Clinical trial NCT05888103
Conditions: Primary Hypercholesterolemia or Mixed Dyslipidemia
Keywords: Inclisiran LDL-C monotherapy atherosclerotic cardiovascular disease atheroma Atherosclerosis lipid lipid lowering therapy (LLT) cholesterol hypercholesteremia mixed dyslipidemia TC (total cholesterol) Apo B non HDL-C Lp(a) PCSK9 PCSK9 inhibitor siRNA low ASCVD risk moderate ASCVD risk
Sponsor: Novartis Pharmaceuticals
Start date: 2023-07-11; Completion date: 2024-10-24
Enrollment: 207 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate the efficacy and safety of inclisiran as a monotherapy in Chinese adults with low or moderate atherosclerotic cardiovascular disease (ASCVD) risk and elevated low-density lipoprotein cholesterol (LDL-C) who were not on any lipid lowering therapy.

Detailed description:
This study was designed as a randomized, double-blind, multi-center Phase III trial, with a placebo-controlled treatment period and an open label treatment period, to evaluate the efficacy and safety of inclisiran sodium 300 mg s.c. in participants aged 18 to 75 years with a low or moderate ASCVD risk and fasting LDL-C value of ≥ 130 mg/dL but \< 190 mg/dL who were not on any lipid lowering therapy.

The study consisted of 3 parts:

* Screening: the screening period was up to 14 days to allow adequate time for the eligibility evaluations.
* Core Part: a double-blind, placebo-controlled treatment period of 180 days in which eligible participants were randomized 1:1 to receive either inclisiran sodium 300 mg s.c.

(inclisiran group) or matching placebo s.c. (control group) on Day 1 and Day 90. The end of core part (EOC) visit was conducted on Day 180. The database lock for the core part was planned to occur after all randomized participants have completed the EOC visit (or have discontinued from the study before EOC). The primary analysis was conducted after the database lock for the core part.

• Extension Part: an extended treatment period of 180 days. In the extension part, participants originally randomized to inclisiran in the core part were to continue the inclisiran treatment while participants initially randomized to placebo were to transit to the inclisiran. The extension part was to start from the Day 180 treatment dose (placebo in the inclisiran group and inclisiran for participants originally randomized to the control group).

Arms: arm 1: Inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) s.c administered on Day 1, Day 90, and Day 270, and placebo on Day 180 arm 2: Placebo on Day 1 and Day 90 and Inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) s.c on Day 180 and 270
Interventions: intervention 1: Inclisiran intervention 2: Matching Placebo for Inclisiran
Intervention descriptions: intervention 1: Inclisiran s.c intervention 2: Matching s.c. placebo

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development 
                                            Clinical Trial Protocol Title: 
A 6 month randomized, double-blind, placebo-controlled 
study followed by a 6 month open- label extension to 
assess the efficacy and safety of inclisiran as monotherapy 
in Chinese adults with low or moderate ASCVD risk and 
elevated low-density lipoprotein cholesterol 
Clinical Trial Protocol Number: CKJX839D12305 / NCT05888103 
Version Number: v00 (Original Protocol) 
Compound: KJX839 
Brief Title: Efficacy and safety of inclisiran as monotherapy in Chinese adults with 
low or moderate ASCVD risk and elevated low-density lipoprotein cholesterol. 
Study Phase: III 
Sponsor Name: Novartis 
Regulatory Agency Identifier Number(s): Not applicable 
Approval Date: 24-Feb-2023 (content final) 
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 5.0 dated 14-Jan-2022 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 6 
1 
Protocol summary ................................................................................................................ 7 
1.1 
Summary .................................................................................................................. 7 
1.2 
Schema ................................................................................................................... 11 
1.3 
Schedule of activities (SoA) .................................................................................. 11 
2 
Introduction ....................................................................................................................... 15 
2.1 
Study rationale ....................................................................................................... 15 
2.2 
Background ............................................................................................................ 15 
2.3 
Benefit/Risk assessment ........................................................................................ 17 
3 
Objectives, endpoints, and estimands ................................................................................ 18 
3.1 
Primary estimands ................................................................................................. 19 
3.2 
Secondary estimands ............................................................................................. 20 
3.2.1 
Secondary estimands for core part ........................................................ 20 
3.2.2 
Secondary estimands for extension part ................................................ 20 
4 
Study design ...................................................................................................................... 21 
4.1 
Overall design ........................................................................................................ 21 
4.2 
Scientific rationale for study design ...................................................................... 23 
4.2.1 
Rationale for choice of background therapy ......................................... 23 
4.3 
Justification for dose .............................................................................................. 23 
4.3.1 
Rationale for study duration .................................................................. 24 
4.4 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 25 
4.5 
Rationale for public health emergency mitigation procedures .............................. 25 
4.6 
Purpose and timing of interim analyses/design adaptations .................................. 25 
4.7 
End of study definition .......................................................................................... 25 
5 
Study population ................................................................................................................ 26 
5.1 
Inclusion criteria .................................................................................................... 26 
5.2 
Exclusion criteria ................................................................................................... 26 
5.3 
Screen failures ....................................................................................................... 27 
5.3.1 
Replacement policy ............................................................................... 28 
5.3.2 
Participant numbering ........................................................................... 28 
6 
Study treatment(s) and concomitant therapy ..................................................................... 29 
6.1 
Study treatment(s) .................................................................................................. 29 
6.1.1 
Additional study treatments .................................................................. 29 


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6.1.2 
Treatment arms/group ........................................................................... 29 
6.1.3 
Treatment duration ................................................................................ 30 
6.2 
Preparation, handling, storage, and accountability ................................................ 30 
6.2.1 
Handling of study treatment .................................................................. 30 
6.2.2 
Handling of other treatment .................................................................. 30 
6.2.3 
Instruction for prescribing and taking study treatment ......................... 31 
6.3 
Measures to minimize bias: randomization and blinding ...................................... 31 
6.3.1 
Treatment assignment, randomization .................................................. 31 
6.3.2 
Treatment blinding ................................................................................ 32 
6.3.3 
Emergency breaking of assigned treatment code .................................. 32 
6.4 
Study treatment compliance .................................................................................. 33 
6.4.1 
Recommended treatment of adverse events .......................................... 33 
6.5 
Dose modification .................................................................................................. 33 
6.5.1 
Definitions of dose limiting toxicities (DLTs) ...................................... 33 
6.5.2 
Follow-up for toxicities ......................................................................... 33 
6.6 
Continued access to study treatment after the end of the study ............................. 35 
6.6.1 
Post trial access ..................................................................................... 35 
6.7 
Treatment of overdose ........................................................................................... 35 
6.7.1 
Reporting of study treatment errors including misuse/abuse ................ 35 
6.8 
Concomitant and other therapy .............................................................................. 36 
6.8.1 
Concomitant therapy ............................................................................. 36 
6.8.2 
Prohibited medication ........................................................................... 36 
7 
Discontinuation of study treatment and participant discontinuation/withdrawal .............. 37 
7.1 
Discontinuation of study treatment ........................................................................ 37 
7.2 
Participant discontinuation from the study ............................................................ 38 
7.3 
Withdrawal of informed consent and exercise of participants’ data privacy 
rights ...................................................................................................................... 38 
7.4 
Lost to follow-up ................................................................................................... 39 
7.5 
Early study termination by the Sponsor................................................................. 39 
8 
Study Assessments and Procedures ................................................................................... 40 
8.1 
Screening ............................................................................................................... 40 
8.2 
Participant demographics/other baseline characteristics ....................................... 40 
8.3 
Efficacy assessments ............................................................................................. 41 
8.3.1 
LDL-C ................................................................................................... 41 
8.3.2 
Additional efficacy assessments ........................................................... 42 
8.3.3 
Appropriateness of efficacy assessments .............................................. 42 


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8.4 
Safety assessments ................................................................................................. 42 
8.4.1 
Physical examinations ........................................................................... 42 
8.4.2 
Vital signs.............................................................................................. 43 
8.4.3 
Electrocardiograms ............................................................................... 43 
8.4.4 
Clinical safety laboratory tests .............................................................. 43 
8.4.5 
Pregnancy testing .................................................................................. 44 
8.4.6 
Appropriateness of safety measurements .............................................. 45 
8.5 
Additional assessments .......................................................................................... 45 
8.6 
Adverse events (AEs), serious adverse events (SAEs), and other safety 
reporting ................................................................................................................. 45 
8.6.1 
Adverse events ...................................................................................... 45 
8.6.2 
Serious adverse events .......................................................................... 47 
8.6.3 
SAE reporting........................................................................................ 48 
8.6.4 
Pregnancy .............................................................................................. 49 
8.6.5 
Disease-related events and/or disease-related outcomes not 
qualifying as AEs or SAEs .................................................................... 49 
8.6.6 
Adverse events of special interest ......................................................... 49 
8.7 
Pharmacokinetics ................................................................................................... 49 
 
 49 
8.9 
Immunogenicity assessments................................................................................. 50 
8.10 
Health economics OR Medical resource utilization and health economics .......... 50 
9 
Statistical considerations ................................................................................................... 50 
9.1 
Analysis sets .......................................................................................................... 50 
9.2 
Statistical analyses ................................................................................................. 51 
9.2.1 
General considerations .......................................................................... 51 
9.2.2 
Participant demographics and other baseline characteristics ................ 51 
9.2.3 
Treatments ............................................................................................. 51 
9.3 
Primary endpoint(s)/estimand(s) analysis.............................................................. 51 
9.3.1 
Definition of primary endpoint(s) ......................................................... 52 
9.3.2 
Statistical model, hypothesis, and method of analysis .......................... 52 
9.3.3 
Handling of intercurrent events of primary estimand (if applicable) .... 52 
9.3.4 
Handling of missing values not related to intercurrent event ............... 53 
9.3.5 
Multiplicity adjustment (if applicable).................................................. 53 
9.3.6 
Sensitivity analyses ............................................................................... 53 
9.3.7 
Supplementary analysis ......................................................................... 53 
9.4 
Secondary endpoint(s)/estimand(s) analysis.......................................................... 53 
9.4.1 
Efficacy and/or pharmacodynamic endpoint(s) .................................... 53 


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9.4.2 
Safety endpoints .................................................................................... 55 
 
