have both the Baseline (Day 1 of ORION-3) and the Day 210 follow-up LDL-C assessment. 
Treatment classification will be based on the allocated treatment. This will be the primary 
population for analysis of the primary and secondary endpoints.
10.2.2.3 Safety Population
The Safety Population will include all subjects who received at least one dose of study drug. 
Treatment classification will be based on the actual treatment received. This will be primary 
population for the safety analyses.
10.2.3
Analysis Windows and Day 1
Data analysis windows and definitions of Baseline will be provided in the SAP.
10.2.4
Missing Data Handling
Unless otherwise specified, missing data will not be imputed and will be excluded from the 
associated analysis.
10.3
Statistical Analyses
10.3.1
Demographic and Background Characteristics
Subject demographics and baseline characteristics will be summarized by treatment group using 
the ITT, mITT, and Safety Populations.
10.3.2
Study Drug and Concomitant Medications
Study drug administration will be summarized by treatment group (including actual dose received 
by visits, and missed doses). Summaries of each prior medication, Baseline (Day 1 of ORION-3) 
concomitant, and new or changed medications will be provided by treatment. Separate summaries 
will be provided for prior medication use. Medications will be coded using the WHO drug 
dictionary. Subjects will be counted only once within each period by medication.
10.3.3
Efficacy Analysis
10.3.3.1 Primary Efficacy Endpoint (Inclisiran Only Arm)
The primary efficacy endpoint is the percentage change from Baseline of ORION-1 in LDL-C at 
Day 210 in this study (Group 1; inclisiran only arm).
Descriptive summaries and confidence intervals will be provided.




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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.
10.3.4.3 Vital Signs
Change and percent change from Baseline (Day 1 of ORION-3) in vital signs will be summarized 
descriptively at each scheduled time point by treatment group.
10.3.4.4 Neurological Examinations
The percentage of subjects with a treatment-emergent abnormal neurological examination and the 
specific abnormality reported will be summarized by treatment group. Any neurological 
AEs/SAEs that occur prior to dosing under this extension study will be evaluated as part of the 
ORION-1 safety assessment.
11
Records Retention
US Food and Drug Administration (FDA) regulations require all investigators participating in 
clinical drug trials to maintain detailed clinical data for one of the following periods:

At least 2 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 European Union (EU) Directives/Regulations and International Conference on 
Harmonisation (ICH) guidelines collectively require that essential clinical trial documents 
(including CRFs) 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 2 years after the last approval of a marketing application in an ICH region and until there 
are no pending or contemplated marketing applications in an ICH region

Or at least 2 years have elapsed since the formal discontinuation of clinical development of 
the investigational product
Investigators shall retain the documents for a longer period, where so required by applicable local 
requirements.
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 any data clarification forms (DCFs) received from the Sponsor. Such 
documentation is subject to inspection by the Sponsor or its agents, the FDA and/or other 
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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, 
drug supply, presence of required documents, the informed consent process, and comparison of 
eCRFs with source documents. The investigator agrees to permit audits conducted at a reasonable 
time in a reasonable manner.
Regulatory authorities worldwide may also inspect the investigator during or after the study. The 
investigator should contact the Sponsor immediately if this occurs, and must permit regulatory 
authority inspections.
12.3
Protocol Deviations
Deviations from the protocol identified during the conduct of the trial will be recorded in the e-
CRF and will be reviewed periodically:

Missing lipid and/or PCSK9 assessments at Day 1 and/or Day 210

Inclusion criteria violation

Exclusion criteria violation. 

Subject taking any prohibited concomitant medication

Missing an inclisiran dose or a dose delayed by more than 30 days
Additional protocol deviations and associated actions depending on the nature and impact of the 
protocol deviation will be defined and periodically reviewed by standard automated and/or manual 
checks by the clinical team or monitors.
13
Ethics and Responsibility
This study will be conducted in compliance with the protocol, the Sponsor’s standard operating 
procedures and/or guidelines, the FDA regulations, the ICH GCP guidelines, the Declaration of 
Helsinki and other local regulations, as applicable.


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13.1
Informed Consent
Written informed consent will be obtained from all subjects before any study-related procedures 
(including any pretreatment procedures) are performed. The investigator(s) has both ethical and 
legal responsibility to ensure that each subject 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 
(ICF), which shall be approved by the same IRB or EC responsible for approval of this protocol. 
Each ICF 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 ICF 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 ICF. The subject shall be given a copy of the signed ICF, 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 ICF 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 ICF were 
discussed. The investigator will not participate in the decision. If the investigator is an IRB or EC 
member, the written approval must indicate such nonparticipation in the voting session. The 
investigator will submit status reports to the IRB or EC as required by the governing body. The 
IRB or EC must be notified by the investigator in writing of the interruption and/or completion of 
the study; the investigator must promptly report to the IRB or EC all changes in research (protocol 
amendments) and will not make such changes without IRB or EC approval, except where 
necessary to eliminate apparent immediate hazards to human subjects. In cases where it is 
necessary to eliminate immediate hazards to subjects, the IRB or EC must then be notified of the 
change as per local requirements. The investigator is required to maintain an accurate and complete 
record of all written correspondence to and received from the IRB or EC and must agree to share 
all such documents and reports with the Sponsor.
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 


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adheres to the privacy principles of notice, choice, accountability for onward transfer, security, 
data integrity, purpose limitation, access, and enforcement regarding the collection, use, and 
retention of personal information from European Economic Area countries and Switzerland. In 
addition, Sponsor’s Global Commercial General Liability with Umbrella Liability and Global 
Products / Clinical Trial Liability policy includes coverage for the processing of subjects’ data.
15
Investigator Agreement
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 investigational new 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 Institutional Review Board (IRB) or Ethics 
Committee (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 entered in the study.


