Conditions: ASCVD Elevated Cholesterol Heterozygous Familial Hypercholesterolemia Homozygous Familial Hypercholesterolemia
Keywords: Inclisiran sodium ASCVD LDL-C HeFH HoFH
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3275
Healthy volunteers: no

Brief summary:
The purpose of this extension study was to evaluate the efficacy, safety, and tolerability of long-term dosing of Inclisiran. The study was a global multicenter study.

Detailed description:
This study was an open label, long term extension study in subjects with atherosclerotic cardiovascular disease (ASCVD), ASCVD-risk equivalents (eg, diabetes and familial hypercholesterolemia), or heterozygous familial hypercholesterolemia (HeFH) and elevated low density lipoprotein cholesterol (LDL-C) despite maximum tolerated dose of LDL-C lowering therapies who have completed the inclisiran Phase II trial MDCO-PCS-16-01 (ORION-3; NCT03060577), or any of the following Phase III lipid lowering studies: MDCO-PCS-17-03 (ORION-9; NCT03397121), MDCO-PCS-17-04 (ORION-10; NCT03399370), or MDCO-PCS-17-08 (ORION-11; NCT03400800).

The End of Study (EOS) visit in the previous feeder studies was Day 1 in this extension study.The duration that each subject participated in this study was a maximum of 3 years. However, for subjects from the Study ORION-3, the Sponsor decided to end the study prior to completion of their full 3-year of participation. It is recorded in the database as discontinuation was due to Sponsor's decision.

In this Phase III extension study, the same study drug of inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) was administered as a single subcutaneous (SC) dose every 180 days from the last dose in previous feeder study (except for subjects newly initiating inclisiran, who received the first two doses 90 days apart) until the end of the study.

On Day 1 (EOS visit in the feeder study), subjects from the previous feeder studies received blinded study medication except subjects from Study ORION-3. Subjects who received placebo in the previous Phase III feeder study received blinded inclisiran and subjects who received inclisiran in the previous feeder study received blinded placebo at this visit, so that subjects previously on placebo received the correct dosing regime, i.e. a dose at Day 1, Day 90 and every 180-days thereafter. Subjects previously treated with inclisiran did not need a dose of inclisiran to maintain every 180-dosing regime and therefore, were given placebo in order to maintain the blinding of the feeder study. Subjects that moved over from ORION-3 received the first study medication at Day 90, as this study was already open-label.

On Day 90, all subjects received inclisiran sodium 300 mg. This is 180 days after the last injection in the previous feeder study for subjects that received inclisiran and was the second dose of inclisiran for the subjects that received placebo in the feeder study. The EOS visit occurred at Day 1080.

This extension study allowed subjects continued access to inclisiran treatment and allowed the collection of additional efficacy and safety data for long-term use beyond the end of the feeder studies.

Arms:
arm 1: Inclisiran sodium 300 milligrams (mg) was administered as a single SC injection on Day 1\*, 90, then every 180 days to Day 990.

\*Subjects who received blinded placebo in the feeder study received blinded inclisiran and subjects who received blinded inclisiran in the feeder study received blinded placebo on Day 1 in ORION-8. Subjects from the open label ORION-3 study did not receive any injection of study drug on Day 1. Their first dose of study medication was at day 90

Interventions: intervention 1: Inclisiran Sodium
Intervention descriptions: intervention 1: Inclisiran is a small interfering ribonucleic acid (RNA) that inhibits PCSK9 synthesis.

Protocol document:
Prot_000.pdf: 
Novartis Research and Development 
KJX839/Inclisiran 
Clinical Trial Protocol MDCO-PCS-17-05 (CKJX839A12306B) / NCT03814187
A long-term extension trial of the phase III lipid-lowering 
trials to assess the effect of long-term dosing of inclisiran 
given as subcutaneous injections in subjects with high 
cardiovascular risk and elevated LDL-C (Orion-8) 
Document type: 
Amended Clinical Trial Protocol 
EUDRACT number: 
2018-000893-31 
Version number: 
02 (Clean) 
Clinical Trial Phase: 
III 
Release date: 
06-Oct-2020 (content final)
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 


Novartis 
Confidential 
Page 2 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
Protocol Synopsis 
Name of Sponsor/Company:   Novartis 
Name of Finished Drug/Device:  Inclisiran for Injection (also referred to as KJX839), 
Name of Active Ingredient:  Inclisiran sodium 
Title of Study:  A long-term extension trial of the Phase III lipid-lowering trials to assess the effect of long-term 
dosing of inclisiran given as subcutaneous injections in subjects with high cardiovascular risk and elevated LDL-C 
(ORION-8 also referred to as CKJX839A12306B) 
Phase of Development: III 
Study Centers: Global Multicenter study (approximately 300 sites).  
Central Facilities:  This list is maintained by the Sponsor 
Number of Subjects: Maximum of up to 3300 subjects 
Study Period: The estimated study period for the study will be approximately 4 years from first subject enrolled in 
this extension study to last subject completed, or until the investigator's recommendation of discontinuation, 
sponsor's recommendation of discontinuation, until an administrative decision is made to end the study. 
Objectives:   
Primary : 
The primary objectives are to evaluate: 
• 
The effect of inclisiran treatment on the proportion of subjects achieving prespecified low density lipoprotein 
cholesterol (LDL-C) targets at end of study (EOS)   
• 
The safety and tolerability profile of long-term use of inclisiran 
Secondary: 
The secondary objectives are to evaluate the effect of inclisiran on: 
• 
LDL-C levels 
• 
Other lipids and lipoproteins 
Methodology:  
This study will be a long-term extension study in up to 3300 subjects with atherosclerotic cardiovascular disease 
(ASCVD), ASCVD-risk equivalents (eg, diabetes and familial hypercholesterolemia), or heterozygous
 
 familial hypercholesterolemia (HeFH 
) and elevated low density lipoprotein cholesterol (LDL-
C) despite treatment with  LDL-C lowering therapies who have completed the Phase II trial MDCO-PCS-16-01 
(ORION-3, also referred to as CKJX839A12201E1) or Phase III lipid lowering studies: MDCO-PCS-17-03(ORION-
9 also referred to as CKJX839A12303), MDCO-PCS-17-04 (ORION-10, also referred to as CKJX839A12304, or 
MDCO-PCS-17-08(ORION-11, also referred to as CKJX839A12305). The purpose of this extension study is to 
evaluate the efficacy, safety, and tolerability of long-term dosing of inclisiran. Informed consent will be obtained 
from subjects before the initiation of any study-specific procedures. The EOS visit in the previous study will be Day 
1 in ORION-8.  
Subjects completing one of the previously mentioned inclisiran trials (the Phase II trial (ORION-3,  Phase III 
inclisiran studies (ORION-9, ORION-10 or  ORION-11 trial) and fulfilling all inclusion and exclusion criteria of this 
study will receive blinded inclisiran sodium 300 milligrams (mg) which is equivalent to 284 mg inclisiran, or blinded 
placebo on Day 1 in this tria,. except for subjects moving over from ORION-3. These subjects will receive the first 
study medication at day 90.  Subjects who received placebo in the previous Phase III feeder study will receive 
blinded inclisiran and subjects who received inclisiran in the previous feeder study will receive blinded placebo at 
this visit, in order to maintain the blinding of the feeder study until database lock of those studies.  For subjects 
enrolled in Sweden, Sweden Specific Protocol Amendment 1 (to Global Amendment 1 version, dated 1 Nov 2018) 
was implemented to allow limited lab tests to be done on Day 1 and to collect any safety information during the 
gap between feeder’s EOS and Day1of this study until ethics committee approval was granted in that country. 
After first study drug administration, all subjects will be observed in the clinic for 30 minutes post injection before 
being discharged.  
All subjects will return at Day 90 for the next visit and will receive open label inclisiran sodium 300 mg which is 
equivalent to 284 mg inclisiran. Subjects will then return for open label drug administration of inclisiran sodium 300 
mg every 180 days until EOS and be observed for 30 minutes at each visit.  
Efficacy assessments will measure the effects of inclisiran on levels of LDL-C.  
At each visit, adverse events (AEs), serious adverse events (SAEs), concomitant medications, and safety 
laboratory parameters will be collected. 
 


Novartis 
Confidential 
Page 3 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
An Independent Data Monitoring Committee (IDMC) will review safety data on a regular schedule as specified in 
the IDMC charter from subject enrollment in the double-blind phase until the end of the open label phase of the 
study. A recommendation may be taken to stop or amend the study after any of these reviews. 
The duration of each subject is expected to be a maximum of 3 years (or until the investigator’s recommendation 
of discontinuation, sponsor's recommendation of discontinuation, the subject's decision to discontinue for any 
reason, until an administrative decision is made to end the study.. At this time, EOS evaluations will be conducted 
at the EOS visit. 
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 a previously qualifying inclisiran Phase II trial MDCO-PCS-16-01 (ORION-3, or Phase III lipid-
lowering ORION feeder study [MDCO-PCS-17-03  (ORION-9), MDCO-PCS-17-04 (ORION-10) or MDCO-
PCS-17-08 (ORION-11)], meaning the subject received the last dose of study drug and completed the final 
study visit per applicable protocol. 
2. 
On current lipid-lowering therapies (such as a statin and/or ezetimibe) from previous study with no planned 
medication or dose change during study participation. 
3. 
Willing and able to give informed consent before initiation of any study-related procedures and willing to 
comply with all required study procedures. 
Subjects will be excluded from the study if any of the following exclusion criteria apply immediately prior to 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. 
Severe concomitant noncardiovascular disease that carries the risk of reducing life expectancy to less than 3 
years.  
4. 
Active liver disease defined as any known current infectious, neoplastic, or metabolic pathology of the liver or 
unexplained elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), >3x the upper 
limit of normal (ULN), or total bilirubin (TBIL) elevation >2x ULN at last recorded visit in the feeder study prior 
to study entry visit. 
5. 
Females who are pregnant or nursing, or who are of childbearing potential and unwilling to use at least one 
method of acceptable effective 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. 
Planned use of other investigational medicinal products other than inclisiran or devices during the course of 
the study.  
7. 
Any condition that according to the investigator could interfere with the conduct of the study, such as but not 
limited to:  
a. 
Subjects who are unable to communicate or to cooperate with the investigator 
b. 
Unable to understand the protocol requirements, instructions and study-related restrictions, the nature, 
scope, and possible consequences of the study (including subjects whose cooperation is doubtful due to 
drug abuse or alcohol dependency) 
c. 
Unlikely to comply with the protocol requirements, instructions, and study-related restrictions 
(eg, uncooperative attitude, inability to return for follow-up visits, and improbability of completing the 
study) 
d. 
Have any medical or surgical condition, which in the opinion of the investigator would put the subject at 
increased risk from participating in the study 
e. 
Persons directly involved in the conduct of the study 
Test Drug/Device, Dose and Mode of Administration:  Inclisiran sodium 300 mg (equivalent to 284 mg 
inclisiran) will be administered as a single subcutaneous (SC) dose every 180 days from the last previous study 
dose until the end of the study. Visit 1 dose will be blinded; subsequent doses will be open label. 


Novartis 
Confidential 
Page 4 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
Duration of Treatment: The expected duration of each subjects’ involvement in the study will be a maximum of 3 
years. 
Reference Therapy, Dose and Mode of Administration:   The placebo pre-filled syringes will contain saline 
solution. Placebo pre-filled syringes will be blinded and look identical to the inclisiran pre-filled syringes. Placebo 
will be administered as a 1.5 mL SC injection to match the dose of the inclisiran group. 
Criteria for Evaluation:   
Efficacy:   
Primary Endpoint: 
• 
Proportion of subjects who attain global lipid targets (entry criterion from respective previous study) for their 
level of ASCVD risk at EOS 
Secondary Endpoints: 
• 
Absolute change and percentage change in LDL-C from baseline (defined as baseline in feeder study) to EOS 
• 
Absolute change and percentage change in other lipids and lipoprotein from baseline (defined as baseline in 
feeder study) to EOS 
Safety Endpoint:   
The safety and tolerability profile of long-term use of inclisiran by evaluation of adverse events, SAEs, vital signs, 
and clinical laboratory values (hematology, coagulation testing, chemistry, and urinalysis) collected at specified 
visits through the EOS visit.  
Cardiovascular events will be reported as AEs for the compilation of information on cardiovascular (CV) events 
such as CV death, resuscitated cardiac arrest, nonfatal myocardial infarction (MI), and nonfatal stroke (ischemic 
and hemorrhagic). 
Pharmacology: N/A; not collected 
Statistical Methods:   
Sample Size and Power 
This is a long-term open label extension of the Phase II trial MDCO-PCS-16-01 (ORION-3),  and Phase III lipid-
lowering studies [MDCO-PCS-17-03 (ORION-9), MDCO-PCS-17-04 (ORION-10), or MDCO-PCS-17-08 (ORION-
11) ]. All eligible and willing subjects from these studies may be enrolled into this study. 
The statistical analysis are noncomparative. Sample size considerations do not apply. 
Efficacy Endpoint Analysis: 
All analysis will be descriptive. Confidence intervals will be provided whenever necessary.  
 
Safety Endpoint Analysis: 
The analysis of the safety endpoints will be descriptive. 
Interim Analysis: 
No interim analysis is planned in this study. 


Novartis 
Confidential 
Page 5 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
Table of contents 
Protocol Synopsis ................................................................................................................ 2 
Table of contents .................................................................................................................. 5 
List of tables ......................................................................................................................... 8 
List of figures ....................................................................................................................... 8 
List Of Abbreviations .......................................................................................................... 9 
Amendment 2 (06-Oct-2020) ............................................................................................. 11 
1 
Introduction ........................................................................................................................ 12 
1.1 
Background ............................................................................................................ 12 
1.1.1 
Disease Overview .................................................................................. 12 
1.1.2 
PCSK9 Biology and Target Rationale ................................................... 13 
1.1.3 
Mechanism of RNA Interference .......................................................... 13 
1.2 
Inclisiran, an siRNA Therapeutic for Hypercholesterolemia ................................. 14 
1.2.1 
Nonclinical Studies ................................................................................ 14 
1.2.2 
Clinical Studies ...................................................................................... 15 
1.3 
Known and Potential Risks and Benefits ............................................................... 18 
1.4 
Study Rationale ...................................................................................................... 19 
1.4.1 
Study Rationale ..................................................................................... 19 
1.4.2 
Dose Rationale ....................................................................................... 19 
1.5 
Study Population .................................................................................................... 19 
2 
Study Objectives and Purpose ........................................................................................... 19 
2.1 
Primary Objectives ................................................................................................. 19 
2.2 
Secondary Objectives ............................................................................................. 19 
3 
Study Design ...................................................................................................................... 20 
3.1 
Type/Design of Study ............................................................................................ 20 
3.2 
Schematic Diagram of Study Design ..................................................................... 21 
3.3 
Primary Efficacy Endpoint..................................................................................... 21 
3.4 
Secondary Efficacy Endpoints ............................................................................... 21 
3.5 
Safety Endpoints .................................................................................................... 21 
3.6 
Measures to Minimize/Avoid Bias ........................................................................ 21 
4 
Subject Population ............................................................................................................. 22 
4.1 
Number of Subjects ................................................................................................ 22 
4.2 
Inclusion Criteria.................................................................................................... 22 
4.3 
Exclusion Criteria .................................................................................................. 22 
4.4 
Withdrawal Criteria................................................................................................ 23 
4.4.1 
Individual Subject Dosing Stopping Criteria ........................................ 23 
5 
Treatment of Subjects ........................................................................................................ 24 


Novartis 
Confidential 
Page 6 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
5.1 
Study Medications.................................................................................................. 24 
5.1.1 
Placebo .................................................................................................. 25 
5.1.2 
Packaging and Labeling ........................................................................ 25 
5.1.3 
Storage ................................................................................................... 25 
5.1.4 
Accountability ....................................................................................... 25 
5.1.5 
Product and Device Deficiencies Reporting .......................................... 26 
5.2 
Concomitant Medications ...................................................................................... 26 
5.2.1 
Prohibited Concomitant Medications .................................................... 26 
5.2.2 
Permitted Concomitant Medications ..................................................... 27 
5.3 
Medical Management Guidelines .......................................................................... 27 
5.3.1 
Adverse events ....................................................................................... 27 
5.3.2 
Pregnancy .............................................................................................. 27 
5.4 
Restrictions............................................................................................................. 27 
6 
Schedule and sequence of procedures ............................................................................... 27 
6.1 
Schedule of Events/Assessments ........................................................................... 28 
6.2 
General Conduct of the Study ................................................................................ 31 
6.3 
Study Entry/Double-blind Treatment phase (Day 1) ............................................. 31 
6.4 
Open-label inclisiran Treatment Phase [Day 90 and Subsequent dosing visits] .... 32 
6.5 
End of Study Visit (Day 1080 or ≥ 90 days post final dose) ................................. 32 
7 
Protocol Assessments ........................................................................................................ 33 
7.1 
Assessment of Safety ............................................................................................. 33 
7.1.1 
Adverse Events ...................................................................................... 33 
7.1.2 
Demographics and Medical History ...................................................... 33 
7.1.3 
Vital Signs ............................................................................................. 33 
7.1.4 
Physical Examination ............................................................................ 33 
7.1.5 
Cardiovascular Events ........................................................................... 33 
7.1.6 
Clinical Laboratory Assessments .......................................................... 33 
7.1.7 
Stored samples ....................................................................................... 34 
7.2 
Assessment of Efficacy .......................................................................................... 35 
8 
Adverse Events .................................................................................................................. 35 
8.1 
Definitions .............................................................................................................. 35 
8.1.1 
Adverse Event ....................................................................................... 35 
8.1.2 
Serious Adverse Event .......................................................................... 35 
8.1.3 
Special Situations – Adverse Events ..................................................... 36 
8.2 
Collection and Assessment of Adverse Events ...................................................... 36 
8.2.1 
Adverse Event Severity ......................................................................... 36 
8.2.2 
Relationship to Investigational Product ................................................. 36 


Novartis 
Confidential 
Page 7 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
8.3 
Requirements For Additional Safety Data Collection ........................................... 36 
8.3.1 
Special Situations – Additional Safety Data Collection ........................ 36 
8.3.2 
Other safety related information ............................................................ 37 
8.4 
Procedure for Adverse Event Reporting ................................................................ 37 
8.4.1 
Serious Adverse Events (SAEs) ............................................................ 37 
8.4.2 
Non-Serious AEs ................................................................................... 38 
8.4.3 
Special situations – Adverse Event Reporting ...................................... 38 
8.5 
Expectedness .......................................................................................................... 38 
8.5.1 
Expectedness Determination ................................................................. 38 
8.6 
Study Stopping Criteria .......................................................................................... 39 
8.6.1 
Independent Data Monitoring Committee (IDMC) Stopping Rules ..... 39 
8.6.2 
Sponsor Discontinuation Stopping Criteria ........................................... 39 
9 
Data Collection .................................................................................................................. 39 
10 Statistical Plan .................................................................................................................... 40 
10.1 
Sample Size ............................................................................................................ 40 
10.2 
General Statistical Considerations and Definitions ............................................... 40 
10.2.1 
General Statistical Methods ................................................................... 40 
10.2.2 
Analysis Population - Safety population ............................................... 40 
10.2.3 
Analysis Windows ................................................................................. 40 
10.2.4 
Missing Data Handling .......................................................................... 41 
10.3 
Statistical Analyses ................................................................................................ 41 
10.3.1 
Demographic and Background Characteristics ..................................... 41 
10.3.2 
Study Drug and Concomitant Medications ........................................... 41 
10.3.3 
Efficacy Analysis................................................................................... 41 
10.3.4 
Safety Analysis ...................................................................................... 41 
10.4 
Interim Analysis ..................................................................................................... 42 
10.4.1 
Interim Safety Reviews ......................................................................... 42 
11 Records Retention .............................................................................................................. 42 
12 Quality Control and Quality Assurance ............................................................................. 43 
12.1 
Monitoring ............................................................................................................. 43 
12.2 
Auditing ................................................................................................................. 43 
12.3 
Protocol Deviations ................................................................................................ 43 
13 Ethics and Responsibility ................................................................................................... 44 
13.1 
Informed Consent ................................................................................................... 44 
13.2 
Institutional Review Board (IRB)/Ethics Committee (EC) ................................... 44 
14 Confidentiality ................................................................................................................... 45 
15 Investigator agreement ....................................................................................................... 45 