 55 
 
 55 
9.6 
(Other) Safety analyses .......................................................................................... 56 
9.7 
Other analyses ........................................................................................................ 56 
9.8 
Interim analysis ...................................................................................................... 57 
9.9 
Sample size determination ..................................................................................... 57 
9.9.1 
Primary endpoint(s) ............................................................................... 57 
9.9.2 
Secondary endpoint(s) ........................................................................... 57 
10 Supporting documentation and operational considerations ............................................... 58 
10.1 
Appendix 1: Regulatory, ethical, and study oversight considerations................... 58 
10.1.1 
Regulatory and ethical considerations .................................................. 58 
10.1.2 
Informed consent process ...................................................................... 59 
10.1.3 
Data protection ...................................................................................... 60 
10.1.4 
Committees structure ............................................................................ 60 
10.1.5 
Data quality assurance ........................................................................... 61 
10.1.6 
Source documents ................................................................................. 62 
10.1.7 
Publication policy.................................................................................. 62 
10.1.8 
Protocol adherence and protocol amendments ...................................... 63 
10.2 
Appendix 2: Abbreviations and definitions ........................................................... 64 
10.2.1 
List of abbreviations .............................................................................. 64 
10.2.2 
Definitions ............................................................................................. 66 
10.3 
Appendix 3: Clinical laboratory tests .................................................................... 69 
10.3.1 
Clinically notable laboratory values and vital signs ............................. 69 
10.4 
Appendix 4: Participant Engagement .................................................................... 70 
10.5 
Appendix 5: Liver safety monitoring .................................................................... 71 
10.5.1 
Liver event and laboratory trigger definitions & follow-up 
requirements .......................................................................................... 71 
10.6 
Appendix 6: Renal safety monitoring .................................................................... 74 
10.7 
Appendix 7: Diagnostic Criteria for Low or Moderated ASCVD risk .................. 74 
11 References ......................................................................................................................... 76 
List of tables 
Table 1-1 
Objectives and Endpoints ........................................................................ 7 
Table 1-2 
Assessment Schedule ............................................................................ 13 
Table 3-1 
Objectives and related endpoints .......................................................... 18 
Table 6-1 
Investigational and control drug ............................................................ 29 


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Table 6-2 
Dose and treatment schedule ................................................................. 31 
Table 6-3 
Guidance on clinical and diagnostic assessments to rule out 
alternative causes of observed LFT abnormalities ................................ 34 
Table 6-4 
Prohibited medication ........................................................................... 37 
Table 8-1 
Safety Laboratory Assessments ............................................................ 43 
Table 10-1 
Liver event and laboratory trigger definitions ...................................... 71 
Table 10-2 
Follow up requirements for liver laboratory triggers - ALT, AST, 
TBL ....................................................................................................... 72 
Table 10-3 
Follow up requirements for liver laboratory triggers - Isolated 
Hyperbilirubinemia ............................................................................... 72 
Table 10-4 
ASCVD Risk Assessment Flowchart .................................................... 74 
List of figures 
Figure 1-1 
Study Design ......................................................................................... 11 
 


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1 
Protocol summary 
1.1 
Summary 
Protocol Title: 
A 6 month randomized, double-blind, placebo-controlled study followed by a 6 month open-
label extension to assess the efficacy and safety of inclisiran as monotherapy in Chinese adults 
with low or moderate ASCVD risk and elevated low-density lipoprotein cholesterol 
Brief Title: 
Efficacy and safety of inclisiran as monotherapy in Chinese adults with low or moderate 
ASCVD risk and elevated low-density lipoprotein cholesterol. 
Purpose 
To evaluate the efficacy and safety of inclisiran as a monotherapy in Chinese adults with low 
or moderate atherosclerotic cardiovascular disease (ASCVD) risk and elevated low-density 
lipoprotein cholesterol (LDL-C) who are not on any lipid lowering therapy. 
Study Indication /Medical Condition: 
Primary hypercholesterolemia or mixed dyslipidemia 
Treatment type 
Drug 
Study type 
Interventional 
Objectives, Endpoints, and Estimands: 
Table 1-1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
To demonstrate the superiority of inclisiran as 
monotherapy, compared to placebo,  on mean 
percentage change from baseline in LDL-C at Day 
150, in Chinese adults with low or moderate ASCVD 
risk and elevated LDL-C who are not on any lipid 
lowering therapy. 
Percentage change in LDL-C from baseline at Day 
150 
Secondary 
 
To demonstrate the efficacy of inclisiran as 
monotherapy, compared to placebo on absolute 
change from baseline in LDL-C at Day 150. 
Absolute change in LDL-C from baseline at Day 150 
To demonstrate the efficacy of inclisiran as 
monotherapy, compared to placebo on percentage 
and absolute change from baseline in Proprotein 
● Percentage change from baseline at Day 150 in 
PCSK9 


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Objectives 
Endpoints 
Convertase Subtilisin/Kexin type 9 (PCSK9), total 
cholesterol (TC), high-density lipoprotein cholesterol 
(HDL-C), non-high-density lipoprotein cholesterol 
(non-HDL-C), apolipoprotein B (ApoB), apolipoprotein 
A-1 (ApoA-1), lipoprotein (a) (Lp(a)) and triglycerides 
(TG) at Day 150. 
● Absolute change from baseline at Day 150 in 
PCSK9 
● Percentage change from baseline at Day 150 in TC, 
HDL-C, non-HDL-C, ApoB, ApoA-1, Lp(a) and TG 
● Absolute change from baseline at Day 150 in TC, 
HDL-C, non-HDL-C, ApoB, ApoA-1, Lp(a) and TG 
To evaluate the effect of inclisiran as monotherapy on 
percentage and absolute change in LDL-C from 
baseline at Day 330. 
● Percentage change in LDL-C from baseline at Day 
330 for inclisiran group 
● Absolute change in LDL-C from baseline at Day 330 
for inclisiran group 
To evaluate the safety and tolerability of inclisiran as 
monotherapy compared to placebo during core part. 
Adverse Events (AEs); vital signs and safety 
laboratory values 
To evaluate the safety and tolerability of inclisiran as 
monotherapy during extension part. 
Adverse Events (AEs), vital signs and safety 
laboratory values 
Trial Design: 
This study is designed as a randomized, double-blind, multi-center phase 3 trial, with a placebo-
controlled treatment period and an open label treatment period, to evaluate the efficacy and 
safety of inclisiran sodium 300mg s.c. in participants aged 18~75 years with low or moderate 
ASCVD risk and fasting LDL-C value of ≥ 130 mg/dl but < 190 mg/dl who are not on any lipid 
lowering therapy. 
The study consists of 3 parts: 
• Screening: At screening, participants will sign the Informed Consent Form (ICF) and 
their eligibility will be assessed through the review of study inclusion/exclusion criteria. 
The screening period can be up to 14 days to allow adequate time for the eligibility 
evaluations. 
• Core Part: a double-blind, placebo-controlled treatment period of 180 days in which 
eligible participants will be randomized 1:1 to receive either inclisiran sodium 300mg s.c. 
(Inclisiran Group) or matching placebo s.c. (Control Group) on Day 1 and Day 90. The 
end of core part (EOC) visit will be conducted on Day 180. The database lock for the core 
part is planned to occur after all randomized participants have completed the EOC visit (or 
have discontinued from the study before EOC). The primary analyses will be conducted 
after the database lock for the core part. 
• Extension Part: an extended treatment period of an additional 180 days. After all "Core 
part" study assessments are completed on Day 180, the extension part starts. In the 
extension  all patients randomized to inclisiran in the core part will continue on inclisiran 
while patients initially randomized to placebo will transit to inclisiran therapy.  The 
extension part starts with a dose of study treatment on Day 180 (placebo in the inclisiran 
group and inclisiran for patients originally randomized to the control group). Thereafter, 
all participants will receive inclisiran sodium 300mg s.c. on Day 270. Treatment on Day 
270 will be open-label. Participants and investigators/site staff will remain blinded to the 
original randomized treatment group assignment (inclisiran vs placebo) throughout the 
study until final database lock. The EOS visit (Day 360) will be the last visit of the study. 


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At Day 1 (Baseline), all participants will be instructed to comply with lifestyle adjustment 
according to clinical guidelines, including but not limited to diet and regular exercise. These 
instructions will be reinforced at every visit throughout the study. 
Participants who discontinue from study treatment should continue to attend the rest of the 
scheduled visits as indicated in Section 1.3. 
Participants who discontinue from study should be scheduled for an Early Exit visit if they 
agree. This Early Exit visit contains the same assessments of the EOS visit, and is suggested to 
be scheduled at least 30 days after last injection. If not possible, to set an Early Exit visit as 
soon as possible is also acceptable. No data beyond Early Exit visit will be collected in the 
electronic Case Report Form (eCRF). 
Investigators, site staff, participants, and the study team should be blinded to on-treatment lipid 
measurement results throughout the core part after randomization. Investigators, site staff and 
participants should continue to remain blinded to the on-treatment lipid measurement results 
and original randomized treatment group assignment (inclisiran vs placebo) throughout 
the study until final database lock.. 
Brief Summary: 
The purpose of this study is to evaluate the efficacy and safety of inclisiran sodium 300mg s.c. , 
in reducing LDL-C in participants with low or moderate ASCVD risk and elevated LDL-C who 
are not on any lipid lowering treatment 
• The overall study duration is approximately 374 days but can vary depending on 
individual screening and the visit window. 
• Participants will receive inclisiran/placebo subcutaneous injections on Day 1, Day 90, Day 
180. And all participants will receive inclisiran treatment on Day 270. 
• Visits will be on Day 1, Day 30, Day 90, Day 150 (primary endpoint), Day 180 (end of 
core part, EOC), Day 210, Day 270, Day 330 and Day 360 (EOS). 
Treatment of interest 
For primary estimand, the treatment of interest is inclisiran sodium 300 mg s.c. at Day 1 and 
Day 90 as monotherapy (no other lipid lowering therapy) comparing to matching placebo s.c. 
at Day 1 and Day 90 as monotherapy, regardless of study treatment discontinuation. 
Number of Participants: 
Approximately 200 participants will be randomized 1:1 to inclisiran and placebo . 
Key Inclusion criteria 
• Written informed consent must be obtained before any assessment is performed 
• Adults ≥ 18 and ≤ 75 years of age 
• Fasting LDL-C value of ≥ 130 mg/dL but <190mg/dL at screening 
• Triglycerides ≤ 400 mg/dL at screening 