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I agree to provide all subjects with informed consent forms, as required by government and ICH 
regulations. I further agree to report to the Sponsor any adverse experiences in accordance with 
the terms of this protocol, ICH guideline, Part E6, Section 4.11 and applicable local regulations.
Principal Investigator
(Signature)
Date
Principal Investigator
(Printed Name)
Protocol Version: 
Global Amendment 5
Institution Name




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


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


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


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APPENDIX B
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 for age 1 
month to 1 year; <70 mmHg + [2 x age] for age 1 to years; <90 mmHg for age 11 to 17 years.
Source: Sampson et al, 2005; Sampson et al, 2006.


Approval Signatures
Compound:
KJX839
Document Title:
ckjx839a12201e1-protocol amendment 05
Document Name:
02.01.0201 Protocol - v05
Document Version:
1.0
Username
User ID
Signing Reason
Date
Content Approval
2020-11-03
12:47:12 (UTC)
Content Approval
2020-11-03
12:51:36 (UTC)
Content Approval
2020-11-03
13:58:00 (UTC)
Content Approval
2020-11-04
13:07:03 (UTC)
Document electronically signed

SAP_001.pdf: 


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SAP Amendment v03 
 
Study No. CKJX839A12201E1 
 
 
 
 
 
 
 
 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
20-
Sep-
2021 
Prior 
to 
DB 
lock 
Creation of 
amendment 
(version 2) 
to MDCO 
SAP 
version 
v1.2 using 
Novartis 
template. 
Amendment based on Novartis 
template. 
All 
24-
Jan-
2022 
Prior 
to 
DB 
lock 
Creation of 
amendment 
v03. 
Removed “on-treatment” wording from 
diabetes analyses. 
Section 2.7.4.2 
and 2.7.4.3 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of contents 
Table of contents ................................................................................................................. 3 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
1 
Introduction ......................................................................................................................... 8 
1.1 
Study design............................................................................................................. 8 
1.2 
Study objectives, endpoints and estimands ........................................................... 11 
2 
Statistical methods ............................................................................................................. 13 
2.1 
Data analysis general information ......................................................................... 13 
2.1.1 
General definitions ................................................................................ 14 
2.2 
Analysis sets .......................................................................................................... 16 
2.2.1 
Subgroup of interest .............................................................................. 16 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 17 
2.3.1 
Patient disposition ................................................................................. 17 
2.3.2 
Demographics and other baseline characteristics ................................. 17 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 18 
2.4.1 
Study treatment / compliance ................................................................ 18 
2.4.2 
Prior and concomitant therapies ............................................................ 18 
2.5 
Analysis supporting primary objective(s) .............................................................. 19 
2.5.1 
Primary endpoint(s) ............................................................................... 19 
2.5.2 
Handling of missing values ................................................................... 19 
2.6 
Analysis supporting secondary objectives ............................................................. 19 
2.6.1 
Secondary endpoint(s) ........................................................................... 20 
2.6.2 
Handling of missing values ................................................................... 20 
2.7 
Safety analyses ....................................................................................................... 20 
2.7.1 
Adverse events (AEs) ............................................................................ 21 
2.7.2 
Deaths .................................................................................................... 22 
2.7.3 
Laboratory data ..................................................................................... 22 
2.7.4 
Diabetes assessment .............................................................................. 23 
2.7.5 
Other safety data ................................................................................... 26 
 
 
 
 
 
 
 
 29 


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2.10 
Interim analysis ...................................................................................................... 30 
3 
Sample size calculation ..................................................................................................... 30 
4 
Change to protocol specified analyses .............................................................................. 30 
5 
Appendix ........................................................................................................................... 30 
5.1 
Imputation rules ..................................................................................................... 30 
5.1.1 
Study drug ............................................................................................. 30 
5.1.2 
AE date imputation ............................................................................... 30 
5.1.3 
Concomitant medication date imputation ............................................. 31 
5.2 
Standardized MedDRA queries (SMQ) and AE terms for additional AE 
investigations ......................................................................................................... 31 
5.3 
Clinically relevant adverse events at injection site preferred terms ...................... 32 
5.4 
Criteria for potentially clinically significant and clinically significant 
abnormal laboratory tests ....................................................................................... 33 
6 
Reference ........................................................................................................................... 34 


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Study No. CKJX839A12201E1 
 
 
 
List of tables 
Table 1-1 
Objectives and related endpoints .......................................................... 11 
Table 2-1 
Summary of baselines ........................................................................... 14 
 
List of figures 
Figure 1-1 
Study design .......................................................................................... 11 
 


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Study No. CKJX839A12201E1 
 
 
 
List of abbreviations 
 
 
ATC 
Anatomical Therapeutic Chemical classification system 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
Apo-A1 
Apolipoprotein A1 
Apo-B 
Apolipoprotein B 
ASCVD 
Atherosclerotic Cardiovascular Disease 
AST 
Aspartate Aminotransferase 
BMI 
Body Mass Index 
CK 
Creatine Kinase 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CRP 
C-reactive Protein 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
 