Novartis 
Confidential 
Page 8 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
16 References .......................................................................................................................... 47 
Appendix A: Sampson Criteria for Diagnosing Anaphylaxis ........................................... 51 
 
List of tables 
Table 1-1 
Renal Function Categories by Estimated CrCl Ranges ......................... 18 
Table 5-1 
Investigational Product .......................................................................... 24 
Table 6-1 
Schedule of Assessments ....................................................................... 29 
 
List of figures 
Figure 3-1 
Study Design ......................................................................................... 21 
 


Novartis 
Confidential 
Page 9 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
List Of Abbreviations 
 
AE 
adverse event 
ALP 
alkaline phosphatase  
ALT 
alanine aminotransferase  
aPTT 
activated partial thromboplastin 
ASCVD 
atherosclerotic cardiovascular disease  
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BUN 
total protein urea 
CFR 
Code of Federal Regulations 
CHD 
coronary heart disease 
CK 
creatine kinase 
Cmax 
maximum plasma concentration 
CrCl 
creatinine clearance 
CV 
cardiovascular 
CVD 
cerebrovascular disease  
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 
HbA1c 
glycated hemoglobin A1C 
HDL-C 
high density lipoprotein cholesterol 
HeFH 
heterozygous familial hypercholesterolemia 
HoFH 
homozygous familial hypercholesterolemia 
hsCRP 
high sensitivity C-reactive protein  
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals  
IDMC 
Independent Data Monitoring Committee 
IL6 
interleukin 6  
INR 
International normalized ratio  
IRB 
Institutional Review Board 
ISR 
injection site reaction 
IV 
intravenous 
LDL-C 
low density lipoprotein cholesterol 
LDLR 
low density lipoprotein receptor 
 
 


Novartis 
Confidential 
Page 10 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
LS mean 
least square mean 
MCH 
mean cell hemoglobin  
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MDCO 
The Medicines Company 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MI 
myocardial infarction 
mL 
milliliter(s) 
mmHg 
millimeters of mercury 
mmol 
millimole 
mRNA 
messenger ribonucleic acid 
PCS 
potentially clinical significant 
PCSK9 
proprotein convertase subtilisin/kexin type 9 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PT 
prothrombin time 
RISC 
RNA-induced silencing complex 
RNA 
ribonucleic acid 
RNAi 
ribonucleic acid interference 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
standard deviation 
siRNA 
small interfering ribonucleic acid 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
terminal half-life 
TBIL 
total bilirubin 
TC 
total cholesterol 
TEAE 
treatment emergent adverse event 
TTR 
target transthyretin 
ULN 
upper limit of normal 
US 
United States 
WHO 
World Health Organization 


Novartis 
Confidential 
Page 11 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
Amendment 2 (06-Oct-2020) 
Amendment rationale 
The first subject for this trial was enrolled in April 2019 and enrollment was completed in February 
2020 (with 2991 subjects enrolled).  
This amendment is written to address the change in sponsorship from The Medicines Company to 
Novartis after acquisition of The Medicines Company by Novartis in January 2020. At the time of 
this amendment, all subjects in the trial are receiving open label treatment.  Additional changes 
incorporate Novartis processes, language and change in sponsor contacts, allow for flexibility 
during the COVID-19 pandemic.  
Additional changes include: 
• Introduction of Novartis protocol number and IMP code: CKJX83906 and KJX839 
respectively 
• Handling of protocol deviations including those for COVID-19 related issues 
• COVID-19 considerations: remote visits and extended visit windows.    
• Update of section 5.1.5 about reporting of drug and  device deficiencies when using pre filled 
syringe 
• Incorporation of language about Sweden Specific Protocol Amendment in Section 3.1 
• Remove section 7.3 Assessment of Pharmacodynamics as deem not relevant 
• Amending Section 8.4.3.2 – Pregnancy, to include follow up on newborns for 12 months 
• Additional feeder trial to ORION-8 was added: ORION-3 (also referred to as 
CKJX839A12201E1) subjects can move over to ORION-8 after completing the treatment in 
the Phase II trial. 
• ORION-5 was deleted as feeder trial to ORION-8 
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 protocol number and IMP 
code. Additional minor changes to correct typos and provide clarifications were incorporated 
directly into the protocol.  
Changes to specific sections of the protocol are shown in the track changes version of the protocol 
using strike through red font for deletions and red underlined for insertions. 
IRBs/ECs 
A copy of this amended protocol will be sent to the Institutional Review Board (IRBs)/Ethics 
Committee (ECs) and Health Authorities as appropriate. 
The changes described in this amended protocol require IRB/IEC and Health Authority approval 
according to local regulations prior to implementation.  
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.  


Novartis 
Confidential 
Page 12 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
1 
Introduction 
 Inclisiran (also referred to as KJX839) is a novel synthetic ribonucleic acid (RNA) interference 
(RNAi) therapeutic used for the treatment of hypercholesterolemia. This protocol describes a study 
to evaluate the effect of inclisiran treatment on low density lipoprotein cholesterol (LDL-C) levels. 
This study is sponsored by Novartis and will be conducted in compliance with Good Clinical 
Practices (GCP) including the Declaration of Helsinki and all applicable regulatory requirements. 
1.1 
Background 
1.1.1 
Disease Overview 
Despite advances in treatment, cardiovascular disease (CVD) is the leading cause of death 
worldwide, resulting in over 17 million deaths annually (WHO 2016). Eighty percent of all CVD 
deaths are due to coronary heart disease (CHD) or strokes. Elevated LDL-C is a major risk factor 
for the development of CVD (Grundy et al, 2004; Go et al, 2014). Lowering LDL-C has been 
shown to reduce the risk of death or heart attack and within the range of effects achieved so far, 
the clinical risk reduction is linearly proportional to the absolute LDL-C reduction (Baigent et al 
2005). 
Approximately 100 million people worldwide are treated with lipid lowering therapies, 
predominantly statins, to reduce LDL-C and the associated risk of death nonfatal myocardial 
infarction (MI) and nonfatal stroke or associated events (Decision Resources Group, 2015). Yet 
residual risk for cardiovascular (CV) events remains and statins are associated with well-known 
limitations. First, not all patients reach LDL-C levels associated with optimal protection against 
clinical events (Foley et al, 2003; Baigent et al 2005; Davidson et al, 2005; CTT Collaborators et 
al, 2008; Foody et al, 2010). Second, not all patients tolerate statins or are able to take statins at 
sufficiently intensive doses. And third, observational studies have demonstrated that >50% of 
patients do not adhere to statin therapy for more than 6 months (Poluzzi et al, 2008; Mann et al, 
2010). 
There is an unmet need for additional treatment options beyond currently available treatments for 
lowering of the LDL-C level to reduce cardiovascular risk. 
Despite statins alone or in combination with other lipid lowering medications, current therapies 
for the management of elevated LDL-C remain insufficient in some patients (Jones et al, 2012; 
Jameson et al, 2014; Barkas et al 2015; Fitzgerald et al, 2017). This is particularly true in patients 
with pre-existing CHD and/or diabetes or a history of familial hypercholesterolemia (FH), who are 
at the highest risk and require the most intensive management (Davidson et al, 2005).  
Proprotein convertase subtilisin/kexin type 9 (PCSK9), a member of the serine protease family, 
plays a key role in controlling the levels of low-density lipoprotein receptors (LDLR) on the 
surface of hepatocytes (Khorova, 2017). PCSK9 is expressed and secreted into the bloodstream 
predominantly by the liver, binds LDLR both intracellularly and extracellularly and promotes the 
lysosomal degradation of these receptors in hepatocytes, (Lakoski et al, 2009; Mousavi et al, 2009) 
thereby increasing the circulating LDL-C levels. Loss of function mutations in PCSK9 have been 
found to lead to increased LDLR in liver, reduced serum LDL-C, and a lower risk for CHD (Berge 
et al, 2006; Cohen et al, 2006; Kotowski et al, 2006; Zhao et al, 2006) with no apparent negative 
health consequences. (Zhao et al, 2006; Hooper et al, 2007; Horton et al, 2009). 


Novartis 
Confidential 
Page 13 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
Recently developed and approved PCSK9-blocking monoclonal antibodies reduce circulating 
PCSK9 levels and lower LDL-C levels. Preliminary reports indicate that treatment with such 
antibodies can lead to reduction of cardiovascular events compared with placebo (Hooper et al, 
2005; Navarese et al, 2015; Robinson et al, 2015; Zhang et al, 2015; Sabatine et al, 2017). Results 
from the first completed large CV outcomes trial (FOURIER) were reported in March 2017. 
Repatha® (evolocumab) significantly reduced the risk of cardiovascular events. The study in 
approximately 27,000 patients with clinically evident atherosclerotic cardiovascular disease 
(ASCVD) met its primary composite endpoint (cardiovascular death, nonfatal MI, nonfatal stroke, 
hospitalization for unstable angina or coronary revascularization) and the key secondary composite 
endpoint (cardiovascular death, nonfatal MI or nonfatal stroke) (Sabatine et al, 2017).  
The data from PCSK9 blocking antibodies such as Repatha® (evolocumab) and Praluent® 
(arilocumab) are very encouraging. However, these products are dosed SC every 2 to 4 weeks 
necessitating up to 26 injections per year (Hooper et al, 2005; Navarese et al, 2015; Zhang et al, 
2015). In contrast, one injection of inclisiran is anticipated to be given three times in the first year 
and every 6 months thereafter. 
1.1.2 
PCSK9 Biology and Target Rationale 
PCSK9 is a member of the subtilisin serine protease family. Proprotein convertase subtilisin kexin 
type 9 is predominantly expressed by the liver and is critical for the down regulation of hepatocyte 
LDLR expression (Mousavi et al, 2009). LDL-C levels in plasma are markedly elevated in humans 
with gain of function mutations in PCSK9, classifying them as having severe familial 
hypercholesterolemia (Abifadel et al, 2003). Data from genetic association studies have identified 
loss of function alleles in human PCSK9 that result in lower PCSK9 protein levels and lower LDL-
C levels (Zhao et al, 2006; Hooper et al, 2007; Horton et al, 2009). In one published study, 
heterozygous individuals (carrying a single copy of a loss of function PCSK9 mutation) had 
significantly lower LDL-C with median levels of approximately 70 mg/dL (1.81 mmol/L) (Cohen 
et al, 2006). Over a 15-year period of retrospective data analysis, this sustained lowering in LDL-
C levels translated to an 88% lower risk of risk for CHD. Follow-up publications describe two 
adult individuals that are compound heterozygous for loss of function alleles of PCSK9. These 
individuals lack detectable plasma PCSK9 protein, have LDL-C levels ≤20 mg/dL, and yet are 
otherwise healthy (Zhao et al, 2006; Hooper et al, 2007). Additionally, recent human clinical trials 
with PCSK9 blocking antibodies have shown significant lowering of LDL-C in healthy volunteers 
and across a range of high CV-risk populations and with elevated LDL-C both with and without 
statins (Banerjee et al, 2012; Dias et al, 2012; Milazzo et al, 2012; Raal et al, 2012; Roth et al, 
2012; Stein et al, 2012; Sullivan et al, 2012; Hooper et al, 2013). Two monoclonal agents to inhibit 
PCSK9 are currently approved in Europe and North America. Recent cardiovascular outcomes 
trials have further confirmed that PCSK9 is a validated drug target whose inhibition results in 
LDL-C lowering and significant outcomes benefit without otherwise negatively impacting overall 
health (Ridker et al, 2017; Sabatine et al, 2017).  
1.1.3 
Mechanism of RNA Interference 
Ribonucleic acid interference (RNAi) is a naturally occurring cellular mechanism for regulating 
gene expression that is mediated by small interfering RNAs (siRNAs). Typically, synthetic 
siRNAs are 19-base to 25-base pair double-stranded oligonucleotides in a staggered duplex with a 
two- to four-nucleotide overhang at one or both of the 3’ ends. Such siRNAs can be designed to 


Novartis 
Confidential 
Page 14 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
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 (IV) delivery of siRNA in lipid 
nanoparticle formulations (Soutschek et al, 2004; Morrissey et al, 2005; Geisbert et al, 2006; Judge 
et al, 2006; Zimmermann et al, 2006; Coelho et al, 2013; Tabernero et al, 2013). Another approach 
for liver-specific gene silencing is subcutaneously administered siRNA conjugated to a 
N-acetylgalactosamine (GalNAc) carbohydrate ligand (Ashwell and Morell, 1974). Conjugation 
of a triantennary GalNAc ligand to an siRNA enables hepatocyte binding and subsequent cellular 
uptake via the asialoglycoprotein receptor, resulting in engagement of the RNAi pathway and 
down regulation of hepatic proteins. Single and multiple doses of subcutaneously administered 
siRNA-GalNAc conjugates have been used to target transthyretin (TTR) mRNA for the treatment 
of TTR-mediated amyloidosis. ALN-TTRCSC has been found to be generally safe and well 
tolerated in Phase I and Phase II clinical trials in over 40 healthy volunteers and 18 subjects with 
familial amyloidotic cardiomyopathy and senile systemic amyloidosis (ALN-TTRSC-001; 
EudraCT 2012-004203-12; and ALN-TTRSC-002; EudraCT 2013-002856-33).  
1.2 
Inclisiran, an siRNA Therapeutic for Hypercholesterolemia 
Inclisiran sodium is a chemically synthesized siRNA double-stranded oligonucleotide, covalently 
linked to a ligand containing three GalNAc residues. 
Inclisiran is a long-acting, subcutaneously delivered, synthetic siRNA directed against PCSK9 that 
is conjugated to triantennary GalNAc carbohydrates. These carbohydrates bind to abundant liver-
expressed asialoglycoprotein receptor, leading to inclisiran uptake specifically into hepatocytes. 
When introduced into the hepatocyte, inclisiran engages the natural pathway of RNAi by binding 
intracellularly to the RNA-induced silencing complex (RISC), enabling it to cleave mRNA 
molecules encoding PCSK9 specifically. The cleaved PCSK9 mRNA is degraded and thus 
unavailable for protein translation, which results in decreased levels of the PCSK9 protein. A 
single siRNA-bound RISC is catalytic and cleaves many transcripts and the duration of action is 
anticipated to be longer than other mechanisms. 
1.2.1 
Nonclinical Studies 
Inclisiran was specifically designed with molecular and biochemical characteristics to minimize 
untoward side effects which are reflected by the absence of dose limiting toxicities in preclinical 
models. For example, GalNAc ligands were added to the RNA strands in order to target inclisiran 
to receptors on hepatocytes, thereby greatly reducing uptake by heterologous tissue. This is 
highlighted by tissue distribution studies in rats showing that compared to liver, inclisiran exposure 
in other tissues was 36-fold to 1076-fold lower than liver. 
 
 


Novartis 
Confidential 
Page 15 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
 
 
 
 
 
 
 
 
 
Inclisiran was well tolerated in all studies. The most common findings were related to the expected 
pharmacological effects of inclisiran on lipid profiles and histopathological findings of vacuolation 
in hepatocytes of rats and lymph node macrophages of monkeys and the presence of basophilic 
granules in hepatocytes of monkeys and kidneys of rats. These microscopic findings are not 
considered adverse because they are not associated with changes in clinical pathology parameters. 
Liver function enzymes were only minimally to mildly increased, and were reversible following 
treatment-free periods, and there were no changes in urinalysis or urine chemistry parameters.  
Additional non-clinical studies are ongoing or planned. 
1.2.2 
Clinical Studies 
1.2.2.1 
Clinical pharmacology 
Inclisiran is inactive in plasma and acts directly in the hepatocytes leading to inhibition of PCSK9 
protein synthesis. After SC administration of inclisiran, peak plasma concentrations were observed 
by 4 hours and became undetectable in plasma in 24 hours to 48 hours with an elimination terminal 
half-life (t1/2) of 7.3 hours and dose-proportional increase in exposure parameters of maximum 
plasma concentration (Cmax) and area under the curve (AUC). There was no accumulation of 
inclisiran plasma concentrations following multiple weekly, biweekly or monthly dosing. Mean 
fraction excreted unchanged in the urine was around 25%. In vitro studies using hepatic P450 
metabolic enzymes showed that inclisiran neither inhibited nor induced common hepatic metabolic 
pathways.  
In a Phase I study in subjects with renal impairment (ORION-7, also referred to as 
CKJX839A12103) (Section 1.2.2.2.4), a single 300 mg SC dose of inclisiran sodium which is 
equivalent to 284 mg inclisiran was observed to increase Cmax and AUC up to approximately two-
fold in subjects with mild and moderate renal impairment, and increased Cmax up to four-fold and 
AUC up to three-fold in subjects with severe renal impairment compared to subjects with normal 
renal function. However, by 48 hours plasma levels of inclisiran were below the level of 
quantification in all groups.  
Despite the differences observed in pharmacokinetic (PK) parameters over the first 48 hours 
following injection of inclisiran, there were generally no relevant differences between the groups 
with respect to PCSK9 reduction and LDL-C reduction. In addition, there was no difference in the 
overall safety profile between subjects with normal renal function and those with mild, moderate, 
or severe renal impairment. 
This finding is consistent with that observed in the previous Phase I (ALN-PCSSC-001, also 
referred to as CKJX839A12101.) study (Section 1.2.2.2.1) where doses above 300 mg, which is 