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• Categorized as low or moderate ASCVD risk by the 2016 Chinese guideline for the 
management of dyslipidemia in adults at screening 
• No plan of introducing other lipid lowering therapy during the study participation 
Key Exclusion criteria 
• Use of any lipid-lowering therapy within 90 days prior to screening visit 
• Previous exposure to inclisiran or any non-mAb PCSK9-targeted therapy, either as an 
investigational or marketed drug within 2 years prior to screening visit 
• History of ASCVD 
• Diabetes mellitus or fasting plasma glucose at screening ≥ 7.0 mmol/L or glycated 
hemoglobin (hemoglobin A1c) (HbA1c) ≥ 6.5% 
• Active liver disease defined as any known current infectious, neoplastic, or metabolic 
pathology of the liver or unexplained elevations in alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), >3x the upper limit of normal (ULN), or total 
bilirubin >2x ULN at screening 
• Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 at screening 
Treatment Groups: 
At Day 1 (Baseline), all participants will be randomized 1:1 to one of the two treatment groups: 
• Inclisiran Group: 100 participants. Treated with inclisiran sodium 300mg s.c. on Day 1, 
Day 90 and Day 270, and with matching placebo s.c. on Day 180. 
• Control Group: 100 participants. Treated with matching placebo s.c. on Day 1 and Day 
90, and with inclisiran sodium 300mg s.c. on Day 180 and Day 270. 
Steering Committee: Yes (see Section 10.1.4 Committees Structure) 
Key words 
Inclisiran, LDL-C, monotherapy 


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1.2 
Schema 
Figure 1-1 
Study Design 
 
1. Participants who discontinue from study treatment should continue to attend the rest of the 
scheduled visits. 
2. Participants randomized to Inclisiran Group will be treated with inclisiran sodium 300mg s.c. on Day 
1 and Day 90 and Day 270, and with matching placebo s.c. on Day 180. Participants randomized 
to Control Group will be treated with matching placebo s.c. on Day 1 and Day 90, and with 
inclisiran sodium 300mg on Day 180 and Day 270. 
3. The end of core part visit. The database lock for the core part is planned to occur after all 
randomized participants have completed the EOC visit (or have discontinued from the study 
before EOC). The primary endpoint analysis will be conducted after the database lock for the core 
part. 
4. Participants who discontinue from study should be scheduled for an Early Exit visit if they agree. 
This Early Exit visit is suggested to be scheduled at least 30 days after last injection. If not 
possible, to set an Early Exit visit as soon as possible is also acceptable. 
1.3 
Schedule of activities (SoA) 
The SoA lists all of the assessments when they are performed. All data obtained from these 
assessments must be supported in the participant’s source documentation. The “X” in the table 
denotes when a study assessment is to be performed and results recorded in the clinical database 
or received electronically from a vendor. The “S” in the table also denotes when certain study 
assessment is to be performed. While in this case the result is only captured in the participant’s 
source documentation and do not need to be recorded in the clinical database. 
Participants should be seen for all visits/assessments as outlined in the SoA or as close to the 
designated day/time as possible. A window of +/- 7 days from the scheduled day is acceptable 
for visits after Visit 1 (Day 1 or Baseline). Missed or rescheduled visits should not lead to 
automatic discontinuation. 
If it is a visit with treatment (Day 1, Day 90, Day 180 and Day 270), all assessments should be 
performed before study treatment administration. Participants who discontinue from study 
treatment should continue to attend the following visits as indicated in the SoA. Every effort 


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should be made to encourage participants who discontinue from study treatment to remain in 
the study for follow up. Participants who discontinue from study should be scheduled for an 
Early Exit visit if they agree. This Early Exit visit contains the same assessments of the EOS 
visit, and is suggested to be scheduled at least 30 days after last injection. If not possible, to set 
an Early Exit visit as soon as possible is also acceptable. At this final visit, all dispensed 
investigational product should be reconciled, and the adverse events and concomitant 
medications not previously reported must be recorded on the CRF. 
Participants will have to comply with the following restrictions during the study: 
• Fasted for at least 10 hours for all visits to obtain fasting lipids and/or glucose blood 
samples. If the participant is not fasting at the time of Informed Consent signature, he/she 
will have to return for a blood draw in a fasting state. 
• Must refrain from unaccustomed strenuous physical activity for 48 hours prior to any 
study visit. 
As per Section 4.5, during a public health emergency as declared by local authorities i.e. 
pandemic, epidemic or natural disaster that limits or prevents on-site study visits, alternative 
methods of providing continuing care may be implemented by the Investigator as the situation 
dictates. If allowable by a local health authority, national and local regulations and depending 
on operational capabilities, phone calls or virtual contacts (e.g. tele consultation) can replace 
certain protocol assessments, for the duration of the disruption until it is safe for the participant 
to visit the site again. 


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Table 1-2 
Assessment Schedule 
Period 
Screening 
Core Part1 
Extension Part1 
Visit Name 
Screening 
V1 
V2 
V3 
V4 
V5/EOC 
V6 
V7 
V8 
V9/EOS2 
Days 
-14 to -1 
1 
30 
±7 
90 
±7 
150 
±7 
180 
±7 
210 
±7 
270 
±7 
330 
±7 
360 
±7 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
Inclusion / Exclusion criteria 
X 
X3 
  
  
  
  
  
  
  
  
Demography 
X 
  
  
  
  
  
  
  
  
  
Smoking and alcohol history 
X 
  
  
  
  
  
  
  
  
  
Medical history/current 
medical conditions 
X 
  
  
  
  
  
  
  
  
  
Prior or concomitant 
medication4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Surgical/medical 
procedures4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
S 
S 
  
S 
  
S 
  
S 
  
S 
Body Height/Weight 
X 
  
  
  
  
  
  
  
  
  
Vital Signs5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs/SAEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lifestyle instructions 
  
S 
S 
S 
S 
S 
S 
S 
S 
S 
Pregnancy Test (serum)6,7 
X 
  
  
  
  
  
  
  
  
  
Pregnancy Test (urine)8 
  
S 
S 
S 
S 
S 
S 
S 
S 
S 
Follicle stimulating hormone 
(FSH) 7,9 
X 
  
  
  
  
  
  
  
  
  
Fasting Lipid Profile10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting Lp(a)11 
  
X 
  
  
X 
X 
  
  
X 
X 
PCSK911 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistry7 
X 
  
  
  
  
  
  
  
  
  
Limited Chemistry7 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Period 
Screening 
Core Part1 
Extension Part1 
Visit Name 
Screening 
V1 
V2 
V3 
V4 
V5/EOC 
V6 
V7 
V8 
V9/EOS2 
Days 
-14 to -1 
1 
30 
±7 
90 
±7 
150 
±7 
180 
±7 
210 
±7 
270 
±7 
330 
±7 
360 
±7 
Hematology7 
X 
X 
  
  
  
X 
  
  
  
X 
Urinalysis7 
X 
  
  
  
  
X 
  
  
  
X 
Coagulation Panel7 
  
X 
  
  
  
  
  
  
  
  
Enter participant visit in IRT 
X 
X 
  
X 
  
X 
  
X 
  
X 
Randomization 
  
X 
  
  
  
  
  
  
  
  
Study drug administration - 
s.c. inclisiran/placebo12 
  
X 
  
X 
  
X 
  
X 
  
  
Disposition 
X 
  
  
  
  
X 
  
  
  
X 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 The participant who discontinues the study treatment but continues to participate in the study should come to the regular visits per Assessment Schedule.  
2 Participants who discontinue from study should be scheduled for an Early Exit visit if they agree. This Early Exit visit is suggested to be scheduled at least 30 days after 
last injection. If not possible, to set an Early Exit visit as soon as possible is also acceptable.  
3 Inclusion/exclusion criteria will only be assessed and captured once in Electronic Data Capture (EDC) system in screening period including any recheck between 
screening and randomization. 
4 All medications, procedures, and significant non-drug therapies used by/performed on the participant within 30 days prior to the screening visit and throughout the 
study must be documented in the appropriate page of the eCRF 
5 Blood pressure and pulse will be taken 3 times in sitting position. 
6 Only in women of childbearing potential.  
7 Performed by the central lab. See Table 8-1 in Section 8.4. 
8 Only in women of childbearing potential. Performed locally, urine or serum pregnancy test can be used based on local requirements.  
9 Required for any female participant who is considered as surgically sterile or post-menopausal in the absence of medical documentation confirming this 
reproductive/menopausal status at screening.  
10 Performed by the central lab. Fasting lipid profile includes LDL-C, total cholesterol, triglycerides, HDL-C, non-HDL-C, ApoA1 and Apo B. The fasting lipid profile results 
will not be reported to the site except the screening visit, and will be blinded for participants, investigators, site staff, persons performing the assessments, monitors and 
the Novartis Clinical Trial Team (CTT) until the core part database lock. After the core part database has been locked, fasting lipid profile results should remain blind to 
the participants, investigators and site staff throughout the study until final database lock. 
11 Performed by the central lab. The results will not be reported to the site and will be blinded for participants, investigators, site staff, persons performing the 
assessments, monitors and the Novartis Clinical Trial Team (CTT) until the core part database lock. After the core part database has been locked, Lp(a) and PCSK9 
results should remain blind to the participants, investigators and site staff throughout the study until final database lock. 
12 Subcutaneous inclisiran/placebo will be administered by qualified personnel after all other study assessments have been completed for this visit 


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2 
Introduction 
2.1 
Study rationale 
Despite the availability of multiple options of lipid-lowering therapies (LLT), many Chinese 
low/moderate ASCVD risk patients on therapy do not reach LDL-C treatment goals. High statin 
non-adherence rate may be one of the most critical reasons for this high rate of substandard 
LDL-C reduction. Results of previous Phase 3 studies have demonstrated the ability of 
inclisiran to provide sufficient, sustainable LDL-C reduction with much lower treatment 
frequency (see below), which suggests that inclisiran monotherapy may be an alternative option 
for these patients. The purpose of this study is to evaluate the efficacy and safety of inclisiran 
sodium 300 mg s.c., administered as monotherapy to participants with low or moderate ASCVD 
risk and elevated LDL-C who are not on any LLT. 
2.2 
Background 
ASCVD is the leading cause of death and disability worldwide and is expected to remain so 
beyond 2040 (Foreman et al 2018). A trend of increasing cardiovascular (CV) mortality has 
been observed in China mainland population, mainly attributed to heart attack and stroke, the 
two main pathologies associated with ASCVD (Zhou et al 2016). 
Multiple factors contribute to the development of ASCVD, among which, elevated low density 
lipoprotein cholesterol (LDL-C) is one of the most well-recognized and modifiable ones 
(Yusuf et al 2004). Various studies have consistently shown that reductions in LDL-C levels 
could reduce the incidence of major adverse cardiovascular events (MACE) caused by ASCVD, 
regardless of baseline LDL-C or different LDL-C lowering agents (statin or non-statin) 
(Baigent et al 2010,Silverman et al 2016). Moreover, in a meta-analysis including 200 studies 
and 2 million participants with more than 20 million person-years of follow-up and over 
150,000 CV events, a dose-dependent log-linear association is observed between the magnitude 
of exposure to LDL-C and the risk of ASCVD (Ference et al 2017). To conclude, it is well 
recognized, and also recommended by local and international guidelines that, the lower the 
LDL-C level attained – in addition to a reduction in lifetime exposure to LDL-C – the lower the 
CV risk (Zhao et al 2016). While in China, 26.3% of adults have elevated LDL-cholesterol level 
(≥ 130 mg/dL)(Zhang et al 2018). 
In order to ensure that appropriate interventions are offered to individuals at risk of ASCVD, 
guidelines define risk classifications which are used to guide the intensity of intervention – 
ranging from lifestyle modification alone, to intervention with lipid lowering agents – and target 
LDL-C levels which the interventions aim to enable patients to achieve. For low and moderate 
ASCVD risk patients, the Chinese guideline suggests starting with lifestyle adjustment, and 
considering moderate intensity statin therapy if not meeting lipid target (LDL-C ＜
130mg/dL).(Zhao et al 2016) 
Despite the availability of multiple options of lipid-lowering drugs, many low/moderate 
ASCVD risk patients on therapy do not reach LDL-C treatment goals. A nationally 
representative survey of 163,641 Chinese adults reported that 18.1% of low risk patients and 
45.5% of moderate risk patients failed to reach lipid-lowering target(Zhang et al 2018). 