 
DBL 
Database Lock 
DMC 
Data Monitoring Committee 
DMS 
Document Management System 
EAIR 
Exposure-Adjusted Incidence Rate 
ECG 
Electrocardiogram 
eGFR 
Estimated Glomerular Filtration Rate 
EOS 
End of Study 
FAS 
Full Analysis Set 
HbA1c 
Hemoglobin A1C 
HDL-C 
High-Density Lipoprotein Cholesterol 
HLGT 
High Level Group Term 
HLT 
High Level Term 
IA 
Interim Analyses 
ITT 
Intent-to-Treat 
IXRS 
Interactive Voice/Web Response System 
LDL-C 
Low-density Lipoprotein Cholesterol 
LLN 
Lower Limit of the Normal range 
LMT 
Lipid Modifying Therapy 
Lp(a) 
Lipoprotein(a) 
 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial Infarction 
mITT 
Modified Intent-to-Treat 
PCS 
Potentially Clinically Significant 
PCSK9 
Proprotein Convertase Subtilisin/Kexin Type 9 


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PK 
Pharmacokinetics 
PPS 
Per-Protocol Set 
 
 
RAP 
Reporting & Analysis Process 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SD 
Standard Deviation 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SMQ 
Standardized MedDRA queries 
SOC 
System Organ Class 
PT 
Preferred Term 
TC 
Total Cholesterol 
TEAE 
Treatment Emergent Adverse Event 
TESAE 
Treatment Emergent Serious Adverse Event 
TFLs 
Tables, Figures, Listings 
 
 
ULN 
Upper Limit of the Normal range 
VLDL-C 
Very Low-Density Lipoprotein Cholesterol 
WHO 
World Health Organization 


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1 
Introduction 
This document contains details of the planned statistical methods and analyses that will be used 
for the final clinical study report (CSR) of Phase II open label extension trial 
CKJX839A12201E1. The purpose of this study is to evaluate the efficacy, safety, and 
tolerability of long-term dosing of inclisiran in subjects with atherosclerotic cardiovascular 
disease (ASCVD) or ASCVD-risk equivalents and elevated low-density lipoprotein cholesterol 
(LDL-C) despite maximum tolerated dose of LDL-C lowering therapies. This statistical 
analysis plan (SAP) has been prepared based on clinical trial protocol CKJX839A12201E1 
(MDCO-PCS-16-01) global amendment 5, content final dated 07-Oct-2020.  
1.1 
Study design 
This study will be an open label, long term extension study with two arms. Group 1 (inclisiran 
only arm) will receive inclisiran only and Group 2 (switching arm) will receive an active 
comparator (evolocumab) for one year followed by inclisiran. The study will be conducted in 
subjects with 
ASCVD 
or 
ASCVD-risk 
equivalents 
(eg, 
diabetes 
and 
familial 
hypercholesterolemia) and elevated LDL-C despite maximum tolerated dose of LDL-C 
lowering 
therapies 
who 
have 
completed 
study 
MDCO-PCS-15-01 
(ORION-1/ 
CKJX839A12201), to evaluate the efficacy, safety, and tolerability of long-term dosing of 
inclisiran. All eligible and willing subjects who have completed the ORION-1 study to at least 
Day 210, and subjects whose LDL-C has returned to within 20% of the Baseline of ORION-1 
value or who have reached Day 360 can be enrolled into the ORION-3 study. The study will be 
a multi-national, multi-center study (approximately 60 centers). Informed consent will be 
obtained from subjects before the initiation of any study-specific procedures. 
Subjects completing study MDCO-PCS-15-01 and fulfilling all inclusion and exclusion criteria 
of this study will receive inclisiran or evolocumab, based on the treatment received in study 
MDCO-PCS-15-01. In countries where applicable, on signing consent and being entered into 
this study, the investigator will be informed by the Interactive Voice/Web Response System 
(IXRS) regarding the treatment allocation, and therefore, whether placebo or inclisiran was 
administered in study MDCO-PCS-15-01 (CKJX839A12201) and the subject will be informed 
accordingly. Those subjects who received inclisiran in MDCO-PCS-15-01 will receive 
inclisiran sodium throughout this study (Group 1; inclisiran only arm), and those subjects who 
received placebo in MDCO-PCS-15-01 (CKJX839A12201) will receive evolocumab as 
comparator for 1 year, and then transition to inclisiran for the remainder of the study (Group 2; 
switching arm). Until study drug is available, subjects will have monthly observation visits until 
study drug administration commences. 
Day 1 of ORION-3 is the day when eligible subjects will receive the first subcutaneous (SC) 
administration of inclisiran or evolocumab. 
Group 1 (Inclisiran Only Arm): 
After first study drug administration of inclisiran, all subjects will be observed in the clinic for 
at least 4 hours post injection before being discharged. 