Novartis 
Confidential 
Page 16 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
equivalent to 284 mg inclisiran,  led to a dose related increase in PK parameters. A single 500 mg 
dose increased AUC two to three fold and Cmax four to five fold compared to a single 300 mg 
dose, which is similar to the increase observed in subjects with severe renal impairment compared 
to those with normal renal function in this study. In both the Phase I (ALN-PCSSC-001) and Phase 
II (ORION-1 also referred to as CKJX839A12201) studies single doses above 300 mg did not lead 
to greater reductions in PCSK9 or LDL-C levels over time or differences in the safety profile. 
These data support the administration of inclisiran to subjects with mild, moderate, or severe renal 
impairment in future and ongoing clinical studies with inclisiran. 
Additional clinical pharmacology studies are ongoing or planned. 
1.2.2.2 
Clinical  
Results are presented from four clinical studies: 
1.2.2.2.1 Study ALN-PCSSC-001 (also referred to as CKJX839A12101) 
ALN-PCSSC-001 (completed) was a Phase I study in which single (25 mg, 100 mg, 300 mg,  
500 mg and 800 mg) and multiple [125 mg once weekly (four doses), 250 mg every 2 weeks (two 
doses), 300 mg every 4 weeks (two doses) and 500 mg every four weeks (two doses)] doses of 
inclisiran sodium were evaluated. Subjects in this study were followed until their LDL-C levels 
returned to ≥80% of the baseline value or until 180 days after the last dose was given, whichever 
occurred first. At cumulative doses of 100 mg or greater, the majority of subjects reached 180 days 
of follow-up after the last dose, confirming the extended duration of action of inclisiran. No further 
follow-up occurred beyond this time point in this Phase I study. All adverse events (AEs) were 
mild or moderate (Grade 1 or 2) in severity with no differences relative to placebo other than skin 
reactions which were infrequent, mild and reversible following inclisiran. 
The Phase I study demonstrated that the 300 mg dose of inclisiran sodium administered as a single 
or multiple dose is the lowest dose to achieve near-maximal reductions in PCSK9 and LDL-C 
levels. Two 300 mg doses of inclisiran sodium given 30 days apart achieved an additional 10% 
LDL-C reduction compared to a single 300 mg dose. PK parameters of inclisiran demonstrated a 
short plasma half-life (t1/2 = ~6 hours) and did not correlate with the observed pharmacodynamic 
(PD) effects of inclisiran. 
1.2.2.2.2 Study ORION-1 (MDCO-PCS-15-01 also referred to as CKJX839A12201 
ORION-1 (MDCO-PCS-15-01, completed study) was a Phase II, double-blind, randomized, multi-
national, multi-center study in subjects with ASCVD or ASCVD-risk equivalents (eg, diabetes and 
FH) and elevated LDL-C despite maximum tolerated dose of LDL-C lowering therapies to 
evaluate the efficacy, safety, and tolerability of inclisiran injection(s). 
A total of 501 subjects were randomized to a single dose regimen of placebo, 200 mg inclisiran 
sodium, or 300 mg inclisiran sodium, 500 mg inclisiran sodium (on Day 1) or a double-dose 
regimen of placebo, 100 mg inclisiran sodium, 200 mg inclisiran sodium, or 300 mg inclisiran 
sodium (on Day 1 and Day 90). 
The 300 mg dose provided near maximal PCSK9 and LDL-C reductions. The 500 mg dose did 
not provide a meaningful further increase in PD effect. The double-dose regimen of 300 mg 
regimen led to reduced LDL-C of 52.6% (LS mean) compared to a 1.8% increase in the placebo 


Novartis 
Confidential 
Page 17 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
group (p<0.0001) at Day 180. Similarly, this regimen led to reduced PCSK9 of 69.1% (mean) 
compared to a 1.2% decrease in the placebo group at Day 180. At Day 360 (9 months after the 
second 300 mg dose), LDL-C reduction was 33.8%. 
There were no clinically significant safety observations other than mild-moderate, short-lived skin 
reactions at the injection site in approximately 5% of subjects. Local injection site reactions were 
not dose-related. 
1.2.2.2.3 Study ORION-2 (MDCO-PCS-16-02,  also referred to as CKJX839A12202) 
ORION-2 (MDCO-PCS-16-02 completed study) was a Phase II, open label, single arm, 
multicenter pilot study in subjects with homozygous familial hypercholesterolemia (HoFH). Four 
subjects were randomized and  received open-label inclisiran sodium 300 mg  SC on Day 1. The 
subsequent dosing interval was determined by PCSK9 level at Day 60 or 90 or rate of change of 
PCSK9 between Days 60 and 90.  In three subjects mean serum PCSK9 levels were not suppressed 
by >70% at Day 60 or 90, as compared to baseline and received a second injection on Day 90. 
Inclisiran treatment resulted in robust and durable reductions in PCSK9 levels in all four subjects 
treated at a dose of 300 mg SC. Three of the four subjects also had significantly reduced levels of 
LDL-C. One subject had a significant reduction in PCSK9 but not a concomitant reduction in LDL-
C. The mean percentage LDL-C reduction from baseline was 12.3% and 21.0% at Day 90 and Day 
180, respectively. The maximum reductions in LDL-C were at Day 120 for two subjects and at 
Day 150 for a third subject. Therefore, the second dose achieved a greater reduction in LDL-C 
than after the first dose. 
The mean percentage PCSK9 reduction from baseline was 59.0% and 62.9% at Day 90 and Day 
180, respectively. Decreases in other lipids, lipoproteins, and apolipoproteins were commensurate 
with the decreases in LDL-C. 
No safety observations were noted and inclisiran was generally well tolerated. Three of the four 
subjects reported adverse events. None were considered related to study drug and the majority 
have resolved. One adverse event of leg pain was not resolved at the most recent visit. There were 
no deaths and one SAE (unstable angina, which was not considered related to study drug). No 
subjects withdrew due to an adverse event and no adverse events at the injection site were reported. 
Elevations in chemistry parameters were observed. One subject with an elevated total bilirubin 
(>1x ULN) at screening experienced a single elevation of total bilirubin >2x ULN on Day 120. 
There were no ALT or AST elevations >3 x ULN or CK elevations >5x ULN. 
 
 
The results from this pilot study support the 300mg dose and dose regimen for the ongoing Phase 
III ORION-5 study in HoFH. 
1.2.2.2.4 Study ORION-7 (MDCO-PCS-16-03, also referred to as CKJX839A12103) 
ORION-7 (MDCO-PCS-16-03); completed study) was a Phase I, single-dose, open-label study to 
evaluate the PK, safety, and PD of a single dose of inclisiran sodium 300 mg, SC injection in 
subjects with renal impairment compared to subjects with normal renal function. Subjects were 
classified into one of four renal function groups (normal, mild, moderate, and severe), as defined 


Novartis 
Confidential 
Page 18 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
by creatinine clearance (CrCl) which was calculated using the Cockcroft and Gault estimation 
from a spot serum creatinine level (Table 1-1). 
Table 1-1 
Renal Function Categories by Estimated CrCl Ranges 
Group 
Description 
Estimated CrCl (mL/min) 
1 
Normal renal function 
≥ 90  
2 
Mild renal impairment 
60 to 89 
3 
Moderate renal impairment 
30 to 59 
4 
Severe renal impairment 
15 to 29 
CrCl=creatinine clearance 
These subjects were matched for age (+/- 10 years), body weight (+/- 20%), and proportional race 
and gender in order to ensure that the normal renal function group was comparable to the renal 
impairment groups for average demographics. Thirty-one subjects were randomized into the study, 
eight subjects in each of the normal renal function and the mild and moderate renal impairment 
groups and seven in the severe renal impairment group. All subjects completed the study to Day 
60. 
In individuals with mild, moderate and severe renal impairment, inclisiran Cmax was 2.33, 1.97 and 
3.31 fold higher, respectively; AUC0-24 was 1.75, 1.91 and 2.50 fold higher, respectively; AUC0-48 
was 1.58, 1.83 and 2.33 fold higher, respectively; AUC0-t was 1.53, 1.73 and 2.35 fold higher, 
respectively; AUC0-inf was 1.44, 1.39 and 2.23 fold higher, respectively, relative to subjects with 
normal renal function. However, inclisiran was not detectable in plasma 48 hours after 
administration of a single 300 mg dose in any group irrespective of renal impairment. 
At Day 60, LDL-C (beta-quantification) was reduced by 57.56%, 35.11%, 53.09%, and 49.20%, 
in the normal renal function group and the mild, moderate, and severe renal impairment groups 
respectively. Mean LDL-C reduction was less in the mild renal impairment group compared to the 
other three groups. Overall, LDL-C reduction was generally similar between groups with no 
impact of renal function on LDL-C response. 
A single injection of 300 mg inclisiran was generally well tolerated in all study groups with no 
clinically significant safety findings to date. There was no difference in the overall safety profile 
between subjects with normal renal function and those with mild, moderate, or severe renal 
impairment and therefore no dose adjustment of inclisiran is considered necessary in subjects with 
renal impairment. 
1.3 
Known and Potential Risks and Benefits 
Subjects taking part in this clinical study will receive guideline recommended standard of care as 
background therapy (including maximally-tolerated statin therapy and/or other LDL-C lowering 
therapies) when administered inclisiran. Reduction of LDL-C has been associated with reduced 
CV risk both by epidemiology and in controlled clinical trials. Injection site reaction is the only 
event known to be attributed to inclisiran treatment. The safety profile of inclisiran observed to 
date is considered acceptable for this clinical trial.  
An expanded risk-benefit summary is provided in the current/approved version of the investigator 
brochure (IB). 


Novartis 
Confidential 
Page 19 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
1.4 
Study Rationale 
1.4.1 
Study Rationale 
The overall safety data from inclisiran in nonclinical studies and clinical data from the Phase I and 
Phase II study (ORION-1 also referred to as CKJX839A12201), and multiple PCSK9 antibody 
studies demonstrated that potent lowering of PCSK9 is well tolerated in human subjects and 
support the dose and dosing schedule proposed in this Phase III extension study. This extension 
study allows subjects continued access to inclisiran treatment and to allow the collection of 
additional efficacy and safety beyond the end of the original studies. 
1.4.2 
Dose Rationale 
Previous studies have shown that a 300 mg dose of inclisiran sodium is well tolerated and provides 
maximum efficacy (ie, doses higher than 300 mg did not provide additional efficacy in LDL-C 
lowering). Subjects completing the Phase II trial MDCO-PCS-16-01 (ORION-3, also referred to 
as CKJX839A12201E1) or one of the Phase III lipid lowering studies [MDCO-PCS-17-03  
(ORION-9, also referred to as CKJX839A12303), MDCO-PCS-17-04 (ORION-10, also referred 
to 
as 
CKJX839A12304) 
or 
MDCO-PCS-17-08 
(ORION-11, 
also 
referred 
to 
as  
CKJX839A12305) ] and fulfilling all inclusion and exclusion criteria of this study will receive 
inclisiran sodium 300mg at the next time point they are scheduled as per the previous study to 
receive inclisiran i.e. 180 days after the last injection in the previous study. Modelling and 
simulation has demonstrated that this regimen will allow for the necessary robust and sustained 
reduction in PCSK9 (and LDL-C) and has the potential to tackle the lack of adherence generally 
seen in the chronic management of subjects with hypercholesterolemia. The 300 mg dose of 
inclisiran sodium will be used for the entire duration of this study for subjects receiving inclisiran.  
1.5 
Study Population 
This study will include male or female subjects who have completed a previous qualifying Phase 
II lipid lowering trial [MDCO-PCS-16-01 (ORION-3)]  or Phase III lipid-lowering ORION feeder 
study [MDCO-PCS-17-03 (ORION-9), MDCO-PCS-17-04 (ORION-10) or MDCO-PCS-17-08 
(ORION-11), ], and fulfill the study entry criteria.  
2 
Study Objectives and Purpose 
2.1 
Primary Objectives 
The primary objectives of the study are to evaluate: 
• The effect of inclisiran treatment on the proportion of subjects achieving prespecified LDL-C 
targets at end of study (EOS)   
• The safety and tolerability profile of long-term use of inclisiran  
2.2 
Secondary Objectives  
The secondary objectives of this study are to evaluate the effect of inclisiran on:  
• LDL-C levels  
• Other lipids and lipoproteins 


Novartis 
Confidential 
Page 20 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
3 
Study Design 
3.1 
Type/Design of Study 
This study will be a long-term extension of the Phase II lipid lowering trial [MDCO-PCS-16-01 
(ORION-3)] and Phase III lipid-lowering studies [MDCO-PCS-17-03 (ORION-9), MDCO-PCS-
17-04 (ORION-10), or MDCO-PCS-17-08 (ORION-11) . Up to 3300 subjects with atherosclerotic 
cardiovascular disease (ASCVD), ASCVD-risk equivalents (eg, diabetes and familial 
hypercholesterolemia), heterozygous 
 familial hypercholesterolemia (HeFH 
 
) and elevated LDL-C despite  treatment with LDL-C lowering therapies who are eligible 
and willing to participate may be enrolled.  The objectives of the study is to evaluate the efficacy, 
safety, and tolerability of long-term dosing of inclisiran. Informed consent will be obtained from 
subjects before the initiation of any study-specific procedures. The EOS visit in the previous feeder 
studies will be Day 1 in the extension trial except for subjects enrolled in Sweden.  Sweden Specific 
Protocol Amendment 1 (to Global Amendment 1 version, dated 1 Nov 2018) was implemented to 
allow limited lab tests to be done on Day 1 and to collect any safety information during the gap 
between feeder’s EOS and Day1of this study until ethics committee approval was granted in that 
country.  Subjects moving over from the open label ORION-3 study will not receive study 
medication at Day 1. Their first dose of study medication in this trial will be at day 90. This is to 
maintain their 6 months dosing schedule on inclisiran treatment. This trial will be a global, 
multicenter study in approximately 300 centers. 
The duration that each subject is expected to participate in this study is a maximum of 3 years or 
the occurrence of one of the following events, whichever occurs first: 
• a recommendation of discontinuation by the investigator or Sponsor, 
• a decision by the subject to discontinue for any reason, 
• an administrative decision is made to end the study 


Novartis 
Confidential 
Page 21 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
3.2 
Schematic Diagram of Study Design 
Figure 3-1 
Study Design 
 
3.3 
Primary Efficacy Endpoint  
The primary endpoint of this study is:  
Proportion of subjects who attain global lipid targets (entry criterion from respective previous 
study) for their level of ASCVD risk at EOS. 
3.4 
Secondary Efficacy Endpoints  
The secondary endpoints of this study are: 
• Absolute change and percentage change in LDL-C from baseline (defined as baseline in 
feeder study) to EOS 
• Absolute change and percentage change in other lipids and lipoprotein from baseline (defined 
as baseline in feeder study) to EOS 
3.5 
Safety Endpoints 
The safety endpoint of this study is: 
• To evaluate the safety and tolerability profile of long-term use of inclisiran   
3.6 
Measures to Minimize/Avoid Bias  
This is a long-termextension study. Subject enrollment will be based on completion of one of the 
Phase III lipid-lowering feeder studies [MDCO-PCS-17-03 (ORION-9), MDCO-PCS-17-04 
(ORION-10) or MDCO-PCS-17-08 (ORION-11)] or Phase II trial [MDCO-PCS-16-01 (ORION-
3)]. To minimize bias, laboratory tests related to efficacy and safety will continue to be conducted 
via a central laboratory. 


Novartis 
Confidential 
Page 22 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
4 
Subject Population 
4.1 
Number of Subjects  
Approximately 3300 subjects will be studied at centers globally (approximately 300 sites). 
4.2 
Inclusion Criteria 
Subjects may be included in the study if they meet all of the following criteria: 
1. Completion of a previously qualifying Phase II lipid lowering trial [MDCO-PCS-16-01 
(ORION-3)] or Phase III lipid-lowering ORION feeder study [MDCO-PCS-17-03 (ORION-
9), MDCO-PCS-17-04 (ORION-10), or MDCO-PCS-17-08 (ORION-11) ] meaning the 
subject received the last dose of study drug and completed the final study visit per applicable 
protocol. 
2. On current lipid-lowering therapies (such as a statin and/or ezetimibe) from previous study 
with no planned medication or dose change during study participation. 
3. Willing and able to give informed consent before initiation of any study-related procedures 
and willing to comply with all required study procedures. 
4.3 
Exclusion Criteria 
Subjects will be excluded from the study if any of the following exclusion criteria apply 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. Severe concomitant noncardiovascular disease that carries the risk of reducing life 
expectancy to less than 3 years.  
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 >3x the upper limit of normal (ULN), or total bilirubin  
(TBIL) elevation >2x ULN at the last recorded visit in the feeder study prior to study entry 
visit. 
5. Females who are pregnant or nursing, or who are of childbearing potential and unwilling to 
use at least one method of acceptable effective 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  


Novartis 
Confidential 
Page 23 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
6. Planned use of other investigational medicinal products other than inclisiran or devices 
during the course of the study.  
7. Any condition that according to the investigator could interfere with the conduct of the study, 
such as but not limited to:  
a. Subjects who are unable to communicate or to cooperate with the investigator 
b. Unable to understand the protocol requirements, instructions and study-related 
restrictions, the nature, scope, and possible consequences of the study (including subjects 
whose cooperation is doubtful due to drug abuse or alcohol dependency) 
c. Unlikely to comply with the protocol requirements, instructions, and study-related 
restrictions (eg, uncooperative attitude, inability to return for follow-up visits, and 
improbability of completing the study) 
d. Have any medical or surgical condition, which in the opinion of the investigator would 
put the subject at increased risk from participating in the study 
e. Persons directly involved in the conduct of the study  
4.4 
Withdrawal Criteria 
All subjects have the right to withdraw from the study at any point during treatment without 
prejudice.  The investigator can discontinue any subject at any time if medically necessary. It will 
be documented whether or not each subject completed the clinical study. If study treatment or 
observations were discontinued, the reason will be recorded and the Sponsor should be notified 
promptly. The reasons that a subject may discontinue participation in a clinical study could be 
from one or more of the following: 
• AE(s) 
• Death 
• Subject withdrew consent 
• Physician decision 
• Lost to follow-up 
• Initiation of protocol-prohibited lipid-lowering therapy (eg, an approved PCSK9 inhibitor) 
The applicable reason(s) above will be recorded in the eCRF and subjects should be encouraged 
to complete the EOS visit. 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.  No further follow-up is allowed with the subject to collect additional information following 
discontinuation from the trial. 
4.4.1 
Individual Subject Dosing Stopping Criteria 
During the study subjects will have clinic visits at regular intervals. Dosing with inclisiran 
should be temporarily discontinued or stopped in subjects with:  
1. 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. Unexplained increases in transaminases (ALT or AST) or total bilirubin as follows: 
a. ALT or AST >8xULN 


Novartis 
Confidential 
Page 24 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
b. ALT or AST >5xULN for more than 2 weeks 
c. ALT or AST >3xULN and (total bilirubin >2xULN or INR >1.5) 
d. ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
The investigator should evaluate to see if other causes for the laboratory abnormalities are 
immediately apparent, such as obstructive gall bladder or bile duct disease, viral or alcoholic 
hepatitis, malignancy involving the liver, congestive hepatopathy, other hepatotoxins or 
heritable disorders. 
3. Unexplained creatine kinase (CK) values >5 x ULN confirmed by repeat test when the CK 
elevation is associated with muscle pain, muscle tenderness and/or muscle weakness, or new 
onset renal dysfunction.  
In the case that study medication is permanently discontinued the subject will be asked to return 
to complete an EOS visit, which should occur at least 90 days following the last dose of inclisiran. 
All subjects should be followed until all clinically significant laboratory abnormalities return to 
normal or to the baseline state.   Subjects discontinuing the trial due to withdrawal of consent or 
initiation of other PSCK9 lipid lowering therapies will not be followed up within the trial. 
5 
Treatment of Subjects 
5.1 
Study Medications 
Investigational product (Inclisiran for Injection also referred to as KJX839) information is 
described in Table 5-1. 
Table 5-1 
Investigational Product 
Product Name: 
Inclisiran for Injection 
Active ingredient 
inclisiran sodium 
Dosage Form: 
Solution for Injection 
Unit Dose 
Inclisiran sodium 300 mg/1.5 milliliter (mL) pre-filled syringe (equivalent to 284 mg 
inclisiran) for injection 
Route of Administration 
SC use 
Physical Description 
Clear, colorless to pale yellow solution essentially free of particulates 
Manufacturer 
, Italy. 
Investigational product preparation: The pharmacist or qualified designee will prepare the 
investigational product under aseptic conditions to be administered to the subject on that day.  
The procedure for preparing investigational product is provided in the Pharmacy Manual.  
Investigational product administration: Subjects will be administered a single SC injection of 
300 mg Inclisiran for Injection at predefined time points as described in the Schedule of 
Assessments (Table 6-1). Investigational product injection will be administered by qualified 
clinical study site staff under the supervision of the investigator or designee. The site of injection 
is the abdomen, arm or thigh, alternating sites for each injection. Do not inject into areas of active 
skin disease or injury such as sunburns, skin rashes, inflammation, tattoos or skin infections.  