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High statin non-adherent rate may be one of the most critical reasons for the high rate of 
substandard LDL-C reduction. According to an observational study involving 109,306 Chinese 
patients under statin therapy, the mean (standard deviation) proportion of days covered (PDC) 
was only 0.19 (0.15) in primary prevention subgroup (patients without prior ASCVD), with 
only 5.4% patients having PDC ≥ 0.5. (Zhao et al 2020). In addtion, as reported in another 
study, the statin adherence levels tend to decline over time in primary prevention patients, and 
a transition to levels of adherence lower than a PDC of 0.8 is associated with increased risk of 
CV events (Slejko et al 2014). Clearly, there is an urgent need for a new effective lipid-lowering 
therapy that imposes less medication administration burden and improves compliance. 
Inclisiran is a double-stranded small interfering ribonucleic acid (siRNA) that causes 
degradation of protein convertase subtilisin/kexin type 9 (PCSK9) messenger RNA (mRNA) 
leading to the reduction of PCSK9 protein. PCSK9 is predominantly expressed by the liver and 
is critical for the down regulation of hepatocyte low density lipoprotein receptor (LDLR) 
expression (Mousavi et al 2009). Inclisiran mediated reduction of PCSK9 protein results in 
higher levels of LDLR on hepatocytes and subsequent reduction of serum LDL-C. siRNA is 
covalently linked to a ligand comprising N-acetylgalactosamine(GalNAc) residues that enables 
preferential uptake by hepatocytes through binding to liver-expressed asialoglyco protein 
receptors (ASGPR). In hepatocytes, the antisense strand released from inclisiran is inserted in 
the Ribonucleic acid-Induced Silencing Complex (RISC), which directly cleaves the mature 
mRNA for PCSK9, thereby inhibiting the synthesis of the PCSK9 protein. Reduced intrahepatic 
PCSK9 increases LDL-R on the hepatocyte cell surface, thereby increases LDL-C uptake and 
lowers plasma LDL-C levels (Fitzgerald et al 2017). 
The efficacy and safety of inclisiran has been shown in the phase 3 studies (ORION-9, -10, and 
-11). Treatment with inclisiran 300 mg administered by subcutaneous injection on Day 1, Day 
90 and every 6 months thereafter resulted in placebo-adjusted percentage reductions in LDL-C 
from baseline at Day 510 of 47.9% to 52.3%, with time-adjusted average reduction of 44.3% to 
53.8% in participants with ASCVD, ASCVD risk equivalent, and/or heterozygous familial 
hypercholesterolemia (HeFH) (Raal et al 2020, Ray et al 2020).  Longer-term treatment to >3 
years in ORION-3, support and extend the observation. ORION-18 is another phase 3 study 
with a similar study design as ORION-9, -10 and -11 but conducted in an Asian population. 
The observed placebo-adjusted percentage change in LDL-C from baseline was -57.2% at Day 
330. The totality of evidence collected from the ORION-18 study demonstrated that the 
substantial benefits of inclisiran in reducing LDL-C in Asian patients is consistent with that in 
the global population. (Investigator's Brochure) 
There were no clinically relevant differences in the safety profile of inclisiran compared with 
placebo in the above trials, except for a higher incidence of treatment-emergent adverse events 
(TEAEs) at the injection site. AEs at the injection site were localized, mild and transient in 
nature. Inclisiran is not associated with an increased risk for hepatic or renal dysfunction, 
hypersensitivity, neurologic events and neurocognitive disorders, or ophthalmological events 
and there's no difference from placebo in new onset or worsening of diabetes. The potential for 
immunogenicity of inclisiran is low. 
Additional details on the efficacy and safety of inclisiran are available in the Investigator's 
Brochure (IB). 


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2.3 
Benefit/Risk assessment 
In general, the risk of participation in this trial may be minimized by compliance with the 
eligibility criteria and study procedures, and close clinical monitoring of safety parameters. The 
risk is further reduced by a minimal duration of placebo-controlled period (core part) of only 
approximately 6 months. In particular any concern about the theoretical risk to participants 
randomized to Control Group not being on any LLT during the core part of the study is mitigated 
by the following: 1) The study population is limited to patients with only low and moderate 
ASCVD risk, who had not been treated with prior LLT and for whom the investigator had not 
planned to start LLT in the next 6 months. 2) Lifestyle modification is the first line treatment 
recommended to these patients in the Chinese Lipid Guidelines, with consideration to add lipid 
lowering therapy (eg. moderate intensity statin) only if patients can not reach lipid targets with 
3~6 months of lifestyle adjustment (Zhao et al 2016). While in this study, participants 
randomized to Control Group will only receive placebo treatment for 6 months. 3) Instruction 
on lifestyle modification is provided to all participants in the study according to clinical 
guidelines throughout the study participation. 4) Additionally, all participants will receive 
inclisiran treatment in the extension part. In addition to the potential reduction in LDL-C, the 
benefit a participant may have by participating in this study is the close monitoring of their 
condition, the opportunity to learn more about primary hypercholesterolemia and how to reduce 
future progression to clinical ASCVD and prevention of ASCVD events. In case of new onset 
of ASCVD events (eg. myocardial infarction, ischemic stroke), which is expected to be very 
rare in these low/moderate risk patients, investigators and treating physician are encouraged to 
take any action deemed necessary for the safety of the participants based on clinical standard 
of care. 
Women of child-bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study, and agree that in order 
to participate in the study they must adhere to the contraception requirements outlined in the 
exclusion criteria. If there is any question that the participant will not reliably comply, they 
should not be entered or continue in the study. 
In non-clinical toxicity studies, inclisiran was not carcinogenic or genotoxic. There was no 
effect on paternal performance, spermatogenesis, estrous cycle, and uterine or ovarian 
parameters. Inclisiran did not show evidence of embryo lethality, fetotoxicity, or teratogenicity. 
In addition, there were no effects of inclisiran on the development of the F1 generation, 
including survival, growth, physical and reflexological development, behavior and reproductive 
performance. 
The overall clinical experience with inclisiran includes the following completed studies: 
• Four completed Phase I studies: ALN-OCSSC-001 in participants with elevated LDL-C, 
ORION-6 in participants with mild to moderate hepatic impairment, ORION-7 in 
participants with renal impairment (mild, moderate, severe), and ORION-14 in Chinese 
patients with elevated LDL-C 
• Two completed Phase II studies: ORION-1 in participants with ASCVD or ASCVD risk 
equivalent, and ORION-2 in participants with homozygous familial hypercholesterolemia 


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• Four completed Phase III studies: ORION-9, -10, and -11 in participants with HeFH, 
ASCVD or ASCVD risk equivalents, and ORION-18 in Asian participants with ASCVD 
or High ASCVD risk. 
The safety profile of inclisiran in clinical studies is well characterized and based on data 
obtained from 3 large pivotal trials (ORION-9, -10,-11) that include 1,833 participants treated 
with inclisiran for up to 18 months and was generally comparable to placebo. The only 
inclisiran-related adverse drug reaction (ADR) identified in clinical studies was a higher 
incidence of TEAEs at the injection site, including injection site erythema, injection site 
hypersensitivity, injection site pruritus, injection site rash, and injection site reaction. All 
TEAEs at injection site were localized, mild or occasionally moderate, transient and resolved 
without sequelae. The impact of this side effect is further mitigated by the infrequent dosing 
regimen of inclisiran. 
In Phase 3 studies (ORION-9, -10 and -11) in participants with HeFH, ASCVD or ASCVD risk 
equivalents, inclisiran administered on Day 1, Day 90 and every 6 months thereafter lowered 
LDL-C by approximately 50% or more versus placebo in participants on maximally tolerated 
statin therapy with or without other LLT. 
Results of the Phase 3 study ORION-18 further demonstrated that the efficacy and safety of 
inclisiran in reducing LDL-C in Asian patients is consistent with that in global patients. 
It is widely recognized that LDL-C plays a major role in the initiation and progression of 
ASCVD, and accumulated exposure of elevated LDL-C is causally related to the development 
of ASCVD. As the degree and duration of exposure to elevated LDL-C levels increases the 
atherosclerotic burden, early treatment of hypercholesterolemia in primary prevention is 
essential to the prevention of ASCVD events. 
3 
Objectives, endpoints, and estimands 
Table 3-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
● To demonstrate the superiority of inclisiran as 
monotherapy, compared to placebo, on mean 
percentage change from baseline in LDL-C at Day 
150, in Chinese adults with low or moderate ASCVD 
risk and elevated LDL-C who are not on any lipid 
lowering therapy. 
● Percentage change in LDL-C from baseline at Day 
150 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
● To demonstrate the efficacy of inclisiran as 
monotherapy, compared to placebo on absolute 
change from baseline in LDL-C at Day 150. 
● Absolute change in LDL-C from baseline at Day 150 
● To demonstrate the efficacy of inclisiran as 
monotherapy, compared to placebo on percentage 
and absolute change from baseline in PCSK9, total 
cholesterol (TC), high-density lipoprotein (HDL-C), 
non-high-density lipoprotein cholesterol (non-HDL-C), 
apolipoprotein B (ApoB), apolipoprotein A-1 (ApoA-1), 
lipoprotein (a) (Lp(a)) and triglycerides (TG) at Day 
150. 
● Percentage change from baseline at Day 150 in 
PCSK9 
● Absolute change from baseline at Day 150 in 
PCSK9 
● Percentage change from baseline at Day 150 in TC, 
HDL-C, non-HDL-C, ApoB, ApoA-1, Lp(a) and TG 
● Absolute change from baseline at Day 150 in TC, 
HDL-C, non-HDL-C, ApoB, ApoA-1, Lp(a) and TG 


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Objective(s) 
Endpoint(s) 
● To evaluate the effect of inclisiran as monotherapy 
on percentage and absolute change in LDL-C from 
baseline at Day 330. 
● Percentage change in LDL-C from baseline at Day 
330 for inclisiran group 
● Absolute change in LDL-C from baseline at Day 330 
for inclisiran group 
● To evaluate the safety and tolerability of inclisiran 
as monotherapy compared to placebo during core 
part. 
● Adverse Events (AEs), vital signs and safety 
laboratory values 
● To evaluate the safety and tolerability of inclisiran 
as monotherapy during extension part. 
● Adverse Events (AEs), vital signs and safety 
laboratory values 
3.1 
Primary estimands 
The estimand is the precise description of the treatment effect and reflects strategies to address 
events occurring during trial conduct which could impact the interpretation of the trial results 
(e.g premature discontinuation of treatment). 
The clinical question of primary interest is: what is the reduction in LDL-C, quantified by 
difference of mean percentage change from baseline at Day 150, in Chinese adults with low or 
moderate ASCVD risk and elevated LDL-C who are not on any lipid-lowering therapy, who 
receive inclisiran as monotherapy, compared to placebo, regardless of discontinuation from 
study treatment, if other lipid-lowering therapy were not taken, and where death due to CV or 
non-CV causes is considered an unfavorable outcome. 