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The subsequent visit schedule is as follows: 
• Dosing visits: Every 180 days until Day 720, an additional dose on Day 810, then back 
to every 180 day dosing until end of study (EOS). Therefore, dosing after Day 1 
(ORION-3) will occur on Days 180, 360, 540, 720, 810*, 990, 1170 and 1350. 
*Day 810 dose added to assess the effect of giving 2 doses 90 days apart (at Days 720 
and 810). 
• Safety follow-up visits: Days 30, 90, 210, 270, 390, 450, 570, 630, 870, 1080, 1260, and 
EOS (Day 1440). 
• The primary analysis time point is Day 210. 
Group 2 (Switching Arm): 
Subjects receiving evolocumab will receive the first dose on Day 1 (ORION-3), administered 
by the investigator at the site, and will then self-administer evolocumab at home every 14 days 
until Day 336.  Sites will then be assigned to have their evolocumab treated subjects placed into 
one of two transition groups. 
• Transition 1 (staged): Day 336 will be the final dose of evolocumab therapy and the first 
dose of inclisiran will be administered at the Day 360 visit. 
• Transition 2 (concurrent): Day 336 will be the final dose of evolocumab therapy at home. 
At the Day 360 visit subjects will receive an additional dose of evolocumab and their 
first dose of inclisiran, both administered by the investigator. 
After first study drug administration of inclisiran on Day 360, all subjects in Group 2 (switching 
arm) will be observed in the clinic for at least 4 hours post injection before being discharged. 
The subsequent visit schedule is as follows: 
• Dosing visits: Day 450 (2nd dose), then every 180 days until end of study (Days 630, 
810, 990, 1170 and 1350). 
• Safety follow-up visits: Days 390, 510, 540, 720, 900, 1080, 1260, and EOS (Day 1440). 
End of Study (EOS) 
EOS visit will occur at Day 1440, 90 days after the final administration of study drug (at Day 
1350). However, if the study ends early or if the subject discontinues the study, the EOS visit 
should occur at least 30 days following the final administration of study drug. 
Efficacy assessments will measure the effects of inclisiran on levels of LDL-C, lipids and 
lipoproteins including total cholesterol (TC), triglycerides, high-density lipoprotein cholesterol 
(HDL-C), non-HDL-C, very low-density lipoprotein cholesterol (VLDL-C), apolipoprotein A1 
(Apo-A1), apolipoprotein B (Apo-B), lipoprotein(a) (Lp(a)), C-reactive protein (CRP), and 
proprotein convertase subtilisin/kexin type 9 (PCSK9). 
At each visit, adverse events (AE), serious adverse events (SAE), concomitant medications, and 
safety laboratory assessments will be collected. 




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SAP Amendment v03 
 
Study No. CKJX839A12201E1 
 
 
 
Figure 1-1 
Study design 
 
1.2 
Study objectives, endpoints and estimands  
This study is designed to evaluate the efficacy, safety, and tolerability of inclisiran injection(s). 
The objectives and the corresponding endpoints are listed in Table 1-1. 
Table 1-1 
Objectives and related endpoints 
Objectives 
Endpoints 
Primary objective 
The primary objective of this study is: 
To evaluate 
• The effect of inclisiran treatment on LDL-C 
levels at Day 210 compared to Baseline of 
ORION-1 in Group 1 (inclisiran only arm). 
Endpoint for primary objective 
 
 
• The percentage change from Baseline of 
ORION-1 in LDL-C at Day 210 in this study 
(Group 1; inclisiran only arm). 
Secondary objectives 
The secondary objectives of this study are: 
• To evaluate the effect of inclisiran on the 
following (Group 1; inclisiran only arm): 
- 
LDL-C levels over time 
 
 
 
- 
PCSK9 levels over time 
 
 
- 
Other lipids, lipoproteins, and 
apolipoproteins over time 
 
 
 
 
Endpoints for secondary objectives 
(all for Group 1; inclisiran only arm) 
 
 
• Observed value, absolute change and 
percentage change from Baseline of 
ORION-1 in LDL-C over time in this study 
• Change and percentage change in LDL-C at 
Day 210 compared to Day 870 of ORION-3 
• Observed value, absolute change and 
percentage change from Baseline of 
ORION-1 in PCSK9 levels over time in this 
study 
• Observed value, absolute change and 
percentage change from Baseline of 
ORION-1 in other lipids, lipoproteins, and 
apolipoproteins, over time in this study 
 






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Study No. CKJX839A12201E1 
 
 
 
2.1.1 
General definitions  
Study drugs 
The study drugs in this trial are the following: 
• Investigational drug: Inclisiran will be administered as a single SC injection of 300 mg 
inclisiran sodium (equivalent to 284 mg inclisiran)/1.5 mL 
• Comparator drug: Evolocumab (REPATHA®) will be administered as a single SC 
injection at 140 mg. 
Date of first/last administration of study drug 
Date of first/last administration of study drug is defined as the first/last date of administration 
of either inclisiran or evolocumab in ORION-3, unless otherwise specified. 
Gap period 
The time between the end of ORION-1 and the beginning (date of informed consent) of 
ORION-3 is called the gap period. 
Study day 
Study day will be defined as the number of days since the date of first administration of study 
drug. The date of first administration of study drug will be defined as Day 1 and the day before 
the first administration of study drug will be defined as Day -1. 
Therefore, for a particular date, study day will be calculated as follows: 
For dates on or after the date of first administration of study drug, 
 
Study day = Assessment date – Date of first administration of study drug + 1; 
For dates prior to the date of first administration of study drug, 
 
Study day = Assessment date – Date of first administration of study drug. 
Baselines 
Depending on the specific analysis, either baseline of ORION-1 or baseline of ORION-3 is 
considered. The precise definitions of the baselines for each analysis are summarized in Table 
2-1. 
Table 2-1 
Summary of baselines 
Analysis 
category 
Analysis 
Baseline used 
Explanation 
Baseline 
Characteristics 
Age*, weight, body 
mass index (BMI), 
country 
Study entry of 
ORION-3 
To provide a more accurate value of 
parameters that may change, baseline 
of ORION-3 is used. 


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Study No. CKJX839A12201E1 
 
 
 
 
Estimated 
glomerular filtration 
rate (eGFR) 
Last non-
missing record 
prior to first 
study drug 
administration of 
ORION-3 
To provide a more accurate value of 
parameters that may change, baseline 
of ORION-3 is used. 
 
Sex, race, 
ethnicity, height 
Screening 
period of 
ORION-1 
These values will not change or will not 
change significantly so baseline of 
ORION-1 is used. 
 