Novartis 
Confidential 
Page 25 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
5.1.1 
Placebo 
The placebo pre-filled syringes will contain saline solution. Placebo pre-filled syringes will be 
blinded and look identical to the inclisiran pre-filled syringes. Placebo will be administered as a 
1.5 mL SC injection to match the dose of the inclisiran group. 
5.1.2 
Packaging and Labeling  
Investigational product (Inclisiran for Injection and matching placebo) will be provided by the 
sponsor. All pre-filled syringes, inclisiran or placebo, will look identical. Medication labels will 
comply with regulatory requirements. The storage conditions for each medication provided will 
be described on the medication label. 
The container closure system for the pre-filled syringe consists of a Type I glass syringe with a 
stainless steel 27G ½” staked needle covered by a removable rigid needle shield and Fluorotech 
coated bromobutyl plunger. 
All inclisiran and placebo investigational product used for the Day 1 dose will have a yellow 
shroud to maintain the blind.  
5.1.3 
Storage  
Investigational product (pre-filled syringes) will be stored at controlled room temperature (20°C 
to 25°C [68°F to 77°F] with allowable excursions between 15°C and 30°C [59°F to 86°F]) as 
specified in the Pharmacy Manual. Access should be strictly limited to the investigator, 
pharmacists, and their designees. No special procedures are required for the safe handling of 
Inclisiran for Injection. 
5.1.4 
Accountability  
The investigator or designee must maintain an inventory record of the investigational product 
(inclisiran/placebo) received and all administered to assure the regulatory authorities and the 
Sponsor that the new investigational product will not be dispensed to any person who is not a 
subject under the terms and conditions set forth in this protocol. Investigational product 
accountability forms and/or specific instructions can be found in the Pharmacy Manual. 
The investigational product supplied for use in this study is to be prescribed only by the Principal 
Investigator or designated sub-investigators and may not be used for any purpose other than that 
outlined in this protocol. 
Since used syringes must be discarded during the study, the box that the pre-filled syringes came 
in will be kept until the monitor has reviewed the accountability records.  
All unused investigational product will be destroyed on site (or returned to the packaging and 
labeling facility for destruction) once the investigational product has been inventoried and the 
monitor has reviewed the accountability records. In the event that investigational product needs to 
be returned for any other reason, the site will receive a written request listing the investigational 
product lot number(s) to be returned and the reason for the return request. 


Novartis 
Confidential 
Page 26 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
5.1.5 
Product and Device Deficiencies Reporting 
Sites are required to report any product and device deficiency observed to Sponsor immediately 
but no later than 24 hours from the time of awareness All product and device deficiencies observed 
during the conduct of the trial and leading to a preference or Technical Quality Deficiency 
reporting must be recorded in the eCRF. 
 
Product deficiency reporting (complaints): 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 US 21 Code of Federal Regulations [CFR] 
211.198) and Medical Device Regulation (EU) 2017/745). 
There are two types of Product Deficiencies:  
Preference complaints: A report of dissatisfaction with service, delivery, packaging or other 
preference. 
Technical Quality Deficiency reporting (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 closure 
or the label  
• An indication that the product is mislabeled 
• An indication that the product is falsified, tampered with or adulterated 
• An indication that the product did not meet its pharmacologic effect, ie lack of efficacy 
• Medical Device Incidents/deficiencies (such as failure to deliver the drug, breakage of a 
syringe tip, breakage of needleless connector, failure to securely lock the syringe to a needle, 
etc); in case the drug or device deficiency is leading to an Adverse Event or Serious Adverse 
Event these have to be recorded on the CRF and reported as specified in Section 8,4. and 
relationship to the device or drug deficiency must be indicated. 
5.2 
Concomitant Medications  
5.2.1 
Prohibited Concomitant Medications 
The following medications/treatments are not permitted to be added during the study: 
• Medications prescribed to lower LDL-C (eg, statins, ezetimibe, lomitapide, mipomersen, 
niacin, colesevelam, bile acid absorption inhibitors, monoclonal antibodies directed towards 
PCSK9) 


Novartis 
Confidential 
Page 27 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
• Any medication taken for the purpose of lipid lowering, including over-the-counter or herbal 
therapies 
5.2.2 
Permitted Concomitant Medications 
The following medications/treatments are permitted during the study: 
• Hormone replacement therapy  
• Lipid-lowering medications; subjects already on a stable lipid-lowering medication at 
enrollment (such as statins and/or ezetimibe) should remain on the dose that they have 
received during participation in the previous feeder study  protocol unless clinically indicated 
• 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 becomes pregnant during the course of 
the study, the investigational product administration must be discontinued and the pregnancy 
should be followed through to outcome. Follow-up information on newborns will be sought. 
Reporting of pregnancy and any associated AEs are specified in Section 8.4.3.2. 
5.4 
Restrictions  
Subjects will have to comply with the following restrictions during the study: 
• Fasted for at least 8 hours for all visits for fasting lipids and glucose blood samples 
• Blood donation will not be allowed at any time during the study  
• Must refrain from unaccustomed strenuous physical exercise for 48 hours before the 
screening and any study visit until the follow-up has been completed  
6 
Schedule and sequence of procedures 
The Schedule of Events/Assessments (Table 6-1) summarizes the study assessments by time point.  
This study will be a long-term extension study for subjects considered “completers” of the Phase 
II lipid lowering MDCO-PCS-16-01 (ORION-3) or Phase III lipid lowering ORION feeder studies 
[MDCO-PCS-17-03 (ORION-9), MDCO-PCS-17-04 (ORION-10), or MDCO-PCS-17-08 
(ORION-11) ]. A “completer” of the previous study is defined as having received the final protocol 
dose of study drug and completing the final study visit/and being considered a successful 
completion during the EOS visit. The EOS visit in the previous feeder study will be Day 1 in 


Novartis 
Confidential 
Page 28 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
ORION-8 trial except for subjects enrolled in Sweden (Section 3.1 and Section 6.3). The expected 
duration of the subjects’ involvement in the study will be a maximum of 3 years. 
On Day 1 (EOS visit in the feeder study), subjects will receive blinded study medication except 
for subjects moving over from ORION-3. These subjects will receive the first study medication at 
day 90. Subjects who received placebo in the previous Phase III feeder study will receive blinded 
inclisiran and subjects who received inclisiran in the previous feeder study will receive blinded 
placebo at this visit, in order to maintain the blinding of the feeder study until database lock of 
those studies.  
On Day 90, all subjects will receive inclisiran sodium 300 mg which is equivalent to 284 inclisiran. 
This is 180 days after the last injection in the previous feeder study for subjects that received 
inclisiran and will be the second dose of inclisiran for the subjects that received placebo in the 
feeder study.  
The three study periods are: 
• Study Entry (Day 1):   
• 
The EOS visit procedures from the previous ORION feeder study will be used as the 
Day 1 data for this study except for subjects enrolled in Sweden (Section 3.1 and Section 
6.3). In addition, consent and eligibility assessment for this study will be completed. 
• Treatment Phases:   
• 
Double Blind: Day 1 (blinded inclisiran or blinded placebo) to Day 90 
• 
Open Label: Day 90 (open label inclisiran for all subjects ) and subsequent dosing visits 
with inclisiran every 180 days 
• End of Study (EOS): 
• 
The EOS visit will occur at Day 1080 or  90 days following the last Inclisiran for 
Injection dose once one of the following criteria are met: 
• 
the investigator's recommendation of discontinuation 
• 
sponsor's recommendation of discontinuation 
• 
an administrative decision is made to end the study 
• 
NOTE:  For subjects prematurely and permanently discontinued from study treatment, 
who are not willing to return within the 90 day timeframe, the EOS visit will be 
scheduled as soon as possible, or if decision to discontinue and not return is made at a 
specific visit, this visit will become the EOS visit and EOS visit procedures should be 
followed. 
6.1 
Schedule of Events/Assessments 
The schedule of assessments is provided in Table 6-1. 
If the COVID-19 pandemic limits or prevents on-site study visits, alternative methods of providing 
continuing care may be implemented. Phone calls or 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 during the pandemic.


Novartis 
Confidential 
Page 29 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-05 (CKJX839A12306B) 
 
 
Table 6-1 
Schedule of Assessments 
 
Study Entry/ 
Double blind 
treatment 
Open Label Treatment Phase 
EOS 1 
Study Day 
Visit window (± days) 
Day 1 2  
(N/A) 
Day 90 
(First Dose) 
(±30) 
Subsequent dosing visits 3  
(i.e. Days 270, 450, 630, 810, 
990) 
(±30) 
Final Follow-up 
Day 1080 
(≥ 90 days post final 
dose) 
Informed consent 
x 
 
 
 
Inclusion/exclusion Criteria 
x 
 
 
 
Physical examination  
 
 
 
x 
Vital signs 4 
 
x 
x 
x 
Full serum chemistry 5 
 
 
 
x 
Limited serum chemistry 5 
 
x 
x 
 
Hematology and coagulation 6 
 
 
 
x 
Urinalysis (local) 7 
 
 
 
x 
Pregnancy test (local) 8 
 
x 
x 
x 
Lipids and lipoproteins 
 
x 
x 
x 
Double blinded inclisiran or placebo10, 11 
x 
 
 
 
Open label Inclisiran administration 11 
 
x 
x 
 
Concomitant medications 12 
 
x 
x 
x 
AE/SAE reporting 12  
 
x 
x 
x 
Drug and device deficiencies (including AE/SAEs 
related to the drug or device deficiency 
x 
x 
x 
x 
AE = adverse event; EOS = end of study; SAE = serious adverse event 
1.  EOS visit should occur at least 90 days following the last inclisiran dose once a decision is made to end the study (either by the subject, investigator or 
sponsor). For subjects prematurely and permanently discontinued from study treatment, who are not willing to return within the 90 day timeframe, the EOS visit will 
be scheduled as soon as possible, or if decision to discontinue and not return is made at a specific visit, this visit will become the EOS visit and EOS visit 
procedures should be followed. 
2.  Day 1 visit is the same as EOS visit in the previous qualifying ORION study. Aside from informed consent and eligibility, procedures will not be repeated but will 
be those captured during feeder study EOS visit except for subjects enrolled in Sweden.   See Section 3.1.and Section 6.3 Sweden Specific Protocol Amendment 
1 (to Global Amendment 1 version), dated 1 Nov 2018. 
3.  Dosing visits will occur every 180 days until the study ends for each respective subject. Visit windows have been extended to +/-2 months due to COVID-19.    


Novartis 
Confidential 
Page 30 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-05 (CKJX839A12306B) 
 
 
4.  Vital signs: blood pressure and heart rate will be measured prior to injection on dosing days.  When available, an automated BP device is recommended for 
collection of BP and the result recorded to the nearest mmHg. The subject should be sitting at rest for at least 5 minutes prior to these assessments. One 
assessment for each vital sign (HR, BP) is required per applicable visit. 
5.  See Section 7.1.6.3 for details of specific tests to be analyzed 
6.  See Section 7.1.6.1 and Section 7.1.6.2 for details of specific tests to be analyzed 
7.  Urinalysis collection is prior to the injection; supplies from the central laboratory must be used to perform the urinalysis 
8.  Only in women of childbearing potential (performed locally, prior to any dosing, using central laboratory kit supplies and with results prior to injection; urine 
pregnancy test). Results of the pregnancy test from Day 540 of the feeder study will be used on Day 1 in ORION-8  
  
10.  Subjects who received blinded placebo in the feeder study will receive blinded inclisiran and subjects who received blinded inclisiran in the feeder study will 
receive blinded placebo on Day 1 in ORION-8. Subjects moving over from the ORION-3 trial will not receive any treatment at Day 1; all subjects were on inclisiran 
in the feeder trial and will receive their first dose of inclisiran in this study at day 90  
11. Subjects will be observed in the clinic for 30 minutes post injection in order to have additional vital and/or laboratory assessments completed if needed. For any 
suspected episode of anaphylaxis, the investigator will need to collect a blood sample for tryptase within 30 minutes of an onset of anaphylaxis (or as soon as 
logically possible). 
12.  Concomitant medications (relevant) and AE/SAE collection for this study will begin at time of consent and continue through EOS. Ongoing concomitant 
medications and AEs/SAEs from the feeder study will continue to be followed in this study until resolution. 


Novartis 
Confidential 
Page 31 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
 
6.2 
General Conduct of the Study 
Discussion about participation and consent for the ORION-8 study should occur after conduct of 
the ORION feeder study EOS procedures and include discussion that the EOS visit data in the 
previous study will be considered for Day 1 in this trial. Written informed consent will be obtained 
for this study by the principal investigator or designee from all subjects before the performance of 
any protocol-specific procedure. 
Please see the Schedule of Assessments (Table 6-1) for a detailed schedule and Section 7 for details 
of all tests required in each panel. 
6.3 
Study Entry/Double-blind Treatment phase (Day 1)  
The following procedures and laboratory assessments are conducted as part of the EOS visit from 
the feeder study and are not repeated for Day 1 of this trial. The same values/samples data will be 
used for  Day 1 assessments in  ORION-8  were applicable except for subjects enrolled in Sweden. 
Sweden Specific Protocol Amendment 1 (to Global Amendment 1 version, dated 1 Nov 2018) was 
implemented to allow limited lab tests to be done on Day 1 and to collect any safety information 
during the gap between feeder’s EOS and Day1of this study until ethics committee approval was 
granted in that country 
• Physical examination 
• Vital signs (blood pressure and heart rate) 
• Central clinical laboratory (full serum chemistry, hematology and coagulation) (Section 
7.1.6) 
• Urinalysis (performed locally, using central laboratory supplies) (Section 7.1.6.4) 
• Pregnancy test (performed locally, using central laboratory supplies) (women of childbearing 
potential only) (results of test must be reviewed prior to dosing) 
• Fasting lipid and lipoprotein profile (Section 7.2) 
 
 
• Concomitant medication assessment (relevant ongoing concomitant medications from feeder 
study are reported at this visit) 
• AE/SAE reporting (ongoing AEs/SAEs from feeder study are reported at this visit) 
The following ORION-8 specific procedures will be performed on Day 1: 
• Informed consent for the ORION-8 study 
• Assessment of inclusion and exclusion criteria 
• Administration of double-blinded placebo or inclisiran treatment (except for subjects moving 
over from ORION-3)  
The following additional procedures were performed on Day 1 for subjects in Sweden only and 
data used for Day 1 assessments (the feeder study EOS data was not used for the following 
assessments): 
• Central clinical laboratory (limited chemistry, hematology (no coagulation) (Section 7.1.6) 
• Pregnancy test (performed locally, using central laboratory supplies) (women of childbearing 
potential only) (results of test must be reviewed prior to dosing) 


Novartis 
Confidential 
Page 32 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
 
• Fasting lipid, lipoprotein profile and PCSK9 (Section 7.2) 
6.4 
Open-label inclisiran Treatment Phase [Day 90 and Subsequent 
dosing visits] 
Prior to the start of dosing of Inclisiran for Injection on Day 90, central laboratory blood results 
from Day 1 must be reviewed. If these results suggest any contraindication to treatment with 
Inclisiran for Injection, dosing should be delayed until repeat results at an interval agreed upon by 
the investigator and medical monitor have been conducted and returned to levels that deem dosing 
acceptable per investigator and medical monitor judgement (Section 4.2 and Section 4.3). The 
following procedures will be performed on Day 90 and every 180 days thereafter (see schedule of 
assessments): 
• Vital signs (blood pressure and heart rate) 
• Central clinical laboratory (limited serum chemistry) (Section 7.1.6.3) 
• Pregnancy test (performed locally, using central laboratory supplies with results prior to 
dosing) (women of childbearing potential only) 
• Fasting lipid and lipoprotein profile (Section 7.2) 
 
 
• Open-label inclisiran administration (all subjects) 
• Relevant concomitant medications assessment 
• AE/SAE reporting 
Subjects must be observed in the clinic for at least 30 minutes after injection. 
Should a subject develop signs or symptoms of anaphylaxis when investigational product is 
injected, the investigator will need to collect a blood sample for tryptase within 30 minutes of the 
onset of anaphylaxis (or as soon as logically possible). 
Detailed instructions for investigational product administration are found in the Pharmacy Manual.  
6.5 
End of Study Visit (Day 1080 or ≥ 90 days post final dose) 
A subject’s participation in the study is complete when the final visit (EOS) has occurred. The 
following assessments will be completed during this visit: 
• Physical examination (including weight) 
• Vital signs (blood pressure and heart rate)  
• Central clinical laboratory (full serum chemistry, hematology and coagulation) (Section 
7.1.6) 
• Urinalysis (performed locally, using central laboratory supplies) 
• Pregnancy test (performed locally, using central laboratory supplies, if applicable) (women 
of childbearing potential only) 
• Fasting lipid and lipoprotein profile (Section 7.2) 
 
 
• Relevant concomitant medication assessment 
• AE/SAE reporting 


Novartis 
Confidential 
Page 33 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
 
7 
Protocol Assessments 
7.1 
Assessment of Safety  
7.1.1 
Adverse Events  
Subjects will be carefully monitored for AEs by the investigator during the designated study period 
(see Section 8 for details).  
7.1.2 
Demographics and Medical History 
Baseline demographic and medical history information from the previous ORION study will be 
used. 
7.1.3 
Vital Signs 
Vital signs include heart rate and blood pressure. 
7.1.4 
Physical Examination 
The physical examination should include a focused examination, which may include general, 
respiratory, cardiovascular, neurological, abdominal, and extremities evaluations, and recording 
of weight.  
7.1.5 
Cardiovascular Events 
Information on CV events such as CV death, resuscitated cardiac arrest, nonfatal MI, and nonfatal 
stroke (ischemic and hemorrhagic) will be collected as AE data. 
7.1.6 
Clinical Laboratory Assessments 
Specimens will be obtained at the time points in the Schedule of Assessments (Table 6-1).  
Subjects will be in a fasted state for all clinical laboratory assessments. Study entry laboratory tests 
(EOS tests from the original qualifying Phase II or Phase III lipid lowering ORION feeder study) 
will be performed by the central laboratory, with the exception of urinalysis and pregnancy test, 
which will be done in house at the participating institution’s laboratory using testing materials 
supplied by the central laboratory. Details regarding the processing, shipping, and analysis of 
samples will be provided in the Laboratory Manual. Note: Efficacy laboratory assessments 
(eg, LDL-C) are described in Section 7.2. 
7.1.6.1 
Hematology 
Blood draws for hematology will include: 
• Hemoglobin, hematocrit, erythrocytes, reticulocytes, mean cell hemoglobin (MCH), mean 
corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), platelet 
count, white blood cell count with differential.  
7.1.6.2 
Coagulation 
Blood draws for coagulation will include: 


Novartis 
Confidential 
Page 34 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
 
• Prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin 
(aPTT) 
7.1.6.3 
Chemistry 
Blood draws for chemistry will be performed per the Schedule of Assessments (Table 6-1). 
Analysis will vary based visit day as follows: 
• Full serum chemistry  
AST, ALT, alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), total bilirubin 
(TBIL), direct and indirect bilirubin, creatine phosphokinase (CPK), lactate, bicarbonate, uric 
acid, creatinine, urea (BUN), estimated glomerular filtration rate (eGFR), sodium, potassium, 
calcium, inorganic phosphate, chloride, albumin, total protein, glucose (fasting), glycated 
hemoglobin A1C (HbA1C), high sensitivity C-reactive protein (hsCRP) and tryptase (as 
required) 
• Limited serum chemistry  
ONLY: AST, ALT, ALP, GGT, TBIL, CPK, creatinine, eGFR, HbA1C  and tryptase (as 
required) 
7.1.6.4 
Urinalysis 
Urinalysis will be performed at the time points defined in the Schedule of Assessments (Table 6-
1) and evaluated by dipstick analyses at the investigational site (a standardized dipstick test will 
be supplied by the central laboratory). Urinalysis will be performed from a sample of mid-stream 
urine. In case of abnormal results, microscopy and other assessments will be performed at the local 
laboratory and the abnormality recorded as an AE.  
The following parameters will be assessed:  
• Nitrite, protein, glucose, ketone, urobilinogen, bilirubin, red blood cells/erythrocytes, white 
blood cells/leukocytes, pH, urine sediment (microscopic examination will be only performed 
in the event of abnormalities) 
7.1.6.5 
Urine Pregnancy 
Urine pregnancy testing will be performed locally at the visits specified in the Schedule of 
Assessments (Table 6-1), using the supplies provided by the central laboratory. 
7.1.6.6 
Lipids / Lipoproteins 
Lipids and lipoproteins assessments are described in Section 7.2. 
 