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The primary estimand is described by the following attributes: 
Population: Chinese adults with low or moderate ASCVD risk and elevated LDL-C who are 
not on any lipid-lowering therapy. 
Endpoint: Percentage change from baseline at Day 150 in LDL-C. 
Treatments of interest: Inclisiran as monotherapy compared to the use of placebo, regardless of 
study treatment discontinuation. 
Handling of intercurrent events: 
• Permanent discontinuation of study treatment will be handled with a treatment policy 
strategy, keeping treatment labels as assigned at randomization. 
• Use of prohibited LLT (PCSK9 monoclonal antibodies taken before Day 150 visit 
assessment or other LLT taken within 30 days before Day 150 visit assessment) will be 
treated with a hypothetical strategy of what would happen had those LLT not been taken 
and those participants behaved like other participants in the same treatment group. 
• Participants who died will be handled with a composite strategy, death is considered an 
unfavorable outcome. 
Summary measure: the summary measure to be used is the difference of mean percentage 
changes. 
Complete details on the statistical methods and inference, including missing data handling and 
sensitivity analyses are provided in Section 9.3. 
3.2 
Secondary estimands 
3.2.1 
Secondary estimands for core part 
The secondary estimands for core part address the same clinical question as the primary 
estimand, albeit for different endpoints. They share the same population, intercurrent events,  
summary measure, as well as the same treatments as the primary estimand. They differ by the 
definition of the endpoints, these being: 
• Absolute change in LDL-C from baseline at Day 150 
• Percentage and absolute change in PCSK9, TC, HDL-C, non-HDL-C, ApoB, ApoA-1, 
Lp(a) and TG from baseline at Day 150 
The statistical methods and inference approaches are described in Section 9.4. 
3.2.2 
Secondary estimands for extension part 
The clinical question of interest in extension part is: what is the reduction in LDL-C, quantified 
by mean percentage or absolute change from baseline at Day 330, in Chinese adults with low 
or moderate ASCVD risk and elevated LDL-C who are not on any lipid-lowering therapy, who 
receive inclisiran as monotherapy, regardless of discontinuation from study treatment, if other 
lipid-lowering therapy were not taken, and where death due to CV or non-CV causes is 
considered an unfavorable outcome. 
The secondary estimand for extension part is described by the following attributes: 


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Population: Chinese adults with low or moderate ASCVD risk and elevated LDL-C who are 
not on any lipid-lowering therapy. 
Endpoint: Percentage or absolute change from baseline at Day 330 in LDL-C for inclisiran 
group. 
Treatments of interest: Inclisiran as monotherapy, regardless of study treatment discontinuation. 
Handling of intercurrent events: 
• Permanent discontinuation of study treatment will be handled with a treatment policy 
strategy, keeping treatment labels as assigned at randomization. 
• Use of prohibited LLT (PCSK9 monoclonal antibodies taken before Day 330 visit 
assessment or other LLT taken within 30 days before Day 330 visit assessment) will be 
treated with a hypothetical strategy of what would happen had those LLT not been taken 
and those participants behaved like other participants in the same treatment group. 
• Participants who died will be handled with a composite strategy, death is considered an 
unfavorable outcome. 
Summary measure: the summary measure to be used is the mean percentage or absolute change. 
Complete details on the statistical methods and inference, including missing data handling and 
sensitivity analyses are provided in Section 9.4. 
4 
Study design 
4.1 
Overall design 
This study is designed as a randomized, double-blind, multi-center phase 3 trial, with a placebo-
controlled period and an open label treatment period, to evaluate the efficacy and safety of 
inclisiran sodium 300mg s.c. in participants aged 18~75 years with low or moderate ASCVD 
risk and fasting LDL-C value of ≥ 130 mg/dL but < 190 mg/dL who are not on any lipid 
lowering therapy. 
The study design is depicted in Figure 1-1. The study consists of 3 parts: 
• Screening: a screening period of up to 14 days for all participants 
• Core Part: a double-blind, placebo-controlled treatment period of 180 days in which 
eligible participants will be randomized 1:1 to receive either inclisiran sodium 300mg s.c. 
(Inclisiran Group) or matching placebo s.c. (Control Group) on Day 1 and Day 90. The 
end of core part (EOC) visit will be conducted on Day 180. The database lock for the core 
part is planned to occur after all randomized participants have completed the EOC visit (or 
have discontinued from the study before EOC). The primary endpoint analysis will be 
conducted after the database lock for the core part. 
• Extension Part: an extended treatment period of 180 days. After all "Core part" study 
assessments are completed on Day 180, the extension part starts. In the extension, all 
patients randomized to inclisiran in the core part will continue on inclisiran while patients 
initially randomized to placebo will transit to inclisiran therapy. The extension part starts 
from a dose of study treatment on Day 180 (placebo in the inclisiran group and inclisiran 
for patients originally randomized to the control group) . Thereafter, all participants will 


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receive inclisiran sodium 300mg s.c. on Day 270. Treatment on Day 270 will be open-
label. Participants and investigators/site staff will remain blinded to the original 
randomized treatment group assignment (inclisiran vs placebo) until final database lock. 
The EOS visit (Day 360) will be the last visit of the study. 
The overall study duration is approximately 374 days but can vary depending on individual 
screening and the visit window. 
At screening, participants will sign the Informed Consent Form (ICF) and their eligibility will 
be assessed through the review of study inclusion/exclusion criteria. The ICF must be signed 
before initiation of any study-specific procedures and assessments. If at the time of ICF 
signature the participant is not fasting, he/she has to return for the blood test in a fasting state. 
During the screening visit, the participant’s ASCVD risk will be assessed under guidance of 
2016 China lipid guideline( Zhao et al 2016). The investigator must ensure each participant has 
not been treated with any lipid lowering therapy for at least 90 days prior to the screening visit, 
nor exposure to inclisiran or any other non-mAb PCKS9-targeted therapy 2 years prior to the 
screening visit. The screening period can be up to 14 days to allow adequate time for the 
eligibility evaluations. A participant who enters screening and is determined not eligible during 
the screening period or at the time of randomization will be considered a screen failure. 
On Day 1 (Baseline), eligible participants who meet all inclusion and not meet any exclusion 
criteria will be randomized 1:1 to Inclisiran Group and Control Group. Study visits of core part 
will occur on Day 1 (baseline visit), Day 30, Day 90, Day 150 and Day 180. On Day 1 and Day 
90 visits, inclisiran s.c. or placebo s.c. will be administered at the site by a healthcare 
professional. The primary endpoint will be assessed at Day 150. The EOC visit will be 
conducted on Day 180. 
The extension part starts with  a dose on Day 180 after all core part assessment are completed. 
In order to maintain the blind for the treatment group assignment, participants randomized to 
Control Group will receive inclisiran, while participants randomized to Inclisiran Group will 
receive placebo on Day 180. All participants will then receive inclisiran sodium 300 mg on Day 
270, which will be the third dose of inclisiran for Inclisiran Group, and the second dose of 
inclisiran for Control Group. All injections will be administered at the site by a healthcare 
professional. The EOS visit (Day 360) will be the last visit of the study. 
At Day 1 (Baseline), all participants will be instructed to comply with lifestyle adjustment 
according to clinical guidelines, including but not limited to diet and regular exercise. These 
instructions will be reinforced at every visit throughout the study. 
Participants who discontinue from study treatment should continue to attend the rest of the 
scheduled visits as indicated in Section 1.3. 
Participants who discontinue from study should be scheduled for an Early Exit visit if they 
agree. This Early Exit visit is suggested to be scheduled at least 30 days after last injection. If 
not possible, to set an Early Exit visit as soon as possible is also acceptable. The Early Exit visit 
contains the same assessments of the EOS visit. No data beyond Early Exit visit will be 
collected in the electronic Case Report Form (eCRF). 
Investigators, site staff, participants, and the study team should be blinded to on-treatment lipid 
measurement results throughout the core part after randomization. Investigators, site staff and 