Medical history 
Day 1 of 
ORION-1 
Medical history is reported prior to the 
first treatment in ORION-1, after which 
any new medical conditions will be 
captured as AEs. 
Prior and 
concomitant 
therapies 
Concomitant 
Medications 
Day 1 of 
ORION-3 
Medications taken on or after Day 1 of 
ORION-3 will be considered as 
concomitant for ORION-3.** 
Efficacy 
Efficacy 
parameters in 
Group 1 (inclisiran 
only arm) 
Baseline of 
ORION-1*** 
Due to residual efficacy from ORION-1, 
the true change from baseline should 
use baseline of  
ORION-1, i.e. prior to receiving any 
dose of inclisiran. 
 
Efficacy 
parameters in 
Group 2 (switching 
arm) 
Baseline of 
ORION-3**** 
Placebo was given in  
ORION-1 and since treatment 
adjustments may have occurred during 
ORION-1 in lipid modifying therapies 
(LMT), baseline of ORION-3 will be 
used. 
Safety 
Adverse events 
Day 1 of 
ORION-3 
Previous AEs are collected in ORION-1, 
the gap period and the observation 
period so TEAEs in ORION-3 are 
collected from Day 1 (first dose) of 
ORION-3. 
 
Electrocardiograms 
(ECG) 
Day 1 of 
ORION-3 
To identify untoward change in ECG 
within ORION-3 
 
Safety laboratory 
parameters, vital 
signs 
Baseline of 
ORION-3**** 
To identify untoward change in safety 
laboratory parameters and vital signs 
within ORION-3 
* Since age will not be re-collected in ORION-3, the age at ORION-3 baseline is inferred using 
the ORION-1 baseline: 
• If the difference between consent date in ORION-3 and ORION-1 is greater than 365 
days for a subject then 1 year will be added to the age at ORION-1 baseline; 
• Otherwise, ORION-1 baseline age will be used.  
** Although all medications received 30 days prior to consent in ORION-1 through the EOS in 
ORION-3 will be reported, only medications taken on or after Day 1 of ORION-3 will be 
considered concomitant for ORION-3. 




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Study No. CKJX839A12201E1 
 
 
 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
2.3.1 
Patient disposition 
Subject disposition will be summarized for the ITT population as follows: 
• The number of subjects who were randomized for ORION-1 broken down by eligibility 
and consent status, who had a gap period, and who were treated will be summarized.  
The days from last dose in ORION-1 to first dose of study drug in ORION-3 will also 
be summarized. 
• The number of subjects who consented and the number of subjects who were treated 
will be summarized by group and overall. 
• The number of subjects in each analysis population will be summarized by group and 
overall. 
• The number of subjects who completed the study or who discontinued early along with 
reasons for early discontinuation will be summarized by group and overall. 
• The duration on study (number of days from the first date of study drug administration 
to the date of last recorded visit/contact date in the database) will be summarized by 
group and overall. 
• Protocol deviations and violations of subject restrictions will be summarized by group 
and overall. 
Select tables for Group 2 will be broken down by transition group (Transition 1 (staged) and 
Transition 2 (concurrent)). 
Completers are defined as a subject who completes the Day 1440 visit. 
2.3.2 
Demographics and other baseline characteristics 
Subject demographics and background characteristics including age, sex, weight, height, BMI, 
race, ethnicity, country (country of participation), baseline eGFR and re-evaluation of child-
bearing potential will be summarized using the ITT population. The following categorizations 
of quantitative variables will be performed: 
• Age into ≥ 18 - < 65 and ≥ 65 
• Age into ≥ 18 - < 50, ≥ 50 - < 65, ≥ 65 - < 75, ≥ 75 
• Baseline eGFR into ≥ 15 - < 30, ≥ 30 - < 60, ≥ 60 - < 90, ≥ 90 
Age collected in ORION-1 will be used but if the difference between consent date in ORION-
3 and ORION-1 is greater than 365 days for a subject then 1 year will be added to the age for 
this subject. 
Medical history (targeted and other medical history) will be summarized using the safety 
population. Other medical history will be coded into Medical Dictionary for Regulatory 




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summarized by preferred name with dose and frequency. LMTs are medications with 3rd level 
ATC classification being either C10A (lipid modifying agents, plain) or C10B (Lipid modifying 
agents, combinations) according to the coding by the WHO drug dictionary. LMTs will be 
grouped into statins and other LMT. Statins will be furthered grouped by intensity (low, 
moderate, high) according to American College of Cardiology/American Heart Association 
(ACC/AHA) classification of statin intensity and based on the specific statin drug name, dose, 
and frequency recorded in the data. 
Prior medication/LMT is defined as the medication stopped before Day 1 of ORION-3. 
Concomitant medication/LMT at Baseline (Day 1 of ORION-3), is defined as any medication 
onset before or on Day 1 (Day 1 of ORION-3) and either still ongoing or stopped on Day 1 
(Day 1 of ORION-3) or later. Any medications with start date after study Day 1 (Day 1 of 
ORION-3) are considered as new or changed concomitant medications/LMT.  
Summaries will be presented by group (Group 1 and Group 2). Select tables for Group 2 will 
be broken down by transition group (Transition 1 (staged) and Transition 2 (concurrent)).  
Analyses will be performed on the safety population. 
2.5 
Analysis supporting primary objective(s) 
The primary objective of this study is to evaluate the effect of inclisiran treatment on LDL-C 
levels at Day 210 compared to Baseline of ORION-1 in Group 1 (inclisiran only arm).  
2.5.1 
Primary endpoint(s) 
The primary efficacy endpoint is the percentage change from Baseline of ORION-1 in LDL-C 
at Day 210 in this study (Group 1; inclisiran only arm). 
Summary statistics (n, mean, standard deviation (SD), median, first and third quartiles, 
minimum and maximum) for the percentage change in LDL-C and 95% confidence interval for 
the mean will be provided.  One sample t-test will also be utilized to assess if the mean percent 
change from baseline to Day 210 is 0 or not. P-value (two-sided test) will be provided. 
Analyses will be performed on the ITT and mITT populations. 
 