 
7.1.7 
Stored samples 
The central laboratory will take aliquots of serum and plasma samples from the received routine 
blood sampling noted above and will store these 
 


Novartis 
Confidential 
Page 35 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
 
 
 
 These samples will be retained 
on behalf of the Sponsor for a maximum of 1 year following the last subject's last visit in the study. 
Details regarding the collection, processing, storage, and shipping will be in the Study Laboratory 
Manual.   
7.2 
Assessment of Efficacy 
Subjects will be in a fasted state for all efficacy laboratory assessments of lipids and lipoproteins. 
Specimens will be obtained at the time points in the Schedule of Assessments (Table 6-1). 
Parameters to be assessed will include:  
• Total cholesterol (TC), triglycerides, LDL-C, and high density lipoprotein cholesterol (HDL-
C) 
8 
Adverse Events 
8.1 
Definitions 
8.1.1 
Adverse Event 
An Adverse Event is any untoward medical occurrence in a patient or clinical study subject 
administered a medicinal product that does not necessarily have a causal relationship with this 
treatment. An adverse event can therefore be any unfavorable and unintended sign (eg, an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product.  
8.1.2 
Serious Adverse Event 
A Serious Adverse Event is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening, ie, the subject was, in the opinion of the investigator, at immediate risk of 
death from the event as it occurred (it does not include an event that, had it occurred in a 
more severe form, might have caused death) 
• Results in a significant, persistent or permanent change, impairment, damage or disruption in 
the subject's body function/structure, physical activities and/or quality of life 
• Requires in-subject hospitalization or prolongs hospitalization 
• Is a congenital anomaly/birth defect 
• Is another medically significant event where medical and scientific judgement should be 
exercised in deciding whether other situations should be considered serious reactions, such as 
important medical events that might not be immediately life threatening or result in death or 
hospitalization but might jeopardize the patient or might require intervention to prevent one 
of the other outcomes listed above. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization or development of dependency or abuse. Any suspected 


Novartis 
Confidential 
Page 36 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
 
transmission via a medicinal product of an infectious agent is also considered a serious 
adverse reaction 
A distinction should be drawn between serious and severe AEs. Severity is an estimate or measure 
of the intensity of an AE, while the criteria for serious AEs are indications of adverse subject 
outcomes for regulatory reporting purposes. A severe AE need not necessarily be considered 
serious and a serious AE need not be considered severe. For example, nausea that persists for 
several hours may be considered severe nausea, but not an SAE. On the other hand, a MI that may 
be considered minor could be an SAE if it prolonged hospitalization. 
8.1.3 
Special Situations – Adverse Events 
There are situations when information is not necessarily considered an adverse event but can 
possibly contribute to the overall knowledge concerning the safety of the investigational product.  
Examples include, but are not limited to, reports of pregnancy/lactation exposures with or without 
any AEs related to the parent or child; medication errors – actual and potential; accidental 
exposure; suspected transmission via an investigational product of an infectious agent; drug 
interaction. 
8.2 
Collection and Assessment of Adverse Events 
8.2.1 
Adverse Event Severity 
The severity of AEs will be assessed by the investigator using the 3-point scale below: 
1 = Mild: Discomfort noticed, but no disruption to daily activity 
2 = Moderate: Discomfort sufficient to reduce or affect normal daily activity 
3 = Severe: Inability to work or perform normal daily activity 
8.2.2 
Relationship to Investigational Product  
The relationship between the AE and the investigational product will be assessed by using a 
binary assessment. The investigator should determine whether there is a ‘Reasonable possibility’ 
or ‘No reasonable possibility’ that the investigational product caused the event based on the 
definitions below. 
Reasonable possibility - There is a reasonable possibility that the administration of the 
investigational product caused the AE. There is evidence to suggest a causal relationship between 
the investigational product and the AE 
No reasonable possibility - There is no reasonable possibility that the administration of the 
investigational product caused the AE. There is no temporal relationship between the 
investigational product and event onset, or an alternative etiology has been established 
8.3 
Requirements For Additional Safety Data Collection 
8.3.1 
Special Situations – Additional Safety Data Collection 
Special Situations designated for this study include: 


Novartis 
Confidential 
Page 37 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
 
• Medication errors that fall into the following categories 
o wrong investigational product 
o wrong dose (including overdose, underdose, change in dosing regimen, strength, form 
concentration, amount) 
o wrong route of administration 
o wrong subject (ie, not administered to the intended subject) 
o accidental exposure  
• Pregnancy/lactation exposures with or without any AEs related to the parent or child  
• Suspected transmission via a medicinal product of an infectious agent  
• Drug interactions  
8.3.2 
Other safety related information 
Injection site reactions (ISR) including individual signs or symptoms at the injection site following 
investigational product administration should be recorded on specifically designed eCRF pages. 
Other safety related information that should be reported as adverse events in accordance with the 
process described in section 8.4 are: 
• Potential anaphylactic reactions assessed by Sampson criteria (APPENDIX A). If Sampson 
criteria are positive, confirm by elevation of tryptase in blood plasma measured within 
30 minutes of symptoms  
• Hyperglycemia-related AEs:  
Report ‘New onset of diabetes’ in subjects with no medical history of diabetes when: 
o HbA1C becomes ≥6.5% and/or 
o If a new concomitant medication for control of plasma glucose is added, further 
information to assess for a diagnosis of new onset diabetes will be collected 
Report ‘Worsening of the glycemic control’ or ‘diabetic complications’ in subjects with a medical 
history of disease (HbA1C ≥6.5% at baseline) when: 
o HbA1C increases from baseline > 0.5% and/or 
o New concomitant medication or increase in dose of current antidiabetic therapy is 
initiated to improve the control of plasma glucose level 
8.4 
Procedure for Adverse Event Reporting 
8.4.1 
Serious Adverse Events (SAEs) 
All SAEs that occur from consent (Day1) through EOS must be reported to Novartis safety  within 
24 hours of awareness of the event using the provided study specific SAE Report Form. Each SAE 
must also be recorded on the source documents and on the appropriate page of the eCRF.  
The investigator should provide any follow-up information for the event to the Sponsor on an 
updated SAE Report Form as soon as it becomes available. The Sponsor will contact the 
investigator, if necessary, to clarify any of the event information or request additional information. 


Novartis 
Confidential 
Page 38 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
 
If the investigator is notified of a SAE that occurs post-study period, that he or she wishes to report 
to the Sponsor (eg, an event suspected to be causally related to investigational product), the event 
should be reported through the process described above.  
Where appropriate, if required by local regulations or procedures, the investigator should report 
these events to the Institutional Review Board (IRB)/Ethics Committee (EC) and/or national 
regulatory authority in addition to the Sponsor.  
Detailed instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site. 
8.4.2 
Non-Serious AEs  
All non-serious AEs that occur from consent through EOS must be assessed and recorded on the 
source documents and eCRF, regardless of causal relationship to the investigational product.  
8.4.3 
Special situations – Adverse Event Reporting 
8.4.3.1 
Medication Errors 
All AEs (serious and non-serious) that occur in association with medication errors should be 
recorded in the AE page eCRF. Serious AEs should also be reported to Novartis safety   as 
described in section 8.4.1. No record of Medication Error itself should be included on the AE 
eCRF page. 
8.4.3.2 
Pregnancy/Lactation Exposure 
Occurrences of pregnancy/lactation exposure in a study subject from Day 1 through EOS must be 
reported to the Sponsor within 24 hours using the Pregnancy/Lactation Exposure Report Form.  
In cases where a pregnancy/lactation exposure occurs with a SAE, the SAE Report Form should 
be used to report the SAE and the Pregnancy/Lactation Exposure Report Form should be used to 
report the pregnancy/lactation exposure.  
When 
a 
pregnancy/lactation 
exposure 
occurs 
without 
any 
concurrent 
SAE, 
the 
Pregnancy/Lactation Exposure Report Form must be submitted alone.  
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. 
8.5 
Expectedness 
8.5.1 
Expectedness Determination 
Novartis safety department will be responsible for determining whether an AE is expected or 
unexpected for the purpose of suspected unexpected serious adverse reaction (SUSAR) reporting. 
An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the safety information previously described for the investigational product in the 
current/approved version of the Investigator’s Brochure. 


Novartis 
Confidential 
Page 39 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
 
8.6 
Study Stopping Criteria 
8.6.1 
Independent Data Monitoring Committee (IDMC) Stopping Rules 
The IDMC will use all available evidence and their collective judgment in making a 
recommendation to stop or modify the ORION-8 study for safety. Any statistical considerations 
are not a substitute for the committee’s medical, scientific, or statistical expertise. Details will be 
provided in the respective charter(s). 
8.6.2 
Sponsor Discontinuation Stopping Criteria 
The Sponsor will review data on an ongoing basis and may, on discussion with the IDMC terminate 
the study for any clinically significant drug related safety signal (eg, serious hypersensitivity 
reactions or drug induced liver injury, etc). 
Premature termination of a study may also occur because of a regulatory authority decision, change 
in opinion of the IRB/EC, drug safety problems, or at the discretion of the Sponsor. In addition, 
the Sponsor retains the right to discontinue development of inclisiran at any time.  
If a study is prematurely terminated or discontinued, the Sponsor will promptly notify the 
investigator. After notification, the investigator must contact all participating subjects and the 
hospital pharmacy (if applicable) within 30 days of the notification. Final study visits should occur 
within 30 days of subject contact. As directed by the Sponsor, all study materials must be collected 
and all eCRFs completed to the greatest extent possible. 
The Sponsor, or designee, will inform the health authorities and the IRBs/EC that the study has 
been stopped and the reasons for doing so, within the locally applicable timelines. 
9 
Data Collection 
An electronic data capture (EDC) system which is 21 CFR Part 11 compliant will be used for this 
study. Certain data points from the previous protocol participation (ORION-3, ORION-9, ORION-
10, or ORION-11) may be imported to the EDC system 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 UserID is 
not to be shared amongst the study staff. All users must have a unique account to enter or review 
data. The eCRF should be filled out by the site 3 days after each visit. It is not expected that the 
eCRF will serve as source for any data collected in this study. If there is a reason for a site to do 
so, it must be approved by Sponsor and documented in the site files. 
Prior to the database being locked, the investigator or designee will review, approve and sign/date 
each completed eCRF. This signature serves as attestation of the investigator’s responsibility for 
ensuring that all data entered into the eCRF are complete, accurate and authentic. After the end of 
the study, a copy of the data will be provided to the site. This copy will contain the final data, an 
audit trail of activity on the data, and any queries and answers that were posted for data 
clarification. For this study, the end of the study will be defined as the last visit of the last subject. 


Novartis 
Confidential 
Page 40 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
 
10 
Statistical Plan 
This study will be a long-term extension study in up to 3300 subjects with ASCVD, ASCVD-risk 
equivalents (eg, diabetes and familial hypercholesterolemia), HeFH, 
 and elevated LDL-
C despite maximum tolerated dose of LDL-C lowering therapies who have completed one of the 
Phase III lipid lowering studies [MDCO-PCS-17-03(ORION-9), MDCO-PCS-17-04 (ORION-
10),  MDCO-PCS-17-08 (ORION-11), or Phase II ORION-3 trial (MDCO-PCS-16-01) ] and fulfill 
the entry criteria for this study in order to evaluate the efficacy, safety, and tolerability of long-
term dosing of inclisiran. Following completion of study procedure for the final visit in the feeder 
study, informed consent will be obtained from subjects before the initiation of any study-specific 
procedures. The EOS visit in the previous study will be Day 1 in ORION-8. This will be a global, 
multicenter study in approximately 300 centers. 
The duration that a subject is expected to participate in this study is a maximum of 3 years or the 
occurrence of one of the following events, whichever occurs first: 
• a recommendation of discontinuation by the investigator or Sponsor, 
• a decision by the subject to discontinue for any reason, 
• an administrative decision is made to end the study 
A separate Statistical Analysis Plan (SAP) document will provide more detailed specifications in 
data analysis and presentation. 
10.1 
Sample Size  
Up to 3300 subjects with atherosclerotic cardiovascular disease who have completed one of the 
Phase III lipid-lowering feeder studies [MDCO-PCS-17-03 (ORION-9), MDCO-PCS-17-04 
(ORION-10),  MDCO-PCS-17-08 (ORION-11) or Phase II ORION-3 trial (MDCO-PCS-16-01) ] 
and fulfill the entry criteria for this study will participate in this study. 
10.2 
General Statistical Considerations and Definitions  
10.2.1 
General Statistical Methods 
All study-collected data will be summarized using descriptive statistics, graphs, and/or raw data 
listings. Descriptive statistics for continuous variables will include number of subjects (n), mean, 
standard deviation (SD), median, quartiles (Q1 and Q3), minimum (min) and maximum (max) 
values. Analysis of categorical variables will include frequency and percentage. 
10.2.2 
Analysis Population - Safety population 
The safety population will be used for data analyses and/or presentation.  
All subjects who received at least one dose of study drug will comprise the safety population. 
Treatment classification will be based on the actual treatment received. This will be the primary 
population for the efficacy and safety analyses. 
10.2.3 
Analysis Windows 
The observational period for the study includes Day 1 (EOS visit in the previous study), the 
Treatment phase which consists of the first dose (Day 1), Day 90 dose, and subsequent dosing 


Novartis 
Confidential 
Page 41 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
 
visits every 180 days until Day 990 and EOS (Day 1080) visit.  Any event occurring beyond the 
defined observational period, even if collected in the e-CRF, will not be included in the planned 
statistical analysis.  However, all data, including that reported after the defined observational 
period, will be included in the subject data listings.   
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 except age collected from prior corresponding 
Phase III studies for each subject will be used for the summary using the safety population. For 
subjects moved over from the Phase II ORION-3 study, subject demographics and baseline 
characteristics collected at the ORION-3 study baseline will be used for this summary.  Age will 
be recalculated by adding the duration that each subject spent in the prior corresponding Phase II 
or  Phase III study 
10.3.2 
Study Drug and Concomitant Medications 
Summary of each prior (prebaseline in the previous corresponding Phase II or Phase III study) 
medication and concomitant medication will be provided. Medication will be coded with World 
Health Organization (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 Endpoints  
The primary efficacy analysis of this study is to assess the proportion of subjects who attain global 
lipid targets for their level of ASCVD at EOS. Confidence interval will be provided. 
10.3.3.2 Secondary Efficacy Endpoints  
The actual value, absolute and percentage change in LDL-C and other lipids parameters from 
baseline (defined as baseline in the corresponding Phase II  or Phase III feeder study) to EOS will 
be summarized over time. Descriptive statistics will be provided. 
10.3.4 
Safety Analysis 
The safety objectives of this study are to evaluate the safety and tolerability profile of inclisiran. 
The safety analysis will be descriptive.  
10.3.4.1 Adverse Events  
The Medical Dictionary for Regulatory Activities (MedDRA) dictionary will be used for coding 
AEs. An AE (classified by preferred term) occurring during the study drug treatment period will 


Novartis 
Confidential 
Page 42 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
 
be counted as a treatment emergent AE (TEAE) either if it is not present at Day 1 of this study or 
if it is present at Day 1 of this study but increased in severity during the treatment period. 
The number (percentage) of subjects reporting TEAEs for each preferred term will be tabulated by 
system-organ class, by system-organ class and severity, and by system-organ class and relationship 
to study drug.  If more than one event occurred with the same preferred term for the same subject, 
the subject will be counted only once for that preferred term using the most severe or related 
occurrence for the summary by severity, or relationship to study drug, respectively. 
10.3.4.2 Laboratory Tests  
Laboratory values will be summarized at each time point. Analyses will also be performed for each 
lab parameter for incidence rates of potentially clinical significant (PCS) values for subjects 
without PCS value at baseline (defined as baseline in the corresponding Phase II or Phase III feeder 
study), as well as without PCS value at Day 1 of the study 
10.3.4.3 Vital Signs 
Vital signs will be summarized descriptively at each scheduled time point. 
10.4 
Interim Analysis  
No formal interim analysis will be performed in this study. 
10.4.1 
Interim Safety Reviews 
The IDMC will review safety data on a regular schedule as specified in the IDMC charter from 
first subject enrollment in the double-blind phase until the end of the open label phase of the study. 
A recommendation may be taken to stop or amend the study at any of these reviews. 
11 
Records Retention 
The US Food and Drug Administration (FDA) regulations require all investigators participating in 
clinical study drug/device studies to maintain detailed clinical data for one of the following 
periods: 
• At least two years following the date on which a New Drug Application is approved by the 
FDA, or 
• Two years after the Sponsor notifies the investigator that no further application is to be filed 
with the FDA 
Similarly, current EU Directives / Regulations and International Conference on Harmonization 
(ICH) guidelines collectively require that essential clinical study documents (including case report 
forms) other than patient’s medical files must be retained for the following time period: 
• For at least 15 years after completion or discontinuation of the study 
• Or for at least two years after the granting of the last marketing authorisation in the European 
Community and when there are no pending or contemplated marketing applications in the 
European Community 
• Or for at least two years after formal discontinuation of clinical development of the study 
drug/device 


Novartis 
Confidential 
Page 43 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
 
Subject's medical files should be retained in accordance with applicable legislation and in 
accordance with the maximum period of time permitted by the hospital, institution or private 
practice.  The documents can be retained for a longer period, however, if required by the applicable 
regulatory requirements or by agreement with the Sponsor.  
To comply with these requirements, the investigator will not dispose of any records relevant to 
this study without either (1) written permission from the Sponsor or (2) providing an opportunity 
for the Sponsor to collect such records.  The investigator shall take responsibility for maintaining 
adequate and accurate hard copy source documents of all observations and data generated during 
this study, including the hard copy or discs of the final data received from the Sponsor.  Such 
documentation is subject to inspection by the Sponsor or its agents, the FDA and/or other 
regulatory agencies. 
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/her 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, 
study 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 have to be recorded in the 
e-CRF and will be reviewed periodically: 
• Informed Consent not signed prior to study entry in this study 
• Inclusion criteria violation 
• Exclusion criteria violation 
• SAEs not reported to sponsor within 24 hours 


Novartis 
Confidential 
Page 44 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
 
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 United States FDA regulations, the ICH GCP guidelines, the 
Declaration of Helsinki, and other local regulations, as applicable. 
13.1 
Informed Consent 
Written informed consent will be obtained from all subjects (or their guardian or legally authorized 
representative), and whenever possible, or as per IRB or EC guidelines before any study-related 
procedures (including any pre-treatment procedures) are performed. The investigator(s) has both 
ethical and legal responsibility to ensure that each subject (and their guardian or legally authorized 
representative) being considered for inclusion in this study is given a full explanation of the 
protocol. This shall be documented on a written informed consent form (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, or designee, 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 (IRB)/Ethics Committee (EC) 
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.  