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participants should continue to remain blinded to the on-treatment lipid measurement results 
and original randomized treatment group assignment (inclisiran vs placebo) throughout the 
study until final database lock. 
4.2 
Scientific rationale for study design 
Though the efficacy and safety of inclisiran in reducing LDL-C has been demonstrated in 
multiple previous studies, most of them were conducted in high or very high ASCVD risk 
patients and on top of maximally tolerated statin treatment. It is well recognized that use of 
statin may up-regulate PCSK9 levels. Thus, therapies that target PCSK9 may perform 
differently as monotherapy than when added to statin treatment. This study is aimed to evaluate 
the efficacy and safety of inclisiran sodium 300mg, administrated as monotherapy to 
participants without background lipid lowering therapies. 
As described in Section 2.2, the needs of LDL-C lowering for low or moderate ASCVD risk 
patients are far from being satisfied with many patients not reaching LDL-C targets. 
Considering the baseline LDL-C of low to moderate ASCVD risk patients is below 190 mg/dL, 
while the recommended LDL-C target is 130 mg/dL, an LDL-C reduction of 30~40% may 
fulfill most patients' needs. Therefore, inclisiran may have the ability to provide sufficient LDL-
C reduction when used alone in these patients. To evaluate the efficacy and safety of inclisiran 
as monotherapy in this population, this study will include low or moderate risk patients with 
baseline LDL-C over recommended lipid target (130 mg/dL). Current Chinese guideline 
suggests these patients to start from lifestyle adjustment first, and consider lipid lowering 
therapy only if patients can not reach lipid targets with 3~6 months of lifestyle adjustment. In 
this study, all participants will be instructed to comply with lifestyle adjustment according to 
clinical guidelines throughout study participation. Participants randomized to Control Group 
will receive placebo treatment only during core part, which will be no longer than 6 months. In 
the extension part, all participants will be treated with inclisiran, which is proved to be effective 
and safe in lowering LDL-C in previous studies. 
The extension part of this study is to provide additional efficacy and safety information of 
inclisiran monotherapy. The extended treatment period  design for the study is appropriate to 
obtain additional long-term data, while allowing all patients to obtain the investigational, active 
drug at least at the second part of the study (i.e., 6 months after randomization). 
4.2.1 
Rationale for choice of background therapy 
The participants must fulfill the requirement of not being on any lipid-lowering background 
therapy within 90 days prior to the screening, nor exposure to inclisiran or any other non-mAb 
PCKS9-targeted therapy 2 years prior to the screening visit. Furthermore, there must be no plan 
to start any other LLT in the foreseeable future (during the study period). The purpose is to 
remove any potential confounding effect caused by statin intolerance or concomitant LLT such 
as statins or ezetimibe in the monotherapy setting. 
4.3 
Justification for dose 
The same dose regimen of the first two or three doses in previous Phase 3 studies (300 mg s.c. 
at Day1, Day 90 and Day 270 for Inclisiran Group, and at Day 180 and Day 270 for Control 


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Group) will be used in this study. This is also the approved dose by the United States Food and 
Drug Administration (FDA) and in the European Union (EU). 
Based on the results from Phase I (ALN-PCSSC-001) and Phase II (ORION-1) clinical studies, 
at all doses tested, inclisiran inhibited PCSK9 synthesis and reduced LDL-C after single or 
multiple injections. The maximum reduction of PCSK9 and LDL-C was observed at a dose of 
300 mg with no incremental reductions of clinical importance at higher doses tested. In ORION-
1, a similar reduction was observed in LDL-C at Day 270 compared to Day 90 along with the 
time-adjusted mean LDL-C change of -50.5% over this time interval, further supporting the 
dose regimen of dosing every 6 months after a second loading dose at Day 90. In ORION-9, -
10, and -11, the dose regimen used in the present study resulted in placebo-adjusted percentage 
reductions in LDL-C from baseline at Day 510 of 50% to 58%. In addition, in ORION-18, two 
initial injections (Day 1 and Day 90) following by a third injection at Day 270 also led to a 
similar percentage reduction in LDL-C at Day 330. Based on above and nonclinical data as well 
as pharmacodynamic (PD) modeling in adult participants, the proposed dose regimen is 
expected to provide robust, persistent, and durable reductions in PCSK9 and LDL-C. In those 
studies, this dose regimen also showed good tolerability of inclisiran, with a safety profile 
similar to placebo, except for a higher incidence of AEs at the injection site. 
In three Phase I studies (ALN-PCSSC-001, ORION-6, ORION-7), inclisiran was administered 
to participants (healthy participants or participants with increased LDL-C level) with or without 
other lipid lowering therapy (e.g. statin). At Day 180 after 300 mg single dose administration, 
for those non-ASCVD participants who used inclisiran without other lipid lowering therapy, 
the percentage change of LDL-C level from baseline was generally similar to the ASCVD (or 
ASCVD-risk equivalents) patients in ORION-1 who used inclisiran on top of statin, and both 
of which had no significant safety issues. In addition, it has been demonstrated that concomitant 
use of statin has no clinically significant impact on the LDL-C lowering efficacy. 
Therefore, under the proposed dose regimen, the efficacy of inclisiran in the population of the 
current study and without statin use is expected to be similar to that in previous phase III studies, 
and with no safety concerns. 
4.3.1 
Rationale for study duration 
The study primary endpoint will be assessed at Day 150, after 2 injections of inclisiran/placebo 
on Day 1 and Day 90. It is supported with: 
• ORION-1 demonstrated that 2 injections on Day 1 and on Day 90 produced a significant 
percentage LDL-C reduction of 52.6% at Day 180 
• In ORION-9, -10 and -11, 2 initial injections (Day 1 and Day 90) led to a similar 
percentage reduction in LDL-C at Day 150. The magnitude of this reduction was then 
maintained with subsequent injections every 6 months 
• No difference was observed in PK/PD between Chinese and non-Chinese population in 
ORION-14 
• ORION-18 showed the consistency of efficacy with ORION-9, -10 and -11 in Chinese 
population with a significant percentage LDL-C reduction at Day 150. The magnitude of 
this reduction was also maintained in the following visit after the third injection at Day 
330. 


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Based on the above data, a 180-day duration of the core part with 2 injections is deemed as 
sufficient for evaluating the effect of inclisiran as monotherapy, compared with placebo. The 
primary endpoint will be assessed on Day 150, which is expected to be the nadir of LDL-C 
lowering effect. In addition, this duration will leave placebo-treated participants with the 
shortest unprotected period of no LLT covered. 
The duration with both core part and extension part is also suitable to assess the longer-term 
efficacy as well as safety and tolerability. The additional treatment administered in an extension 
part of the study is suitable to collect meaningful additional long-term data on inclisiran, which 
will be assessed as secondary 
. 
4.4 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
A placebo-controlled arm will be used in the core part of the study. It is a standard design in 
drug development to assess efficacy and safety and ensures that differences in outcome will be 
a reliable and realistic measure of the treatment effect of inclisiran. The use of placebo as a 
comparator is justified in the trial population that consists of patients with low and moderate 
ASCVD risk who are not suggested to consider lipid lowering treatment（unless LDL-C targets 
are not met over a period of time despite lifestyle adjustment), according to current Chinese 
guideline. Moreover, the risk of having a placebo arm in a short duration (6 months) is generally 
acceptable in this population given their relatively low risk. And all participants will be treated 
with investigational medication in the extension part. Therefore, it is reasonable to use a placebo 
arm in the core part of this study. 
4.5 
Rationale for public health emergency mitigation procedures 
In the event of a public health emergency as declared by local authorities (i.e. pandemic, 
epidemic or natural disaster), mitigation procedures may be required to ensure participant safety 
and trial integrity and are listed in relevant sections of the study protocol. Notification of the 
public health emergency should be discussed with Novartis prior to implementation of 
mitigation procedures, and permitted/approved by local health authorities and ethics 
committees as appropriate. 
4.6 
Purpose and timing of interim analyses/design adaptations 
Not applicable. 
4.7 
End of study definition 
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure or follow-up shown in Section 1.3 Schedule of Activities for the last 
participant in the study. 
Study completion is defined as when the last participant finishes his/her last study visit and any 
repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator (e.g. Each participant will be required to complete the study 
in its entirety and thereafter no further study treatment will be made available in the scope of 
the trial). 


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5 
Study population 
The study population consists of approximately 200 randomized Chinese adult participants (≥18 
to ≤75 years of age) with low or moderate ASCVD risk and elevated LDL-C (fasting LDL-C 
≥130mg/dL but ＜190 mg/dL) who are not on any lipid-lowering therapy. 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Written informed consent must be obtained before any assessment is performed. 
2. Adults ≥ 18 to ≤ 75 years of age 
3. Fasting LDL-C value of ≥ 130 mg/dL (equivalent to 3.4 mmol/L) but < 190 mg/dL 
(equivalent to 4.9 mmol/L) at screening 
4. Triglycerides ≤ 400 mg/dL (equivalent to 4.5 mmol/L) at screening 
5. Categorized as low or moderate ASCVD risk by the 2016 Chinese Guideline for the 
Management of Dyslipidemia in Adults at screening(See Section 10.7) 
6. No plan of introducing any lipid lowering therapy other than study treatment during the 
study participation 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. Use of any lipid-lowering therapy including statins (including Xuezhikang), ezetimibe, 
bempedoic acid, fibrates, bile-acid sequestrants, PCSK9 monoclonal antibodies, niacin 
and omega-3 fatty acids (Docosahexaenoic acid (DHA) and/or Eicosapentaenoic acid 
(EPA)) within 90 days prior to screening visit 
2. Previous exposure to inclisiran or any non-mAb PCSK9-targeted therapy, either as an 
investigational or marketed drug within 2 years prior to screening visit 
3. History of ASCVD (including acute coronary syndrome, history of myocardial infarction, 
stable or unstable angina, coronary or other arterial revascularization, stroke, transient 
ischemic attack, and peripheral artery disease including aortic aneurysm) 
4. Diabetes mellitus or fasting plasma glucose at screening ≥ 7.0 mmol/L (equivalent to 126 
mg/dL) or HbA1c ≥ 6.5% (equivalent to 7.8 mmol/L or 140 mg/dL) 
5. 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) > 3 x the upper limit of normal (ULN), or total bilirubin 
(TBL) > 2 x ULN at screening 
6. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 at screening 
7. Secondary hypercholesterolemia, e.g. hypothyroidism or nephrotic syndrome at screening. 
8. Pregnant or nursing (lactating) women at screening 
9. Women who are of child-bearing potential, defined as all women physiologically capable 
of becoming pregnant, unless they are using effective methods of contraception during 
dosing of study treatment. The effective contraception methods include: 


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• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before 
taking investigational drug. In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment 
• Male sterilization (at least 6 months prior to screening). For female participants on the 
study, the vasectomized male partner should be the sole partner for that participant. 
• Barrier method of contraception: Condom or Occlusive cap (e.g. diaphragm or 
cervical/vault caps). 
• Use of oral (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal hormone 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS) 
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 
Women are considered post-menopausal if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate history 
of vasomotor symptoms). Women are considered not of child bearing potential if they are 
post-menopausal or have had surgical bilateral oophorectomy (with or without 
hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks prior to 
enrollment on the study. In the case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow-up hormone level assessment is she 
considered not of child bearing potential. 
10. Severe concomitant disease that carries the risk of reducing life expectancy to less than 2 
years 
11. Participation in another investigational device or drug study currently, or within 5 half-
lives (if drug) or 30 days whichever is longer, prior to screening 
12. Any condition that according to the investigator could interfere with the conduct of the 
study at screening, such as but not limited to 
• Unlikely to understand or comply with the protocol requirements, instructions, and 
study-related restrictions 
• Have any medical or surgical condition, which in the opinion of the investigator 
would put the participant at increased risk from participating in the study 
• Persons directly involved in the conduct of the study 
5.3 
Screen failures 
A screen failure occurs when a participant who consents to participate in the clinical study is 
subsequently found to be ineligible and therefore not randomly assigned to study treatment. A 
minimal set of screen failure information is required to ensure transparent reporting of screen 