2.5.2 
Handling of missing values 
Missing data will not be imputed. Subjects missing any required data for computing the 
endpoint will be excluded from the analysis. 
2.6 
Analysis supporting secondary objectives  
The secondary efficacy objective of this study is to evaluate the effect of inclisiran on the 
following for Group 1 (inclisiran only arm): 
• LDL-C levels over time 
• PCSK9 levels over time 
• Other lipids, lipoproteins, and apolipoproteins over time 


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• Individual responsiveness to inclisiran 
• Proportion of subjects achieving target levels prespecified in global lipid guidelines 
• Proportion of subjects with at least 50% LDL-C reduction from Baseline of ORION-1 
over time 
2.6.1 
Secondary endpoint(s) 
The secondary efficacy endpoints of this study are: 
• Observed value, absolute change and percentage change from Baseline of ORION-1 in 
LDL-C over time in this study 
• Observed value, absolute change and percentage change from Baseline of ORION-1 in 
PCSK9 levels over time in this study 
• Change and percentage change in LDL-C at Day 210 compared to Day 870 of ORION-
3 
• Observed value, absolute change and percentage change from Baseline of ORION-1 in 
other lipids, lipoproteins, and apolipoproteins, over time in this study 
• Individual responsiveness to inclisiran defined as the proportion of subjects reaching on 
treatment LDL-C levels of <25 mg/dL, <50 mg/dL, <70 mg/dL, and <100 mg/dL over 
time and at any time point 
• Proportion of subjects achieving global lipid targets for their level of ASCVD over time 
and at any time point 
• Proportion of subjects with ≥50% LDL-C reduction from Baseline of ORION-1 over 
time and at any time point 
The global lipid target is LDL-C level of < 70 mg/dL for ASCVD subjects and LDL-C level 
of < 100 mg/dL for ASCVD risk equivalent subjects. 
Summary statistics (n, mean, standard deviation (SD), median, first and third quartiles, 
minimum and maximum) along with 95% confidence intervals for the mean will be provided 
for the continuous endpoints.  The categorical variables will be summarized using the number 
and percentage of subjects who achieve each response level. 95% confidence intervals for the 
proportions will be provided. 
Analyses will be performed on the ITT and mITT populations (Group 1; inclisiran only arm). 
2.6.2 
Handling of missing values 
Missing data will not be imputed. Subjects missing any required data for computing an endpoint 
will be excluded from the analysis. 
2.7 
Safety analyses 
All safety evaluations will be performed for the following groups unless otherwise specified: 






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• For eGFR, the categories will be Severe = < 30 mL/min/1.73m2; Moderate = ≥ 30 to < 
60 mL/min/1.73m2; Mild = ≥ 60 to < 90 mL/min/1.73m2; and Normal = ≥ 90 
mL/min/1.73m2. 
• For HbA1c, the categories will be < 5.7%, ≥ 5.7% to < 6.5%, and ≥ 6.5%. 
The shift table for the fasting glucose will require the lab sample to be taken while fasting. 
Samples taken while the subject was not fasting will not be analyzed. 
The number and percentage of subjects with potentially clinically significant (PCS) laboratory 
values and clinically significant (CS) laboratory values (refer to Appendix 5.4 for the criteria) 
will be summarized by treatment group. HbA1c criteria is explicitly stated in Appendix 5.4. All 
other PCS and CS criteria are met when both of the following occur: 
• Worst post-baseline value meets the thresholds listed in Appendix 5.4 
• Baseline value does not meet the thresholds in Appendix 5.4 
Separate listings of all subjects with PCS and CS laboratory values will be presented. Subjects 
will appear once per lab parameter but may appear under multiple lab parameters. The worst 
post-baseline value will be utilized in the analyses. 
The number and percentage of subjects satisfying Hy’s Law will also be tabulated based on the 
following lab findings: 
• Any elevated post-baseline aminotransferases defined as:  
− ALT > 3 x ULN or  
− AST > 3 x ULN 
• Elevated post-baseline serum total bilirubin (TBL) > 2 x ULN and serum alkaline 
phosphatase (ALP) levels < 2 x ULN 
Subjects must meet all of the criteria listed above at the same time point and have normal lab 
parameters (ALT, AST, TBL) at baseline to be considered a Hy’s Law case. A second summary 
will be presented that includes subjects who meet all of the criteria listed above at the same time 
point without regard to the baseline lab parameter results. 
2.7.4 
Diabetes assessment 
Diabetes will be assessed by the analysis of: 
• TEAEs 
• change in glucose-related laboratory values over time 
• shifts from baseline in glucose control category 
• incidence of post-baseline new onset of diabetes. 
Note that diabetes related tables dealing with the fasting glucose parameter will require the lab 
sample to be taken while fasting.  Samples taken while the subject was not fasting will not be 
analyzed. 