Novartis 
Confidential 
Page 45 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
 
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 without written prior permission 
from the Sponsor.  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, unless otherwise agreed to in 
writing by the Sponsor. 
Only unique subject numbers in eCRFs will identify subjects.  Their full names may, however, be 
made known to a product regulatory agency or other authorized official if necessary. 
Sponsor commits to comply with all applicable data protection laws and regulations and take all 
appropriate measures to ensure that subjects’ data is processed securely and appropriately. Sponsor 
adheres to the privacy principles of notice, choice, accountability for onward transfer, security, 
data integrity, purpose limitation, access, and enforcement regarding the collection, use, and 
retention of personal information from European Economic Area countries and Switzerland.  In 
addition, Sponsor’s Global Commercial General Liability with Umbrella Liability and Global 
Products / Clinical Trial Liability policy includes coverage for the processing of subjects’ data 
15 
Investigator agreement 
I have read and understand the protocol (including the Investigator’s Brochure) and agree that it 
contains all the ethical, legal and scientific information necessary to conduct this study.  I will 
personally conduct the study as described. 
I will provide copies of the protocol to all physicians, nurses and other professional personnel 
responsible to me who will participate in the study. I will discuss the protocol with them to assure 
myself that they are sufficiently informed regarding the new study drug, inclisiran, the concurrent 
medications, the efficacy and safety parameters and the conduct of the study in general. I am aware 
that this protocol must be approved by the 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 screened or randomized in the study. 


Novartis 
Confidential 
Page 46 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
 
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 2 
 
Institution Name 
 
 


Novartis 
Confidential 
Page 47 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
 
16 
References 
ALN-TTRSC-001; EudraCT 2012-004203-12. 
ALN-TTRSC-002; EudraCT 2013-002856-33.  
Abifadel M, Varret M, Rabès JP, et al. Mutations in PCSK9 cause autosomal dominant 
hypercholesterolemia. Nat Genet. 2003;34(2):154-6. 
Ashwell G and Morell AG. The role of surface carbohydrates in the hepatic recognition and 
transport of circulating glycoproteins. Adv Enzymol Relat Areas Mol Biol. 1974;41:99-128. 
Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: 
prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. 
Lancet. 2005;8;366(9493):1267-78. 
Banerjee Y, Shah K, and Al-Rasadi K. Effect of a monoclonal antibody to PCSK9 on LDL 
cholesterol. N Engl J Med. 2012;366(25):2425-6; author reply: 2426. 
Barkas F, Liberopoulos EN, Kostapanos MS, et al. Lipid target achievement among patients with 
very high and high cardiovascular risk in a lipid clinic. Angiology. 2015;66:346 53. 
Berge KE, Ose L, Leren TP. Missense mutations in the PCSK9 gene are associated with 
hypocholesterolemia and possibly increased response to statin therapy. Arterioscler Thromb 
Vasc Biol. 2006;26:1094-100. 
Coelho T, Adams D, Silva A, et al. Safety and efficacy of RNAi therapy for transthyretin 
amyloidosis. N Engl J Med. 2013;369(9): 819-29. 
Cohen JC, Boerwinkle E, Mosley TH Jr, et al. Sequence variations in PCSK9, low LDL, and 
protection against coronary heart disease. N Engl J Med. 2006;354(12):1264-72. 
Cholesterol Treatment Trialists' (CTT) Collaborators, Kearney PM, Blackwell L, et al. Efficacy 
of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: 
a meta-analysis. Lancet. 2008;371:117-25. 
Davidson MH, Maki KC, Pearson TA, et al. Results of the National Cholesterol Education 
(NCEP) Program Evaluation ProjecT Utilizing Novel E-Technology (NEPTUNE) II survey and 
implications for treatment under the recent NCEP Writing Group recommendations. Am J 
Cardiol. 2005;96(4):556-63.  
Dias CS, Shaywitz AJ, Wasserman SM, et al. Effects of AMG 145 on low-density lipoprotein 
cholesterol levels: results from 2 randomized, double-blind, placebo-controlled, ascending-dose 
Phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins. J Am Coll 
Cardiol. 2012;60(19):1888-98. 
Dyslipidemia - Disease Landscape & Forecast. Decision Resources Group, December 2015. 
Elbashir SM, Garborth J, Lendeckel W, et al. Duplexes of 21-nucleotide RNAs mediate RNA 
interference in cultured mammalian cells. Nature. 2001;411(6836): 494-8. 
Fitzgerald K, White S, Borodovsky A, et al. A Highly Durable RNAi Therapeutic Inhibitor of 
PCSK9. N Engl J Med. 2017;376:41-51. 
Foley KA, Simpson RJ Jr, Crouse JR 3rd, et al. Effectiveness of statin titration on low-density 
lipoprotein cholesterol goal attainment in patients at high risk of atherogenic events. Am J 
Cardiol. 2003;92(1):79-81. 


Novartis 
Confidential 
Page 48 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
 
Foody JM, Sajjan SG, Hu XH, et al. Loss of early gains in low-density lipoprotein cholesterol 
goal attainment among high-risk patients. J Clin Lipidol. 2010;4(2):126-32. 
Geisbert TW, Hensley LE, Kagan E, et al. Postexposure protection of guinea pigs against a lethal 
ebola virus challenge is conferred by RNA interference. J Infect Dis. 2006;193(12):1650-7. 
Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics-2014 update: a report 
from the American Heart Association. Circulation. 2014;129:e28-e292. 
Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National 
Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 
2004;110(2):227-39. 
Hooper AJ, van Bockxmeer FM, Burnett JR. Monogenic hypocholesterolaemic lipid disorders 
and apolipoprotein B metabolism. Crit Rev Clin Lab Sci. 2005;42:515-45. 
Hooper AJ, Marais AD, Tanyanyiwa DM, et al. The C679X mutation in PCSK9 is present and 
lowers blood cholesterol in a Southern African population. Atherosclerosis. 2007;193(2):445-8. 
Hooper AJ and Burnett JR. Anti-PCSK9 therapies for the treatment of hypercholesterolemia. 
Expert opinion on biological therapy. 2013;13(3):429-35. 
Horton JD, Cohen JC, and Hobbs HH. PCSK9: a convertase that coordinates LDL catabolism. 
J Lipid Res. 2009;50 Suppl:S172-7. 
Investigator’s Brochure for Inclisiran. 
Jameson K, Zhang Q, Zhao C, et al. Total and low-density lipoprotein cholesterol in high-risk 
patients treated with atorvastatin monotherapy in the United Kingdom: analysis of a primary-care 
database. Curr Med Res Opin. 2014;30: 655-65. 
Jones PH, Nair R, Thakker KM. Prevalence of dyslipidemia and lipid goal attainment in statin-
treated subjects from 3 data sources: a retrospective analysis. J Am Heart Assoc. 
2012;1(6):e001800. 
Judge AD, Bola G, Lee AC, et al. Design of noninflammatory synthetic siRNA mediating potent 
gene silencing in vivo. Mol Ther. 2006;13(3):494-505. 
Khorova A. Oligonucleotide Therapeutics — A New Class of Cholesterol-Lowering Drugs. 
N Engl J Med. 2017;376;1:4-7. 
Kotowski IK, Pertsemlidis A, Luke A, et al. A spectrum of PCSK9 alleles contributes to plasma 
levels of low-density lipoprotein cholesterol. Am J Hum Genet. 2006;78:410-22. 
Lakoski SG, Lagace TA, Cohen JC, et al. Genetic and metabolic determinants of plasma PCSK9 
levels. J Clin Endocrinol Metab. 2009;94:2537-43. 
Mann DM, Woodward M, Muntner P, et al. Predictors of Nonadherence to Statins: A Systematic 
Review and Meta-Analysis. Ann Pharmacother. 2010;44:1410-21. 
Milazzo L and Antinori S. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. 
N Engl J Med. 2012;366(25):2425; author reply 2426. 
Morrissey DV, Lockridge JA, Shaw L, et al. Potent and persistent in vivo anti-HBV activity of 
chemically modified siRNAs. Nat Biotechnol. 2005;23(8):1002-7. 
Mousavi SA, Berge KE, and Leren TP. The unique role of proprotein convertase subtilisin/kexin 
9 in cholesterol homeostasis. J Intern Med. 2009;266(6):507-19. 


Novartis 
Confidential 
Page 49 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
 
 
 
 
Poluzzi E, Strahinja P, Lanzoni M, et al. Adherence to statin therapy and patients’ cardiovascular 
risk: a pharmacoepidemiological study in Italy. Eur J Clin Pharmacol. 2008;64:425–432. 
Raal F, Scott R, Somaratne R, et al. Low-Density Lipoprotein Cholesterol-Lowering Effects of 
AMG 145, a Monoclonal Antibody to Proprotein Convertase Subtilisin/Kexin Type 9 Serine 
Protease in Patients With Heterozygous Familial Hypercholesterolemia: The Reduction of 
LDL-C With PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder 
(RUTHERFORD) Randomized Trial. Circulation. 2012;126(20):2408-17. 
 
Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids 
and cardiovascular events. N Engl J Med. 2015;372:1489-99. 
 
 
Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients 
with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713-22. 
Sampson HA, Munoz-Furlong A, Bock SA, et al. Symposium on the definition and management 
of anaphylaxis: summary report. J Allergy Clin Immunol. 2005;115(3):584-91. 
Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the definition and 
management of anaphylaxis: summary report – Second National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 
2006, 117(2):391-7. 
Soutschek J, Akinc A, Bramlage B, et al., Therapeutic silencing of an endogenous gene by 
systemic administration of modified siRNAs. Nature. 2004;432(7014): 173-8. 
Stein EA, Mellis S, Yancopoulos GD, et al. Effect of a monoclonal antibody to PCSK9 on LDL 
cholesterol. N Engl J Med. 2012;366(12): 1108-18. 
Sullivan D, Olsson AG, Scott R, et al. Effect of a Monoclonal Antibody to PCSK9 on Low-
Density Lipoprotein Cholesterol Levels in Statin-Intolerant Patients: The GAUSS Randomized 
Trial. JAMA. 2012;308(23):2497-506. 
Tabernero J, Shapiro GI, LoRusso, et al. First-in-Humans Trial of an RNA Interference 
Therapeutic Targeting VEGF and KSP in Cancer Patients with Liver Involvement. Cancer 
Discov. 2013;3(4):406-417. 
WHO, World Health Organization Cardiovascular diseases. 2016 
http://.who.int/mediacentre/factsheets/fs317/en/ 


Novartis 
Confidential 
Page 50 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
 
 
 
Zhao Z, Tuakli-Wosornu Y, Lagace TA, et al. Molecular characterization of loss-of-function 
mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet. 
2006;79(3):514-23. 
Zimmermann TS, Lee AC, Akinc A, et al. RNAi-mediated gene silencing in non-human 
primates. Nature. 2006;441(7089):111-4. 


Novartis 
Confidential 
Page 51 of 51 
Amended Protocol Version 02 (Clean) 
Protocol No. MDCO-PCS-17-02 (CKJX839A12306B) 
 
 
Appendix A: Sampson Criteria for Diagnosing Anaphylaxis 
Anaphylaxis is highly likely when any one of the following three criteria is fulfilled: 
• 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. 

SAP_001.pdf: 
Clinical Development 
KJX839/Inclisiran 
CKJX839A12306B (MDCO-PCS-17-05) / NCT03814187
A long-term extension trial of the phase III lipid-lowering trials to 
assess the effect of long-term dosing of inclisiran given as 
subcutaneous injections in subjects with high cardiovascular risk 
and elevated LDL-C (ORION-8)  
Statistical Analysis Plan (SAP)  
Document type: 
SAP Documentation 
Document status: 
Final 
Release date: 
04-Jul-2022
Number of pages: 
31 
Property of Novartis 
 Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Template Version 4.0, Effective from 23-Apr-2021


Novartis 
Confidential 
Page 2 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
04-
Jul-
2022 
Prior 
to 
DB 
lock 
Creation of 
final 
version 
N/A - First version 
NA 
 


Novartis 
Confidential 
Page 3 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
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 ........................................................... 10 
2 
Statistical methods ............................................................................................................. 10 
2.1 
Data analysis general information ......................................................................... 10 
2.1.1 
General definitions ................................................................................ 11 
2.1.2 
Decimal places ...................................................................................... 13 
2.2 
Analysis sets .......................................................................................................... 13 
2.2.1 
Subgroup of interest .............................................................................. 13 
2.3 
Subject disposition, demographics and other baseline characteristics .................. 13 
2.3.1 
Subject disposition ................................................................................ 13 
2.3.2 
Demographics and other baseline characteristics ................................. 14 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 16 
2.4.1 
Study treatment / compliance ................................................................ 16 
2.4.2 
Prior and concomitant therapies ............................................................ 17 
2.5 
Analysis supporting primary objective(s) .............................................................. 17 
2.5.1 
Primary endpoint ................................................................................... 17 
2.5.2 
Handling of missing values/censoring/discontinuations ....................... 18 
2.6 
Analysis supporting secondary objectives ............................................................. 18 
2.6.1 
Secondary endpoint(s) ........................................................................... 18 
2.6.2 
Handling of missing values/censoring/discontinuations ....................... 18 
2.7 
Safety analyses....................................................................................................... 18 
2.7.1 
Adverse events (AEs) ............................................................................ 18 
2.7.2 
Deaths .................................................................................................... 21 
2.7.3 
Laboratory data ..................................................................................... 21 
2.7.4 
Diabetes assessment .............................................................................. 22 
2.7.5 
Other safety data ................................................................................... 25 
2.8 
Pharmacokinetic endpoints .................................................................................... 26 
2.9 
PD and PK/PD analyses ........................................................................................ 26 
2.10 
Subject-reported outcomes .................................................................................... 27 


Novartis 
Confidential 
Page 4 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
2.11 
Biomarkers ............................................................................................................. 27 
2.12 
Other Exploratory analyses.................................................................................... 27 
2.13 
Interim analysis ...................................................................................................... 27 
3 
Sample size calculation ..................................................................................................... 27 
4 
Change to protocol specified analyses .............................................................................. 27 
5 
Appendix ........................................................................................................................... 27 
5.1 
Imputation rules ..................................................................................................... 27 
5.1.1 
Study drug ............................................................................................. 27 
5.1.2 
AE date imputation ............................................................................... 27 
5.1.3 
Concomitant medication date imputation ............................................. 27 
5.2 
Standardized MedDRA queries (SMQ) and AE terms for additional AE 
investigations ......................................................................................................... 28 
5.3 
Criteria for potentially clinically significant and clinically significant 
abnormal laboratory tests ....................................................................................... 29 
6 
Reference ........................................................................................................................... 31 
 
 
 


Novartis 
Confidential 
Page 5 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
 
List of tables 
Table 1-1 
Objectives and related endpoints .......................................................... 10 
 
List of figures 
Figure 1-1 
Study design ............................................................................................ 9 
 


Novartis 
Confidential 
Page 6 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
List of abbreviations 
 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ASCVD 
Atherosclerotic Cardiovascular Disease 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical classification system 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CHD 
Coronary Heart Disease 
CI 
Confidence Interval 
CK 
Creatine Kinase 
CS 
Clinically significant 
CVD 
Cerebrovascular Disease 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
DBL 
Database Lock 
EAIR 
Exposure-adjusted Incidence Rate 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
EOS 
End of Study 
GGT 
Gamma Glutamyl Transferase 
HbA1c 
Glycated Hemoglobin A1C 
HDL-C 
High-density Lipoprotein Cholesterol 
HeFH 
Heterozygous Familial Hypercholesterolemia 
HLGT 
High-level Group Term 
HLT 
High-level Term 
hsCRP 
High Sensitivity C-reactive Protein 
IA 
Interim Analyses 
LDL-C 
Low-density Lipoprotein Cholesterol 
LLN 
Lower Limit of the Normal range 
LLQ 
Lower Limit of Quantification 
LMT 
Lipid Modifying Therapy 
MACE 
Major Adverse Cardiovascular Event 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
PAD 
Peripheral Artery Disease 
PCS 
Potentially Clinically Significant 
PPC 
Post-Production Change 
PT 
Preferred Term 
SAE 
Serious Adverse Event 


Novartis 
Confidential 
Page 7 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SD 
Standard Deviation 
SMQ 
Standardized MedDRA Query 
SOC 
System Organ Class 
TBIL 
Total Bilirubin 
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 
WHO 
World Health Organization 


Novartis 
Confidential 
Page 8 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
 
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 the Phase III long-term extension trial 
CKJX839A12306B (ORION-8; MDCO-PCS-17-05). The purpose of this extension study is to 
evaluate the efficacy, safety, and tolerability of long-term dosing of inclisiran in subjects with 
atherosclerotic cardiovascular disease (ASCVD), ASCVD-risk equivalents (e.g., diabetes and 
familial hypercholesterolemia), or heterozygous familial hypercholesterolemia (HeFH) 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 CKJX839A12306B global amendment 2, content final dated 06-Oct-2020, and 
ORION-8 eCRF Post-Production Change (PPC) 1 (also called Revision 2 or R2) implemented 
on 23-Sep-2021. 
1.1 
Study design 
This study will be a long-term extension of the Phase II lipid lowering trial CKJX839A12201E1 
(ORION-3; MDCO-PCS-16-01), which is the extension study of CKJX839A12201 (ORION-
1; MDCO-PCS-15-01), and Phase III lipid-lowering studies CKJX839A12303 (ORION-9; 
MDCO-PCS-17-03), 
CKJX839A12304 
(ORION-10; 
MDCO-PCS-17-04), 
and 
CKJX839A12305 (ORION-11; MDCO-PCS-17-08). This trial will be a global, multicenter 
study in approximately 300 centers. Up to 3300 subjects with atherosclerotic cardiovascular 
disease (ASCVD), ASCVD-risk equivalents (e.g., diabetes and familial hypercholesterolemia), 
or heterozygous familial hypercholesterolemia (HeFH) and elevated LDL-C despite treatment 
with LDL-C lowering therapies who are eligible and willing to participate may be enrolled. The 
objective of the study is to evaluate the efficacy, safety, and tolerability of long-term dosing of 
inclisiran. Informed consent will be obtained from subjects before the initiation of any 
study-specific procedures. The End of Study (EOS) visit in the previous feeder studies will be 
Day 1 in this extension trial except for subjects enrolled in Sweden. Sweden Specific Protocol 
Amendment 1 (to Global Amendment 1 version, dated 1 Nov 2018) was implemented to allow 
limited lab tests to be done on Day 1 and to collect any safety information during the gap 
between feeder’s EOS and Day 1 of this study until ethics committee approval was granted in 
that country.  
Subjects rolled over from the Phase III studies (ORION-9/10/11) will receive blinded inclisiran 
sodium 300 mg which is equivalent to 284 mg inclisiran, or blinded placebo on Day 1 in this 
trial. Subjects who received placebo in the previous Phase III feeder studies will receive blinded 
inclisiran and subjects who received inclisiran in the previous Phase III feeder studies will 
receive blinded placebo at this visit, in order to 
- 
maintain the blinding of the feeder studies until database lock of those studies, 
- 
maintain the semi-annual dosing schedule for subjects who received inclisiran in the 
previous Phase III feeder studies, 