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failure participants to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any serious 
adverse event (SAE). 
Participants who sign an informed consent form and are subsequently found to be ineligible 
prior to randomization will be considered as screen failures. The reason for screen failure should 
be recorded on the appropriate Case Report Form. The demographic information, informed 
consent, and Inclusion/Exclusion pages must also be completed for screen failure participants. 
No other data will be entered into the clinical database for participants who are screen failures, 
unless the participant experienced a serious adverse event during the screening period (see SAE 
section for reporting details). If the participant fails to be randomized, the IRT must be notified 
within 2 days of the screen fail that the participant was not randomized. Data and samples 
collected from participants prior to screen failure may still be analyzed. 
Participants,who randomized in error, are randomized and fail to start treatment, will be 
considered an early terminator. The reason should be recorded on the appropriate Case Report 
Form. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
only rescreened once. Each case must be discussed and agreed with Novartis on a case-by-case 
basis. 
In the case where a safety laboratory assessment at screening is outside of the range specified 
in the eligibility criteria, the assessment may be repeated once prior to randomization. If the 
repeat value remains outside of the specified range, the participant must be excluded from the 
study. 
5.3.1 
Replacement policy 
Not Applicable. 
5.3.2 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. A new Participant No. will be assigned at every 
subsequent enrollment if the participant is rescreened. The Participant No. consists of the Site 
Number (Site No.) (as assigned by Novartis to the investigative site) with a sequential 
participant number suffixed to it, so that each participant’s participation is numbered uniquely 
across the entire database. Upon signing the informed consent form, the participant is assigned 
to the next sequential Participant No. available. 
A new ICF will need to be signed if the Investigator chooses to rescreen the participant after a 
participant has screen failed, and the participant will be assigned a new Participant No. 


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6 
Study treatment(s) and concomitant therapy 
6.1 
Study treatment(s) 
The sponsor will provide the following investigational and control drugs as single-use pre-filled 
syringes for s.c. injection. 
All participants will be randomized 1:1 to inclisiran sodium 300mg s.c. or matching placebo 
s.c. without other lipid lowering therapies on Day 1. Inclisiran Group will receive inclisiran 
treatment on Day 1 and Day 90, and receive placebo treatment on Day 180. While Control 
Group will receive the placebo on Day 1 and Day 90 and inclisiran on Day 180. On Day 270, 
participants from both groups will be treated with inclisiran sodium 300mg s.c. without other 
lipid lowering therapies. Inclisiran and placebo will be administered via pre-filled syringe by 
qualified study site personnel. 
Table 6-1 
Investigational and control drug 
Investigational/ 
Control Drug 
(Name and 
Strength) 
Treatment Form 
or Pharmaceutical 
Dosage Form 
Route of 
Administration 
Presentation 
Sponsor (global or 
local) 
Inclisiran sodium 
300 mg 
(equivalent to 284 
mg inclisiran*) in 
1.5 mL 
Solution for 
injection 
Subcutaneous Use 
Double Blind 
supply; 
prefilled syringe** 
Sponsor (global) 
Matching s.c. 
placebo in 1.5 mL 
Solution for 
injection 
Subcutaneous Use 
Double Blind 
supply; 
prefilled syringe** 
Sponsor (global) 
* Inclisiran is also referred to as KJX839 
** The prefilled syringe (PFS) is a device component of the combination product, and it is regulated as 
part of the combination product in the context of this clinical trial. The PFS is not investigational and no 
separate approval is required. 
6.1.1 
Additional study treatments 
No other treatment beyond investigational drug and control drug are included in this trial. 
6.1.2 
Treatment arms/group 
At baseline, all participants will be randomized 1:1 to one of the two treatment groups: 
• Inclisiran Group: 100 participants. Treated with inclisiran sodium 300mg s.c. on Day 1, 
Day 90 and Day 270, and with matching placebo s.c. on Day 180. 
• Control Group: 100 participants. Treated with matching placebo s.c. on Day 1 and Day 
90, and with inclisiran sodium 300mg on Day 180 and Day 270.  
Subcutaneous injections of the Inclisiran/placebo will not be dispensed to the participants but 
rather administered by qualified personnel at the study site on Day 1, Day 90, Day 180 and Day 
270. 


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6.1.3 
Treatment duration 
The expected duration of the participant’s involvement in the study will be approximately 374 
days, which includes a screening period (14 days), a subsequent 180-day double-blind, placebo-
controlled treatment period (core part), and a 180-day open label treatment period (extension 
part). 
Participants may be discontinued from the study treatment earlier due to any reasons, at the 
discretion of the investigator or the participant. They will continue to be followed up in the 
study until EOS as per Assessment Schedule (Table 1-2). 
6.2 
Preparation, handling, storage, and accountability 
Each study site will be supplied with study treatment in packaging as described under Table 6-1 
Investigational and control drugs section. A unique medication number is printed on the study 
medication label. 
Investigator staff will identify the study medication kits to administer to the participant by 
contacting the IRT and obtaining the medication number(s). The study medication has a 2-part 
label (base plus tear-off label), immediately before dispensing the medication kit to the 
participant, site personnel will detach the outer part of the label from the packaging and affix it 
to the source document. 
6.2.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the Investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis Country Organization Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements. They 
will include storage conditions for the study treatment but no information about the participant 
except for the medication number. 
The Investigator or designated site staff must maintain an accurate record of the shipment and 
dispensing of study treatment in a drug accountability log. Monitoring of drug accountability 
will be performed by field monitors during site or remote monitoring visits, and at the 
completion of the trial. 
The site may destroy and document destruction of unused study treatment, drug labels and 
packaging, as appropriate in compliance with site processes, monitoring processes, and per local 
regulation/guidelines. Otherwise, the Investigator will return all unused study treatment, 
packaging, drug labels, and a copy of the completed drug accountability log to the Novartis 
monitor or to the Novartis address provided in the Investigator folder at each site. 
6.2.2 
Handling of other treatment 
Not applicable 


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6.2.3 
Instruction for prescribing and taking study treatment 
Blinded s.c. injections of inclisiran/placebo, will not be dispensed to the participants, but will 
be administered by qualified personnel at the study site. 
The preferred site of injection is the abdomen. Alternative injection sites include the upper arm 
or thigh. Injections should not be made into areas of active skin disease or injury such as 
sunburns, skin rashes, inflammation, tattoos, or skin infections. 
Participants will be administered an injection of blinded s.c. inclisiran/placebo on Day 1,Day 
90, Day 180 and Day 270 as specified in the Assessment Schedule (Table 1-2) after all other 
study assessments have been completed for the visit. 
Table 6-2 
Dose and treatment schedule  
Investigational / Control Drug (Name and Strength) 
Dose 
Frequency and/or Regimen 
Inclisiran sodium 300 mg (equivalent to 284 mg inclisiran*) 
300  mg Day 1, Day 90, Day 180 and Day 270 
matching s.c. placebo 
0 mg 
Day 1, Day 90 and Day 180 
* also known as KJX839 
All kits of study treatment assigned by the IRT will be recorded in the IRT system. All injections 
of inclisiran/placebo given to the participant as well as study drug interruptions/discontinuations 
(i.e., no injection at a designated dosing visit) during the study must be recorded on an 
appropriate eCRF and within IRT. 
6.3 
Measures to minimize bias: randomization and blinding 
6.3.1 
Treatment assignment, randomization 
At baseline visit (Day 1) , all eligible participants will be randomized via Interactive Response 
Technology (IRT) to one of the treatment arms. The Investigator or his/her delegate will contact 
the IRT after confirming that the participant fulfills all the inclusion/exclusion criteria. The IRT 
will assign a randomization number to the participant, which will be used to link the participant 
to a treatment arm and will specify a unique medication number for the first package of study 
treatment to be dispensed to the participant. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and Investigator staff. A 
participant randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of participant numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the responsibility 
of Novartis Global Clinical Supply (GCS) using a validated system that automates the random 
assignment of medication numbers to packs containing the study treatment. 
The randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Office. 


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6.3.2 
Treatment blinding 
Participants, Investigator, site staff, persons performing the assessments, monitors and the 
Novartis CTT will remain blinded to the identity of the treatment throughout the core part after 
randomization. Participants, investigators and site staff should continue to remain blinded 
throughout the study until final database lock. 
Unblinding a single participant at site for safety reasons (necessary for participant management) 
will occur via an emergency system in place at the site. As a result, the participant should be 
discontinued from the study treatment. 
The following methods will be used to maintain the blind: 
(1) Randomization data will be kept strictly confidential until the time of final database lock. 
(2) the identity of the treatments will be concealed by the use of study treatment that are all 
identical in packaging, labeling, schedule of administration, appearance, taste, and odor. 
(3) data with unblinding potential, such as lipid results and PCSK9 results collected after the 
screening visit, will be kept blind until the time of final database lock. 
6.3.3 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
participant safely. 
Most often, discontinuation from study treatment and knowledge of the possible treatment 
assignments are sufficient to treat a study participant who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
Investigator contacts the system to break a treatment code for a participant, he/she must provide 
the requested participant identifying information and confirm the necessity to break the 
treatment code for the participant. The Investigator will then receive details of the 
investigational drug treatment for the specified participant and a fax or email confirming this 
information. The system will automatically inform the Novartis monitor for the site and the 
study team that the code has been broken. 
It is the Investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The Investigator 
will provide: 
• protocol number 
• participant number 
In addition, oral and written information to the participant must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time. 
After an emergency unblinding, study treatment should be permanently discontinued. The 
participant will continue to be followed up in the study unless informed consent is withdrawn 
(Section 7.3)or until participant have completed the EOS visit as per Assessment Schedule 
(Table 1-2) 


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6.4 
Study treatment compliance 
The treatment information must be captured in the source documents, the appropriate Case 
Report/Record Form (CRF) and in the Drug Accountability Log. 
6.4.1 
Recommended treatment of adverse events 
AEs should be treated according to local practice and guidelines, and is at the discretion of the 
investigator and treating physician. 
For participants with injection site reaction, antihistamines, local or systemic steroids can be 
used at the investigator's discretion depending on the severity of the reaction. 
Medication used to treat adverse events (AEs) must be recorded on the appropriate CRF. 
6.5 
Dose modification 
Investigational or other study treatment dose adjustments and/or interruptions are not permitted. 
6.5.1 
Definitions of dose limiting toxicities (DLTs) 
Not applicable. 
6.5.2 
Follow-up for toxicities 
All participants must be followed up for adverse events and serious adverse events for 30 days 
following the last dose of inclisiran/placebo. 
6.5.2.1 
Follow up on potential drug-induced liver injury (DILI) cases 
Participants with transaminase increase combined with total bilirubin increase may be 
indicative of potentially severe DILI and should be considered as clinically important events 
and assessed appropriately to establish the diagnosis. The required clinical information, as 
detailed below, should be sought to obtain the medical diagnosis of the most likely cause of the 
observed laboratory abnormalities. 
The threshold for potential DILI may depend on the participant’s baseline AST/ALT and total 
bilirubin value; participants meeting any of the following criteria will require further follow-up 
as outlined below: 
• For participants with normal ALT and AST and total bilirubin value at baseline: AST or 
ALT > 3.0 x ULN combined with total bilirubin > 2.0 x ULN 
• For participants with elevated AST or ALT or total bilirubin value at baseline: [AST or 
ALT > 2 x baseline] OR [AST or ALT >300 U/L], whichever occurs first combined with 
[total bilirubin > 2 x baseline AND > 2.0 x ULN] 
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered and their role clarified before DILI is assumed to be the cause of liver injury. 
A detailed history, including relevant information such as review of ethanol consumption, 
concomitant medications, herbal remedies, supplement consumption, history of any pre-
existing liver conditions or risk factors, should be collected. 