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2.7.4.1 
Diabetes TEAE 
New onset/worsening of diabetes will be identified by the search criteria specified in Appendix 
5.2.  The analysis will be performed for all subjects and then by baseline diabetes status.  A 
subject will be identified as being diabetic at baseline if the targeted medical history notes that 
the subject is diabetic or the baseline HbA1c value is ≥ 6.5%. 
2.7.4.2 
Change in glucose-related laboratory values over time 
This analysis only utilizes laboratory data (fasting glucose and HbA1c).  The change from 
baseline to the last observation and the worst observation will be summarized separately for 
fasting glucose and HbA1c overall and then by baseline glucose control status.  Baseline 
glucose control status will be identified separately for fasting glucose and HbA1c using the 
values provided in the table below (note that medical history will not be taken into account for 
this analysis).  Figures will also be created showing mean fasting glucose and HbA1c values 
over time by baseline glucose control status. 
 
Parameter 
Baseline Glucose Control Status 
Baseline Laboratory Values 
 
Fasting Glucose* 
Normal 
<100 mg/dL 
Impaired  
≥100 to <126 mg/dL 
Diabetes  
≥126 mg/dL 
 
HbA1c** 
Normal 
<5.7% 
Impaired 
≥5.7 to <6.5% 
Diabetes  
≥6.5% 
* Baseline uses average of ORION-3 study entry and Day 1 fasting glucose values.  If one 
fasting glucose value is missing, the assessment will be based on the available data. 
** ORION-3 Day 1 assessment will be considered as baseline for HbA1c. If missing, then the 
baseline will be based on assessment at ORION-3 study entry. 
2.7.4.3 
Shifts from baseline in glucose control category 
Shifts from baseline in glucose control category will be summarized two different ways: the 
change from ORION-3 baseline to the worst and then again for the change to last glucose 
control category.  Note that medical history will not be taken into account for this analysis. If 
consecutive fasting glucose measurements fall in two separate categories, or if only one pre- or 
post-baseline fasting glucose measurement is available, then the classification will be based on 
the HbA1c measurements only. If HbA1c is missing then both consecutive fasting glucose 
measurements must fall in a category otherwise the lower category will be used. 
 
Shift Category* 
Baseline Values** 
Post-baseline Values 
Normal to Normal  
(no change) 
Fasting glucose < 100 mg/dL on 
ORION-3 study entry or Day 1 
AND 
HbA1c < 5.7% 
Fasting glucose < 100 mg/dL on 
two consecutive occasions 
AND 
HbA1c < 5.7% 


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Normal to Impaired 
Fasting glucose < 100 mg/dL on 
ORION-3 study entry or Day 1 
AND 
HbA1c < 5.7% 
Fasting glucose ≥ 100 and < 126 
mg/dL on two consecutive 
occasions 
OR 
HbA1c ≥ 5.7 and < 6.5%  
Normal to Diabetes 
Fasting glucose < 100 mg/dL on 
ORION-3 study entry or Day 1 
AND 
HbA1c < 5.7% 
Fasting glucose ≥ 126 mg/dL on 
two consecutive occasions 
OR 
HbA1c ≥ 6.5% 
Impaired to Normal 
Fasting glucose ≥ 100 and < 126 
mg/dL on ORION-3 study entry and 
Day 1 
OR 
HbA1c ≥ 5.7 and < 6.5% 
Fasting glucose < 100 mg/dL on 
two consecutive occasions 
AND 
HbA1c < 5.7% 
Impaired to Impaired 
(no change) 
Fasting glucose ≥ 100 and < 126 
mg/dL on ORION-3 study entry and 
Day 1 
OR 
HbA1c ≥ 5.7 and < 6.5% 
Fasting glucose ≥ 100 and < 126 
mg/dL on two consecutive 
occasions 
OR 
HbA1c ≥ 5.7 and < 6.5% 
Impaired to Diabetes 
Fasting glucose ≥ 100 and < 126 
mg/dL on ORION-3 study entry and 
Day 1 
OR 
HbA1c ≥ 5.7 and < 6.5% 
Fasting glucose ≥ 126 mg/dL on 
two consecutive occasions 
OR 
HbA1c ≥ 6.5% 
Diabetes to Normal 
Fasting glucose ≥ 126 mg/dL on 
ORION-3 study entry and Day 1 
OR 
HbA1c ≥ 6.5% 
Fasting glucose < 100 mg/dL on 
two consecutive occasions 
AND 
HbA1c < 5.7% 
Diabetes to Impaired 
Fasting glucose ≥ 126 mg/dL on 
ORION-3 study entry and Day 1 
OR 
HbA1c ≥ 6.5% 
Fasting glucose ≥ 100 and < 126 
mg/dL on two consecutive 
occasions 
OR 
HbA1c ≥ 5.7 and < 6.5% 
Diabetes to Diabetes  
(no change) 
Fasting glucose ≥ 126 mg/dL on 
ORION-3 study entry and Day 1 
OR 
HbA1c ≥ 6.5% 
Fasting glucose ≥ 126 mg/dL on 
two consecutive occasions 
OR 
HbA1c ≥ 6.5% 
*No change (Normal to Normal, Impaired to Impaired, and Diabetes to Diabetes), Worsened (Normal to 
Impaired, Normal to Diabetes, and Impaired to Diabetes), and Improved (Impaired to Normal, Diabetes 
to Impaired, and Diabetes to Normal) categories will also be summarized. 
** If one fasting glucose value is missing (ORION-3 study entry or Day 1), the assessment will be based 
on the available data. 
2.7.4.4 
Incidence of post-baseline new-onset of diabetes 
The number of subjects who shift from no diabetes at baseline (defined as no medical history 
of diabetes in the targeted medical history CRF, HbA1c <6.5% at baseline, and fasting glucose 
<126 mg/dL at baseline (note that baseline is defined as the average of study entry and Day 1 