Novartis 
Confidential 
Page 9 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
- 
administer the first two doses of inclisiran on the three-monthly initial dosing schedule 
for subjects who received placebo in the previous Phase III feeder studies. 
All subjects will return at Day 90 for the next visit and will receive open label inclisiran sodium 
300 mg. 
Subjects moving over from the open-label ORION-3 study will not receive study drug at Day 
1. Their first dose of study drug in this trial will be at Day 90. This is to maintain their semi-
annual dosing schedule on inclisiran treatment.  
After the Day 90 dosing, subjects rolled over from all feeder trials (ORION-3/9/10/11) will 
return for open-label drug administration of inclisiran sodium 300 mg every 180 days until Day 
990. The EOS visit will be on Day 1080. For subjects who discontinued early, the EOS visit 
should be completed ≥ 90 days following the last inclisiran injection whenever possible. 
The duration that each subject is expected to participate in this study is a maximum of 3 years 
or the occurrence of one of the following events, whichever occurs first: 
- 
a recommendation of discontinuation by the investigator or Sponsor, 
- 
a decision by the subject to discontinue for any reason, 
- 
an administrative decision is made to end the study. In particular, the decision has been 
made to end the study after the last subject from ORION-9/10/11 completes the 3-year 
treatment (or discontinued early). As a result, ORION-3 rollover subjects will have 
shorter than 3 years of participation in this study. 
No formal interim analysis will be performed in this study. 
A schematic diagram of the study design is presented in Figure 1-1. Note that the study duration 
for ORION-3 rollover subjects will be shorter than the three-year duration illustrated in the 
diagram. 
Figure 1-1 
Study design 
 
 


Novartis 
Confidential 
Page 10 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
1.2 
Study objectives, endpoints and estimands  
The purpose of the study is to evaluate the efficacy, safety, and tolerability of long-term dosing 
of inclisiran. The objectives and the corresponding endpoints are listed in Table 1-1. 
Table 1-1 
Objectives and related endpoints 
Objectives 
Endpoints 
Primary objectives:  
The primary objectives of this study are to 
evaluate: 
Endpoints for primary objectives: 
• The effect of inclisiran treatment on the 
proportion of subjects achieving 
prespecified LDL-C targets at end of study 
(EOS) 
• Proportion of subjects who attain global 
lipid targets (entry criterion from respective 
previous study) for their level of ASCVD risk 
at EOS 
• The safety and tolerability profile of long-
term use of inclisiran 
• Adverse events (AE), clinical laboratory 
values, 
 vital 
signs, etc. (See Section 2.7 for all the 
safety analyses) 
Secondary objectives:  
The secondary objectives of this study are to 
evaluate the effect of inclisiran on: 
Endpoints for secondary objectives: 
• LDL-C levels 
• Absolute change and percentage change in 
LDL-C from baseline (defined as baseline in 
feeder study) to EOS 
• Other lipids and lipoproteins 
• Absolute change and percentage change in 
other lipids and lipoprotein from baseline 
(defined as baseline in feeder study) to 
EOS 
 
2 
Statistical methods 
The following sections contain important information on detailed statistical methodologies to 
be used in the analyses for the final CSR. 
2.1 
Data analysis general information 
All analyses will be performed by Novartis, 
 
 The most recent version of SAS available in the statistical programming environment 
of Novartis will be used for the analysis.   
Study-collected data will be summarized by the actual treatment groups of the feeder studies 
(Phase III Inclisiran-Inclisiran, Phase III Placebo-Inclisiran, ORION-3 Rollover) using 
descriptive statistics, graphs, and/or raw data listings. Categorical variables will be summarized 
using counts and percentages. Percentages are based on the number of subjects in the analysis 
set for whom there are non-missing data, unless otherwise specified. For selected categorical 
variables, the 95% confidence interval (CI) for the percentage will be calculated using Blaker’s 
method. Continuous variables, including changes from baseline, will be summarized using 


Novartis 
Confidential 
Page 11 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
descriptive statistics (n (number of non-missing observations), mean, standard deviation (SD), 
median, first and third quartiles (Q1 and Q3), minimum and maximum). For selected continuous 
variables, the CI for the mean will be provided. 
Absolute change and percent change from baseline will be calculated as follows: 
• Absolute change from baseline to Day X =Value at Day X – Baseline value. 
• Percent change from baseline to Day X = (Absolute change/Baseline value)*100%. 
For laboratory measurements below the lower limit of quantification (LLQ), LLQ/2 will be 
used as the numeric value for the measurement. For example, if numeric result is missing in the 
database and character result is “< 3”, the numeric result should be treated as 3/2 = 1.5 during 
analysis. 
Analyses for the final CSR will be conducted after the final database lock (DBL) of the study. 
The final DBL will be performed after ORION-9/10/11 rollover subjects either complete the 
Day 1080 visit or discontinue early and will not wait until ORION-3 rollover subjects complete 
Day 1080 visit. The ORION-3 rollover subjects will have shorter than 3 years of participation 
in this study, and their EOS visit will be scheduled 90 days after their last dosing visit. 
Information regarding DMC analysis will be provided in the DMC charter and a separate DMC 
SAP/TFL shells. 
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 subcutaneous (SC) 
injection of 300 mg inclisiran sodium (equivalent to 284 mg inclisiran)/1.5 mL pre-filled 
syringe. 
• Placebo: Placebo pre-filled syringes will contain saline solution and will be blinded and 
look identical to the inclisiran pre-filled syringes. Placebo will be administered as a 1.5 
mL SC injection to match the dose of inclisiran. 
Study day 
Study day will be defined as the number of days since ORION-8 Day 1, which is defined as the 
date of first study drug administration in ORION-8 for ORION-9/10/11 rollover subjects and 
the date of ORION-8 consent for ORION-3 rollover subjects. 
Therefore, for a particular date, study day will be calculated as follows: 
For dates on or after ORION-8 Day 1, 
 
Study day = Assessment date – Date of ORION-8 Day 1 + 1; 
For dates prior to ORION-8 Day 1, 
 
Study day = Assessment date – Date of ORION-8 Day 1. 


Novartis 
Confidential 
Page 12 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
Treatment group of the feeder studies 
For the rest of this document, “treatment group of the feeder studies” refers to the following 
three groups unless otherwise specified: 
• Phase III Inclisiran-Inclisiran: subjects who received inclisiran (actual treatment) in 
ORION-9/10/11 
• Phase III Placebo-Inclisiran: subjects who received placebo (actual treatment) in 
ORION-9/10/11 
• ORION-3 Rollover: subjects enrolled from ORION-3 
Reflexive LDL-C 
The endpoints involving LDL-C will use a reflexive LDL-C approach. When both calculated 
and beta-quantified LDL-C are available for a sample, calculated LDL-C will be used unless 
triglycerides are greater than 400 mg/dL or calculated LDL-C is less than 40 mg/dL. When only 
calculated LDL-C or beta-quantified LDL-C is available for a sample but not both, the available 
one will be used. 
Feeder study baseline 
When it refers to a timepoint, feeder study baseline is defined as the date/time of first study 
drug administration in ORION-1/9/10/11. 
When it refers to a laboratory parameter baseline, it is defined as the last available record with 
date/time ≤ date/time of feeder study baseline as defined above, unless otherwise specified. 
When time is not available for baseline or for the laboratory assessment, the comparison of 
date/time will be based on the date only. The same rule is applicable throughout this document 
to determination of chronological orders, unless otherwise specified. 
ORION-8 baseline 
When it refers to a timepoint, ORION-8 baseline is defined as follows: 
• For ORION-9/10/11 rollover subjects, ORION-8 baseline is defined as the date/time of 
first study drug administration in ORION-8.  
• For subjects rolled over from ORION-3, ORION-8 baseline is defined as the date 
(without time) of ORION-8 consent (Day 1).  
When it refers to a laboratory parameter baseline, it is defined as the last available record with 
date/time ≤ date/time of ORION-8 baseline as defined above, unless otherwise specified. Note 
that according to the definition of ORION-8 baseline above, when ORION-8 consent date is 
used as baseline, the comparison should be based on the consent date only and consent time 
should not be considered in the comparison even if it is available.  
For most subjects rolled over from ORION-9/10/11, the ORION-8 laboratory baseline will be 
the last available record in ORION-9/10/11, but for some subjects with a gap between feeder 
trial EOS and ORION-8 Day 1, this needs to be taken from ORION-8 laboratory data for certain 


Novartis 
Confidential 
Page 13 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
parameters. For subjects rolled over from ORION-3, the last available record up to ORION-8 
Day 1 (ORION-8 consent date) will be used. 
Last contact/participation date 
The last contact/participation date for a subject is the last available date across all the data 
collected for that subject. For a subject with a death event, the date of death will be used.  
2.1.2 
Decimal places 
The rules for decimal places in data presentation are the following: 
• All percentages and their confidence intervals will be presented to one decimal place.  
• Standard errors and standard deviations: data precision + 2 decimal places  
• Means, medians and quartiles: data precision + 1 decimal place  
• Minimums and maximums: same as data precision 
• Data precision of BMI will be 1 decimal place. 
• Total subject-years of exposure will keep one decimal place. 
2.2 
Analysis sets  
The safety population will be used for data analyses and/or presentation. 
Safety Population 
All ORION-3 rollover subjects who signed the informed consent to ORION-8, and all ORION-
9/10/11 rollover subjects with at least one study drug administration in ORION-8 will comprise 
the Safety Population. Treatment classification will be based on the actual treatment groups of 
the feeder studies (Phase III Inclisiran-Inclisiran, Phase III Placebo-Inclisiran, ORION-3 
Rollover). This will be the primary population for the efficacy and safety analyses. 
2.2.1 
Subgroup of interest 
In general, no subgroup analysis will be performed. Selected analyses in Section 2.7.4 for 
diabetes will be subgrouped by baseline diabetes or glucose control status. 
2.3 
Subject disposition, demographics and other baseline 
characteristics 
2.3.1 
Subject disposition 
The following information will be summarized for the Safety Population overall and by 
treatment group of the feeder studies: 
• The number of subjects in each analysis population 
• The number of subjects by country and site 


Novartis 
Confidential 
Page 14 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
• The number of subjects who completed the study and discontinued early, with reasons 
for discontinuation 
• The duration on study (days) 
• Protocol deviations and violations of subject restrictions 
Completers are defined as subjects indicated in the EOS page of eCRF to have completed the 
study. This will include ORION-9/10/11 rollover subjects who have completed the Day 1080 
visit, and ORION-3 rollover subjects whose study duration is shortened to < 3 years by the 
administrative decision only. 
The duration on study is defined as the number of days from Day 1 of ORION-8 to the date of 
last recorded contact/participation date in the database. 
2.3.2 
Demographics and other baseline characteristics 
The following demographics and baseline characteristics will be summarized for the Safety 
Population overall and by treatment group of the feeder studies: 
• Age (years) using descriptive statistics 
• Age categories:  ≥18 - <65, ≥65 
• Age categories:  ≥18 - <50, ≥50 - < 65, ≥65 - < 75, ≥75  
• Gender 
• Child-bearing potential of females 
• Weight (kg) 
• Height (cm) 
• Body mass index (BMI) (kg/m) 
• Race 
• Ethnicity 
• Country 
• Baseline estimated glomerular filtration rate (eGFR) (mL/min/1.73m) 
• Baseline eGFR categories: ≥15 - < 30, ≥30 - <60, ≥60 - <90, ≥90 
• Medical history (targeted and other medical history) 
For categorical variables in the list above, the percentages will be calculated based on total 
number of subjects (N) in a particular treatment group including subjects with a missing value. 
Subjects with a missing value will be counted in “Missing” category. 
Age at ORION-8 baseline will be calculated by (age collected at ORION-1/9/10/11 screening) 
+ floor[(ORION-8 consent date – ORION-1/9/10/11 consent date)/365.25], where floor(x) is 
the largest integer less than or equal to x. 


Novartis 
Confidential 
Page 15 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
Gender, race, and ethnicity will be taken from the data collected at ORION-1/9/10/11 screening.  
Country will be based on the subject’s participation site in ORION-8. 
For child-bearing potential of females, the percentages are out of the number of female subjects. 
If a female was determined not to have child-bearing potential in the feeder study, the subject 
will also have no child-bearing potential in ORION-8. If a female was determined to have child-
bearing potential in the feeder study, the subject’s child-bearing potential will be re-evaluated 
at ORION-8 Day 1 and the result of the re-evaluation will be used. 
The height collected at ORION-1/9/10/11 screening will be used as the baseline value for 
ORION-8, as no significant change in adult subjects’ height is expected. 
The last available weight in ORION-3/9/10/11 will be used as the baseline value for ORION-8. 
The BMI, which equals to weight in kilogram divided by (height in meter)2, will be calculated 
based on this weight. 
The baseline eGFR will use ORION-8 baseline data. 
Medical History 
Medical history (targeted and other medical history) from the initial feeder studies (ORION-
1/9/10/11) will be summarized for the Safety Population overall and by treatment group of the 
feeder studies. For other medical history, the sites are allowed to report in ORION-8 eCRF any 
relevant medical or surgical issues that occurred prior to consent in the initial feeder study but 
were not recorded in the feeder study, and such information added in ORION-8 eCRF should 
be combined with other medical history from feeder trial databases. Other medical history will 
be coded into Medical Dictionary for Regulatory Activities (MedDRA) terminology using the 
most recent MedDRA version before database lock (DBL), and will be summarized by primary 
system organ class (SOC) and preferred term (PT). 
For targeted medical history, the following data will be summarized: 
• Smoking status: Current, Former, Never, Unknown 
• Hypertension: Yes, No, Unknown 
• Hyperlipidemia: Yes, No, Unknown 
• Congestive heart failure: Yes, No, Unknown 
• Diabetes mellitus: Yes, No, Unknown 
• ASCVD status: ASCVD, ASCVD risk equivalent 
• Prior or current CHD (Coronary Heart Disease): Yes, No, Unknown 
• Prior or current CVD (Cerebrovascular Disease): Yes, No, Unknown 
• Prior or current PAD (Peripheral Artery Disease): Yes, No, Unknown 
• Family history of coronary artery disease: Yes, No, Unknown  
• Family history of dyslipidemia: Yes, No, Unknown 


Novartis 
Confidential 
Page 16 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
A subject is classified as ASCVD if CHD = Yes or CVD = Yes or PAD = Yes. Otherwise, the 
subject is ASCVD risk equivalent. 
In ORION-11, the questions for CHD, CVD and PAD are asked only when the subject is 
indicated as ASCVD in the subject type CRF question (only ORION-11 CRF has this question). 
Therefore, for ORION-11 subjects who are indicated as ASCVD risk equivalent, their answers 
to CHD, CVD and PAD questions are all implicitly “No”. 
For ORION-3 rollover subjects, CHD and CVD are derived as follows: 
• CHD: 
o If prior PCI (Percutaneous Coronary Intervention) = Yes or prior MI 
(Myocardial Infarction) = Yes or prior CABG (Cardiovascular Arterial Bypass 
Graft) = Yes, then CHD = Yes. 
o Else if prior PCI = Unknown or prior MI = Unknown or prior CABG = Unknown, 
then CHD = Unknown. 
o Else CHD = No. 
• CVD: 
o If prior stroke = Yes or prior TIA (Transient Ischaemic Attack) = Yes, then CVD 
= Yes. 
o Else if prior stroke = Unknown or prior TIA = Unknown, then CVD = Unknown. 
o Else CVD = No. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
Study drug administration will be summarized for the Safety Population overall and by 
treatment group of the feeder studies. The summary will include 
• The number and percentage of subjects dosed at each visit 
• The number and percentage of subjects administered 0, 1, 2, ... doses, and total number 
of doses administered 
• The number and percentage of injections at each injection site location (with total 
number of administered doses as the denominator for the percentage) 
• The number and percentage of injections with each injection volume (with total number 
of administered doses as the denominator for the percentage) 
• The number and percentage of subjects who missed 0, 1, 2, ... doses, and total number 
of missed doses. As per protocol, ORION-3 rollover subjects do not receive study 
medication on Day 1, thus ORION-3 rollover subjects who did not receive study 
medication on Day 1 do not count toward missed doses. 


Novartis 
Confidential 
Page 17 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
• The number and percentage of missed injections with each reason of not administering 
study drug (with total number of missed doses as the denominator for the percentage) 
The duration of exposure (days) to inclisiran and the total subject-years of exposure in ORION-
8 will be summarized for the Safety Population overall and by treatment group of the feeder 
studies.  
The duration of exposure to inclisiran is defined as the number of days from Day 1 of ORION-
8 to the earliest of the following: 
• Last recorded contact/participation date of ORION-8 
• Last study drug administration date in ORION-8 (if any) + 180 days 
2.4.2 
Prior and concomitant therapies 
Concomitant medications new or changed since ORION-8 baseline will be summarized by 3rd 
level Anatomical Therapeutic Chemical (ATC) classification and preferred name. Medications 
will be coded using the World Health Organization (WHO) drug dictionary. 
ORION-8 baseline concomitant lipid modifying therapies (LMT) and LMTs new or changed 
since ORION-8 baseline will be summarized by preferred name with dose and frequency. LMTs 
are medications with 2nd level ATC classification being C10 (lipid modifying agents) according 
to the coding by the WHO drug dictionary. LMTs will be grouped into statins and other LMT. 
Statins will be further 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. 
ORION-8 baseline concomitant LMT is defined as any LMT started before or on ORION-8 
Day 1 and either still ongoing or stopped on ORION-8 Day 1 or later. Any medications/LMT 
with start date > ORION-8 Day 1 are considered as new or changed concomitant 
medications/LMT. 
2.5 
Analysis supporting primary objective(s) 
The primary objective of the study is to evaluate: 
• The effect of inclisiran treatment on the proportion of subjects achieving prespecified 
LDL-C targets at EOS. 
• The safety and tolerability profile of long-term use of inclisiran. This objective will be 
addressed in Section 2.7. 
2.5.1 
Primary endpoint 
The primary efficacy analysis of this study is to assess the proportion of subjects who attain 
global lipid targets for their level of ASCVD at EOS. Summaries will include the number and 
percentage of subjects who attain global lipid targets for their level of ASCVD, along with the 
95% CI for the percentage. In addition, the proportion of subjects who attain global lipid targets 
for their level of ASCVD at ORION-8 baseline and at each scheduled visit from Day 90 to Day 


Novartis 
Confidential 
Page 18 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
1080 will be provided. The analysis will be performed for the Safety Population overall and by 
treatment group of the feeder studies. 
2.5.2 
Handling of missing values/censoring/discontinuations  
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 objectives of this study are to evaluate the effect of inclisiran on: 
• LDL-C levels 
• Other lipids and lipoproteins 
2.6.1 
Secondary endpoint(s) 
The actual value, absolute and percentage change in LDL-C and other efficacy parameters from 
feeder study baseline will be summarized over time using descriptive statistics. The 95% CI for 
the mean absolute and percentage change will also be provided. Other efficacy parameters 
include total cholesterol (TC), triglycerides, high density lipoprotein cholesterol (HDL-C), and 
high sensitivity C-reactive protein (hsCRP).  
All the parameters will be summarized at feeder trial baseline, at ORION-8 baseline, at each 
scheduled visit from Day 90 to Day 1080, and at EOS. The exception is that post-baseline 
hsCRP will be summarized at Day 1080 and EOS only because hsCRP in ORION-8 is only 
assessed at EOS per protocol.  
The analysis will be performed for the Safety Population overall and by treatment group of the 
feeder studies. 
2.6.2 
Handling of missing values/censoring/discontinuations  
Missing data will not be imputed. Subjects missing any required data for computing an endpoint 
will be excluded from its analysis. 
2.7 
Safety analyses 
The safety objectives of this study are to evaluate the safety and tolerability profile of long-term 
use of inclisiran. 
Unless otherwise specified, safety evaluations will be performed for the Safety Population 
overall and by treatment group of the feeder studies. 
Safety analyses are based on observed values and missing data will not be imputed. 
2.7.1 
Adverse events (AEs) 
The most recent version of MedDRA before DBL will be used for coding AEs. An AE will be 
counted as an ORION-8 treatment emergent AE (TEAE) if the AE started on or after ORION-
8 baseline or the AE was present prior to ORION-8 baseline but increased in severity on or after 


Novartis 
Confidential 
Page 19 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
ORION-8 baseline. Since the investigators are required to enter any worsened AE as a separate 
record, implementation-wise an AE is a TEAE as long as its onset date/time ≥ date/time of 
ORION-8 baseline.  
The following summaries will be presented for ORION-8 TEAEs using number and percentage 
of subjects with the event: 
• Overall Summary of TEAEs 
• TEAEs by primary SOC and PT 
• TEAEs by PT 
• TEAEs by primary SOC, PT, and maximum severity 
• TEAEs possibly related to study drug by primary SOC and PT 
• Treatment Emergent Serious AEs (TESAEs) by primary SOC and PT 
• TESAEs by PT 
• TESAEs possibly related to study drug by primary SOC and PT 
• TEAEs leading to withdrawal of study treatment by primary SOC and PT 
• TEAEs with a fatal outcome by primary SOC and PT 
Subject data listings will be presented for AEs with a fatal outcome, SAEs, and AEs leading to 
drug discontinuation. Those listings will include all AEs in ORION-8 database, regardless of 
whether they are ORION-8 TEAE. 
If more than one event occurred with the same SOC/PT for the same subject, the subject will 
be counted only once for that SOC/PT, using the most severe occurrence for the summary by 
severity. 
2.7.1.1 
AEs of special interest (AESI) and additional safety topics 
2.7.1.1.1 AEs at the injection site 
TEAEs at the injection site, which is an AESI, include all TEAEs identified as being an AE at 
the injection site on the AE page of eCRF or with “injection site reactions” as the high-level 
term (HLT). 
The number of injection site TEAEs per subject will be summarized using descriptive statistics 
as well as the number of subjects with 0, 1, 2, 3, ... injection site TEAEs. 
The following summaries will be presented for ORION-8 injection site TEAEs using number 
and percentage of subjects with the event: 
• Overall Summary of TEAEs 
• TEAEs by PT 
• TEAEs by PT and maximum severity 


Novartis 
Confidential 
Page 20 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
• TESAEs by PT 
• Signs and symptoms of TEAEs (only applicable to the events identified as AEs at the 
injection site on eCRF) 
• TEAEs by PT and worst outcome 
Outcomes of TEAEs ordered from worst to best will be: 
1) Fatal 
2) Not resolved 
3) Resolved with sequelae 
4) Unknown 
5) Resolving 
6) Resolved 
For subjects whose injection site TEAEs are all resolved (i.e. the worst outcome for the subject 
is “Resolved”), the duration (in days) of injection site TEAEs will be summarized using 
descriptive statistics. If a subject has multiple durations, the median time will be used for that 
subject. 
A subject data listing will be provided for injection site AEs. Such listing will include all AEs 
in ORION-8 database, regardless of whether they are ORION-8 TEAE. 
2.7.1.1.2 Other AESIs and AEs of additional safety topics 
Other AESIs include: 
• Hepatic events 
• Diabetes mellitus (see Section 2.7.4 for additional analyses for diabetes) 
Additional safety topics include: 
• Renal events 
• Hypersensitivity 
• Neurological events and neurocognitive disorders 
• Ophthalmological events 
• Cardiac safety: Major adverse cardiovascular events (MACE) and each of the MACE 
components 
See Appendix 5.2 for the search criteria of each safety topic. 
The following summaries of ORION-8 TEAEs will be presented for other AESIs and AEs of 
additional safety topics using number and percentage of subjects with the event: 
• Overall Summary of TEAEs 
• TEAEs by PT 


Novartis 
Confidential 
Page 21 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
• TEAEs by PT and maximum severity 
• TEAEs possibly related to study drug by PT 
• TESAEs by PT 
• TEAEs leading to study drug withdrawal 
Subject data listings will be provided for hepatic and diabetic AEs. Such listings will include 
all AEs in ORION-8 database, regardless of whether they are ORION-8 TEAE. 
2.7.2 
Deaths 
As mentioned in Section 2.7.1, TEAEs with a fatal outcome will be summarized by SOC and 
PT, and a subject data listing for AEs in ORION-8 database with a fatal outcome will be 
generated. 
2.7.3 
Laboratory data 
Fasting glucose parameter, when used in any analysis, will require the lab sample to be taken 
while fasting. Glucose values recorded at non-fasting state will not be used. 
2.7.3.1 
Summary tables using descriptive statistics 
Summaries for safety laboratory values will include observed value, changes and percent 
changes from ORION-8 baseline over time: 
• Hematology and coagulation parameters will be summarized at ORION-8 baseline (for 
observed value only), at Day 1080, and at EOS. 
• Safety chemistry parameters in the full serum chemistry panel but not in limited serum 
chemistry panel will be summarized at ORION-8 baseline (for observed value only), at 
Day 1080, and at EOS. 
o These include direct and indirect bilirubin, lactate, bicarbonate, uric acid, urea 
(blood urea nitrogen; BUN), sodium, potassium, calcium, inorganic phosphorus, 
chloride, albumin, total protein, fasting glucose. 
• Safety chemistry parameters in limited chemistry panel, which is a subset of the full 
chemistry panel, will be summarized at ORION-8 baseline (for observed value only), at 
each scheduled visit from Day 90 to Day 1080, and at EOS. 
o These include aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), total 
bilirubin (TBIL), creatine kinase (CK), creatinine, eGFR, glycated hemoglobin 
A1C (HbA1c). 
2.7.3.2 
Shift analysis 
A shift analysis from baseline to EOS will be performed for eGFR and HbA1c using the 
following categories: 


Novartis 
Confidential 
Page 22 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
• 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%. 
2.7.3.3 
Clinically significant laboratory values 
The number and percentage of subjects with potentially clinically significant (PCS) laboratory 
values or clinically significant (CS) laboratory values (refer to Appendix 5.3 for the criteria) 
will be summarized. For AST, ALT and CK, the most severe result for each subject will be 
used. For creatinine, the following two categories will also be presented in addition to the CS 
criterion: 
1) Subjects with the baseline value ≤ 2 mg/dL and any post-baseline value > 2 mg/dL. 
2) Subjects who are not in the first category but has ≥ 50% increase from baseline.  
For liver chemistry parameters (ALT, AST, ALP, TBIL), the number and percentage of subjects 
whose PCS/CS value returned to baseline level at the last measurement will also be summarized. 
Here the baseline level is defined as a value of the same category as the baseline category or a 
value of a better category than the baseline. For example, if a subject’s baseline ALT is >3 and 
<=5 x ULN and the subject’s ALT elevated to >5 and <=10 x ULN at the worst measurement 
post baseline, the subject is considered to have returned to baseline level at the last measurement 
if the last ALT value of that subject is <=5 x ULN. 
Listings of all subjects with PCS or CS laboratory values will be presented. Subjects will appear 
once per lab parameter but may appear under multiple lab parameters.  
2.7.3.4 
Hy’s law 
The number and percentage of subjects satisfying Hy’s Law will 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. The baseline here refers to ORION-
8 baseline. 
2.7.4 
Diabetes assessment 
Diabetes will be assessed by the analysis of: 


Novartis 
Confidential 
Page 23 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
• diabetic TEAEs 
• change in glucose-related laboratory values over time 
• shifts from baseline in glucose control category 
• incidence of post-baseline new onset of diabetes. 
Fasting glucose parameter, when used in any analysis, will require the lab sample to be taken 
while fasting. Glucose values recorded at non-fasting state will not be used. 
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 ORION-8 baseline if any of the following is true: 
• The targeted medical history notes that the subject is diabetic 
• The subject has ORION-8 Day 1 concomitant anti-diabetic medication (ATC level 2 
code: A10)  
• The ORION-8 baseline HbA1c value is ≥ 6.5%  
• Fasting glucose ≥126 mg/dL at ORION-8 baseline.  
Baseline fasting glucose uses average of last two assessments at or prior to ORION-8 baseline. 
A subject data listing will be provided for diabetic AEs. Such listing will include all AEs in 
ORION-8 database, regardless of whether they are ORION-8 TEAE. 
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 EOS will be summarized for fasting glucose for all subjects and then by baseline 
glucose control status. The change from baseline to the EOS and to the worst observation will 
be summarized for HbA1c for all subjects 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 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 last two fasting glucose assessments at or prior to ORION-8 baseline.   


Novartis 
Confidential 
Page 24 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
2.7.4.3 
Shifts from baseline in glucose control category 
Shifts from baseline in glucose control category will be summarized in two different ways: the 
change from ORION-8 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 the 
last two measurements at or prior to 
ORION-8 baseline 
AND 
HbA1c < 5.7% 
Fasting glucose < 100 mg/dL on 
two consecutive occasions 
AND 
HbA1c < 5.7% 
Normal to Impaired 
Fasting glucose < 100 mg/dL on the 
last two measurements at or prior to 
ORION-8 baseline 
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 the 
last two measurements at or prior to 
ORION-8 baseline 
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 the last two 
measurements at or prior to 
ORION-8 baseline 
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 the last two 
measurements at or prior to 
ORION-8 baseline 
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 the last two 
measurements at or prior to 
ORION-8 baseline 
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 the 
last two measurements at or prior to 
ORION-8 baseline 
Fasting glucose < 100 mg/dL on 
two consecutive occasions 
AND 


Novartis 
Confidential 
Page 25 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
OR 
HbA1c ≥ 6.5% 
HbA1c < 5.7% 
Diabetes to Impaired 
Fasting glucose ≥ 126 mg/dL on the 
last two measurements at or prior to 
ORION-8 baseline 
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 the 
last two measurements at or prior to 
ORION-8 baseline 
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. 
Diabetes takes precedence over impaired, i.e. if a subject satisfies the diabetes criteria, the subject 
cannot be in impaired category. 
2.7.4.4 
Incidence of post-baseline new onset of diabetes 
The number of subjects who shift from no diabetes at baseline (see Section 2.7.4.1 for definition 
of baseline diabetes) 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. Baseline fasting glucose uses average of last two 
assessments at or prior to ORION-8 baseline. 
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 ORION-8 Day 1. 
2.7.5 
Other safety data 
2.7.5.1 
ECG and cardiac imaging data 
Not applicable to this study. 


Novartis 
Confidential 
Page 26 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
2.7.5.2 
Vital signs 
Observed value, change, and percent change from ORION-8 baseline in vital signs (blood 
pressure and heart rate) will be summarized descriptively at ORION-8 baseline (for observed 
value only) and at each scheduled time point from Day 90 to Day 1080 and at EOS. 
The change from ORION-8 baseline to EOS will also be summarized by the following 
categories: 
• Systolic blood pressure (mmHg):  
o ≤ -20  
o > -20 to ≤ -10  
o > -10 to ≤ -5 
o > -5 to < 5 
o ≥ 5 to < 10 
o ≥ 10 to < 20 
o ≥ 20 
• Diastolic blood pressure (mmHg):  
o ≤ -10 
o > -10 to ≤ -5 
o > -5 to ≤ -3 
o > -3 to < 3 
o ≥ 3 to < 5 
o ≥ 5 to < 10 
o ≥ 10 
 
 
 
 
 
 
2.8 
Pharmacokinetic endpoints   
Not applicable to this study.  
2.9 
PD and PK/PD analyses 
Not applicable to this study.  


Novartis 
Confidential 
Page 27 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
2.10 
Subject-reported outcomes 
Not applicable to this study. 
2.11 
Biomarkers 
Not applicable to this study. 
2.12 
Other Exploratory analyses 
No exploratory analyses are planned for this study.  
2.13 
Interim analysis 
No formal interim analysis will be performed in this study. 
3 
Sample size calculation 
This study will be a long-term extension study of ORION-3/9/10/11 and all completers of those 
studies who fulfill ORION-8 entry criteria and willing to participate can be enrolled into this 
study. 
4 
Change to protocol specified analyses 
No change from protocol specified analysis was made. 
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
Missing/partial start date or end date of treatment will not be imputed. 
5.1.2 
AE date imputation 
An AE with an unknown or partial onset date will be categorized as a TEAE unless there is 
sufficient information to determine that the event began before baseline. For example, if an 
AE’s resolution date/time < baseline date/time, the AE’s onset date/time is logically < baseline 
date/time and thus it is not a TEAE. 
5.1.3 
Concomitant medication date imputation 
Any medication with both start and stop dates missing are considered as baseline concomitant 
medication. Any medication with only start date missing are considered as either prior or 
baseline concomitant medication depending on the stop date. Any medication with only stop 
date missing are considered as either baseline concomitant or new/changed concomitant 
medications depending on the start date. 


Novartis 
Confidential 
Page 28 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
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)  
• Corneal disorders, (SMQ, narrow) 
6. Cardiac safety: Major adverse cardiovascular events (MACE) 
• CV death 
o Fatal SAEs in Cardiac disorders SOC   
o Fatal SAEs in General disorders and administration site conditions SOC:  PTs 
‘Death’, ‘Sudden cardiac death’, ‘Cardiac death’, ‘Apparent death’ 


Novartis 
Confidential 
Page 29 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
o Central nervous system haemorrhages and cerebrovascular accidents (HLT), 
fatal events only 
• Resuscitated cardiac arrest 
o Non-fatal AEs with PT ‘Cardiac arrest’ 
• Non-fatal MI 
o Myocardial infarction (SMQ, broad and narrow), nonfatal events only 
• Non-fatal stroke 
o Central Nervous System hemorrhages and cerebrovascular accidents (HLT), non-
fatal events only 
7. New onset/worsening of diabetes  
• Hyperglycaemia/new onset diabetes mellitus (SMQ, narrow) 
• Diabetic complications (HLGT) 
• Diabetes Mellitus (incl subtypes) (HLT)  
• Carbohydrate tolerance analyses (incl diabetes) HLT, excluding PT “Blood glucose 
decreased” 
5.3 
Criteria for potentially clinically significant and clinically 
significant abnormal laboratory tests 
Hemoglobin A1c criteria is explicitly stated in the table below. For all other parameters, a 
PCS/CS criterion is met when both of the following occur (baseline refers to ORION-8 baseline): 
• There is a post-baseline value that meets the threshold 
• The baseline value does not meet the threshold 
Some examples are: 
• For leukocytes, a subject satisfies “<= 2.8 x 10^9/L” criterion as long as the baseline 
value is > 2.8 x 10^9/L and any post-baseline value is <= 2.8 x 10^9/L; a subject 
satisfies “>=16 x 10^9/L” criterion as long as the baseline value is <16 x 10^9/L and 
any post-baseline value is >=16 x 10^9/L. 
• For CK, a subject satisfies “> 3 and ≤ 5 × ULN” criterion as long as the baseline value 
is ≤ 3 x ULN and any post-baseline value is > 3 and ≤ 5 × ULN. A subject satisfies “> 
5 and ≤ 10 × ULN” criterion as long as the baseline value is ≤ 5 x ULN and any post-
baseline value is > 5 and ≤ 10 × ULN. If a subject satisfies both “> 3 and ≤ 5 × ULN” 
and “> 5 and ≤ 10 × ULN” criteria and does not satisfy the criteria of any more severe 
category, the subject will be presented under “> 5 and ≤ 10 × ULN” but not under “> 3 
and ≤ 5 × ULN” because the most severe category will be used for CK. 
• For serum creatinine, the CS criterion is satisfied if at least one of the following is 
true: 


Novartis 
Confidential 
Page 30 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
o The baseline value is ≤ 2 mg/dL and any post-baseline value is > 2 mg/dL. 
o Any post-baseline value is ≥ 50% increase from baseline, regardless of whether 
the baseline value is ≤ 2 mg/dL. 
 
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 (Leukocyte) 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 
Aspartate Aminotransferase (AST/SGOT) 
U/L 
N/A 
> 3 and ≤ 5 × ULN* 
Aspartate Aminotransferase (AST/SGOT) 
U/L 
N/A 
> 5 and ≤ 10 × ULN* 
Aspartate Aminotransferase (AST/SGOT) 
U/L 
N/A 
> 10 and ≤ 20 × ULN* 
Aspartate Aminotransferase (AST/SGOT) 
U/L 
N/A 
> 20 × ULN* 
Creatine Kinase (CK) 
U/L 
N/A 
> 1 and ≤ 3 × ULN 
Creatine Kinase (CK) 
U/L 
N/A 
> 3 and ≤ 5 × ULN 
Creatine Kinase (CK) 
U/L 
N/A 
> 5 × and ≤ 10 × ULN* 
Creatine Kinase (CK) 
U/L 
N/A 
> 10 and ≤ 20 × ULN* 
Creatine Kinase (CK) 
U/L 
N/A 
> 20 × ULN* 
Hemoglobin A1C 
% 
N/A 
≥ 6.5% and ≥ 0.5% 
change from baseline 
Serum Creatinine 
mg/dL 
N/A 
≥ 50% increase from 
baseline or > 2 mg/dL* 
Total Bilirubin 
mg/dL 
N/A 
> 2 × ULN* 
LLN: Lower limit of the standard reference (normal) range; ULN: Upper limit of the standard 
reference (normal) range. 
For AST, ALT and CK, the most severe result for each subject will be used. 
*Clinically significant laboratory boundaries. 
 
 


Novartis 
Confidential 
Page 31 of 31 
SAP 
 
Study No. CKJX839A12306B 
 
 
 
6 
Reference 
CKJX839A12306B (MDCO-PCS-17-05) Protocol global amendment 2