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fasting glucose values. If one fasting glucose value is missing (study entry or Day 1), the 
assessment will be based on the available data) to diabetes will be summarized.  A 4-component 
definition of diabetes will be utilized.  The 4 components are provided below.   
1. Diabetic TEAEs identified by the search criteria in Appendix 5.2, or 
2. Post-baseline fasting glucose ≥126 mg/dL on two consecutive occasions, or 
3. Initiation of anti-diabetic medication (ATC level 2 code: A10) at any time post-baseline, 
or 
4. At least one post-baseline HbA1c ≥6.5%. 
The number of subjects who have any of the 4 components (post-baseline new-onset of diabetes) 
will be summarized along with each component.  This analysis will be performed for those 
subjects who have fasting glucose at baseline < 100 mg/dL and then for those with fasting 
glucose at baseline ≥100 and <126 mg/dL.   
The time to new-onset diabetes will also be summarized.  Only subjects without diabetes at 
baseline will be included in the analysis.  The time (weeks) to new-onset diabetes will be 
calculated from the date of the first administration of study drug. 
2.7.5 
Other safety data 
2.7.5.1 
Electrocardiograms (ECG) 
The percentage of subjects with any changes from baseline ECG will be summarized over time. 
2.7.5.2 
Vital signs 
Observed value, change, and percent change from ORION-3 baseline in vital signs will be 
summarized descriptively at each scheduled time point by treatment group. 
The change from baseline to EOS will also be summarized by the following categories: 
• Systolic blood pressure (mmHg):  
o ≤ -20  
o > -20 to ≤ -10  
o > -10 to ≤ -5 
o > -5 to < 5 
o ≥ 5 to < 10 
o ≥ 10 to < 20 
o ≥ 20 
• Diastolic blood pressure (mmHg):  
o ≤ -10 
o > -10 to ≤ -5 










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5.1.3 
Concomitant medication date imputation 
Any medication with both start and stop dates missing are considered as baseline concomitant 
medication/LMT. Any medication with only start date missing are considered as either prior or 
baseline concomitant medication/LMT depending on the stop date. Any medication with only 
stop date missing are considered as either baseline concomitant or new/changed concomitant 
medications/LMT depending on the start date. 
5.2 
Standardized MedDRA queries (SMQ) and AE terms for additional 
AE investigations 
1. Hepatic events 
• Drug related hepatic disorders - comprehensive search (SMQ, broad and narrow)   
2. Renal events  
• Acute renal failure (SMQ, broad and narrow)  
3. Hypersensitivity  
• Hypersensitivity' (SMQ, broad and narrow) excluding  
– PTs ‘infusion site %’ (‘'infusion site dermatitis', 'infusion site eczema’, 'infusion 
site hypersensitivity', 'infusion site rash', 'infusion site urticaria', 'infusion site 
vasculitis) and  
– PTs ‘injection site %’ ('injection site dermatitis', 'injection site eczema’, 
'injection site hypersensitivity', 'injection site rash', 'injection site urticaria' and 
'injection site vasculitis') 
4. Neurological events and neurocognitive disorders 
• Neurological events  
o Demyelination, (SMQ, broad and narrow)  
o Peripheral neuropathy, (SMQ, broad and narrow) 
• Neurocognitive disorders  
o Deliria (incl confusion), (HLGT) 
o Cognitive and attention disorders and disturbances, (HLGT) 
o Dementia and amnestic conditions, (HLGT) 
o Disturbances in thinking and perception (HLGT) 
o Mental impairment disorders (HLGT) 
5. Ophthalmologic events 
• Optic nerve disorders, (SMQ, broad and narrow)  
• Retinal disorders, (SMQ, narrow)  




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Injection site lymphadenopathy 
Injection site necrosis 
Injection site nerve damage 
Injection site photosensitivity reaction 
Injection site pruritus 
Injection site pustule 
Injection site rash 
Injection site reaction 
Injection site recall reaction 
Injection site scar 
Injection site thrombosis 
Injection site ulcer 
Injection site urticaria 
Injection site vasculitis 
Injection site vesicles 
5.4 
Criteria for potentially clinically significant and clinically 
significant abnormal laboratory tests 
Hemoglobin A1c criteria is explicitly stated in the table below.  
All other criteria are met when both of the following occur: 
• Post-baseline values meet the thresholds below 
• Baseline value does not meet the thresholds below 
 
Parameter 
Unit 
Lower Boundary 
Upper Boundary  
Hematology 
Hematocrit 
% 
≤ 0.8 × LLN 
N/A 
Hemoglobin 
g/dL 
≤ 10 g/dL 
N/A 
Platelet Count 
10^9/L 
≤ 75* 
≥ 700* 
White Blood Cell Count 
10^9/L 
≤ 2.8 
≥ 16 
 
 
 
 
Serum Chemistry 
Alanine Aminotransferase (ALT/SGPT) 
U/L 
N/A 
> 1 and ≤ 3 × ULN 
Alanine Aminotransferase (ALT/SGPT) 
U/L 
N/A 
> 3 and ≤ 5 × ULN* 
Alanine Aminotransferase (ALT/SGPT) 
U/L 
N/A 
> 5 and ≤ 10 × ULN* 
Alanine Aminotransferase (ALT/SGPT) 
U/L 
N/A 
> 10 and ≤ 20 × ULN* 
Alanine Aminotransferase (ALT/SGPT) 
U/L 
N/A 
> 20 × ULN* 
Alkaline Phosphatase 
U/L 
N/A 
> 2 × ULN* 
Aspartate Aminotransferase (AST/SGOT) 
U/L 
N/A 
> 1 and ≤ 3 × ULN