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Laboratory tests should include ALT, AST, total bilirubin, direct and indirect bilirubin, 
Gamma-glutamyl transferase (GGT), prothrombin time (PT)/International Normalized Ratio 
(INR), alkaline phosphatase, albumin, and creatine kinase. If available, testing of Glutamate 
Dehydrogenase (GLDH) is additionally recommended. 
Perform relevant examinations (Ultrasound or Magnetic resonance imaging (MRI), Endoscopic 
retrograde cholangiopancreatography (ERCP)) as appropriate, to rule-out an extrahepatic cause 
of cholestasis. Cholestasis (is defined as an Alkaline Phosphatase  (ALP) elevation > 2.0 x ULN 
with R value < 2 in participants without bone metastasis, or elevation of the liver-specific ALP 
isoenzyme in participants with bone metastasis). 
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury. In clinical 
situations where it is suspected that ALP elevations are from an extrahepatic source, the GGT 
can be used if available. GGT may be less specific than ALP as a marker of cholestatic injury, 
since GGT can also be elevated by enzyme induction or by ethanol consumption. It is more 
sensitive than ALP for detecting bile duct injury. 
 Table 6-3provides guidance on specific clinical and diagnostic assessments which can be 
performed to rule-out possible alternative causes of observed Liver function test (LFT) 
abnormalities. 
Table 6-3 
Guidance on clinical and diagnostic assessments to rule out 
alternative causes of observed LFT abnormalities 
Disease 
Assessment 
Hepatitis A, B, C, E 
● IgM anti-Hepatitis A Virus (HAV); Hepatitis B virus surface antigen 
(HBsAg), IgM & IgG anti-HBc, Hepatitis B Virus (HBV) Deoxyribonucleic 
acid (DNA); anti-Hepatitis C Virus (HCV), HCV RNA, IgM & IgG anti-
Hepatitis E Virus (HEV), HEV RNA 
Cytomegalovirus (CMV), Herpes 
simplex virus (HSV), Epstein-Barr 
virus (EBV) infection 
● IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV 
Autoimmune hepatitis 
● Antinuclear Antibodies (ANA) & Anti-Smooth Muscle Antibody (ASMA) 
titers, total IgM, IgG, IgE, IgA 
Alcoholic hepatitis 
● Ethanol history, GGT, Mean Corpuscular Volume (MCV), CD-transferrin 
Nonalcoholic steatohepatitis 
● Ultrasound or MRI 
Hypoxic/ischemic hepatopathy 
● Medical history: acute or chronic congestive heart failure, hypotension, 
hypoxia, hepatic venous occlusion. Ultrasound or MRI. 
Biliary tract disease 
● Ultrasound or MRI, ERCP as appropriate. 
Wilson disease (if <40 yrs old) 
● Caeruloplasmin 
Hemochromatosis 
● Ferritin, transferrin 
Alpha-1-antitrypsin deficiency 
● Alpha-1-antitrypsin 
Other causes should also be considered based upon participants’ medical history 
(hyperthyroidism / thyrotoxic hepatitis – T3, T4, TSH; cardiovascular disease / ischemic 
hepatitis – ECG, prior hypotensive episodes; Type 1 diabetes mellitus / glycogenic hepatitis). 
Following appropriate causality assessments, as outlined above, the causality of the treatment 
is estimated as “probable” (i.e. >50% likely), if it appears greater than all other possible causes 


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of liver injury combined. The term “treatment-induced” indicates probably caused by the 
treatment, not by something else, and only such a case can be considered a DILI case and should 
be reported as an SAE. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified, should be considered as “medically 
significant” and thus, meet the definition of SAE and should be reported as a SAE using the 
term “potential treatment-induced liver injury.” All events should be followed up with the 
outcome clearly documented. 
6.6 
Continued access to study treatment after the end of the study 
6.6.1 
Post trial access 
There is no plan for post trial access to study treatment after the end of the study. 
6.7 
Treatment of overdose 
In the event of an overdose, the investigator/ site staff should: 
• Contact the monitor immediately. 
• Evaluate the participant to determine, in consultation with the monitor, whether study 
treatment should be interrupted or whether the dose should be reduced. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities 
• Document the quantity of the excess dose as well as the duration of the overdose. 
6.7.1 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE. Study treatment 
errors and uses outside of what is foreseen in the protocol, misuse or abuse will be collected 
and reported in the safety database irrespective of it being associated with an AE/SAE within 
24 hours of Investigator’s awareness. For more information on AE and SAE definition and 
reporting requirements, please see the respective sections. 


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6.8 
Concomitant and other therapy 
6.8.1 
Concomitant therapy 
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the participant was enrolled into the study must be 
recorded on the appropriate Case Report Forms. 
All other medications, procedures and significant non-drug therapies used by the participant 
within 30 days prior to the screening visit must be recorded on the appropriate eCRFs 
independent if these will be continued during the study or not. Each concomitant drug must be 
individually assessed against all exclusion criteria and prohibited medication. If in doubt, the 
Investigator should contact the Novartis medical monitor before randomizing a participant or 
allowing a new medication to be started. If the participant is already enrolled, contact Novartis 
to determine if the participant should continue participation in the study. 
6.8.1.1 
Permitted concomitant therapy requiring caution and/or action 
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care except for those medication identified as "prohibited" as listed 
in Table 6-4. Specifically, participants should receive full supportive care and guidance on 
lifestyle management during the study. It is preferred to keep the dose of all concomitant therapy 
stable during study participation. 
SARS-CoV-2 (also referred to as COVID-19) vaccines are permitted among participants in this 
trial. There is no evidence to suggest that participants receiving inclisiran are at increased risk 
for AEs following a COVID-19 vaccination. However, since both inclisiran/placebo and 
COVID-19 vaccines are administrated s.c., it is recommended that the COVID-19 vaccine is 
administered +/- 7 days from s.c. inclisiran/placebo administration. Further, it is recommended 
that a different anatomical location is used for COVID-19 vaccine and s.c. inclisiran/placebo to 
help differentiate potential local adverse reactions. COVID-19 vaccination administration that 
occur either within 30 days prior to the Screening Visit and during the course of this study 
should be documented on the appropriate eCRF. 
Other vaccines are also permitted among participants in this trial. Similar to the 
recommendations on COVID-19 vaccines, a 7-day window between these vaccines and s.c. 
inclisiran/placebo administration and a different anatomical location are suggested. 
6.8.2 
Prohibited medication 
Use of the treatments displayed in the below table are not allowed. This table is not considered 
all-inclusive. If in doubt, the investigator should contact Novartis medical monitor before 
randomizing a participant or allowing a new medication to be started. If the participant is 
already enrolled, contact Novartis to determine if the participant should continue his/her 
participation in the study. 


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Table 6-4 
Prohibited medication  
Medication 
Prohibition period 
Action taken 
Any lipid-lowering therapy other 
than PCSK9 targeted therapies 
including statins (including 
Xuezhikang), ezetimibe, 
bempedoic acid, fibrates, bile-acid 
sequestrants, niacin and omega-3 
fatty acids (DHA and/or EPA with a 
total dose ＞ 1000mg), or any drug 
with unknown ingredients taken for 
the purpose of lipid-lowering, 
including over-the-counter or 
herbal therapies. 
At least 90 days prior to screening 
and throughout the study. 
Investigators should request 
participants to stop taking these 
medications. If participants decide 
to continue taking them, or need to 
take them in the judgment of the 
investigators, it must be recorded 
in the source documentation and 
on an appropriated eCRF page. 
PCSK9 monoclonal antibodies 
At least 90 days prior to screening 
and throughout the study. 
Discontinue study treatment 
Any other non-mAb PCSK9-
targeted therapy other than study 
drug (also including commercially 
available inclisiran). 
At least 2 years prior to screening 
and throughout the study 
Discontinue study treatment 
Any RNAi-based therapeutics, 
including but not limited siRNA or 
Antisense Oligonucleotide (ASO) 
therapeutics. 
At least 2 years prior to screening 
and throughout the study 
Discontinue study treatment 
Any other investigational treatment 
At least 30 days or 5 half-lives, 
whichever is longer, prior to 
screening and throughout the 
study 
Discontinue study treatment 
7 
Discontinuation of study treatment and participant 
discontinuation/withdrawal 
7.1 
Discontinuation of study treatment 
Discontinuation of study treatment for a participant occurs when study treatment is permanently 
stopped for any reason (prior to the planned completion of study treatment administration, if 
any) and can be initiated by either the participant or the Investigator. 
The Investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being. 
Discontinuation from study treatment is required under the following circumstances: 
• Participant/guardian decision 
• Pregnancy 
• Use of prohibited treatment as per recommendations in the prohibited treatment section 
• Any situation in which continued study participation might result in a safety risk to the 
participant 
• Following emergency unblinding 


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• Any laboratory abnormalities that in the judgement of the investigator, taking into 
consideration the participant's overall status, prevents the participant from continuing 
participation in the study. 
If discontinuation from study treatment occurs, the Investigator should make a reasonable effort 
to understand the primary reason for the participant’s discontinuation from study treatment and 
record this information. 
Participants who discontinue study treatment should NOT be considered withdrawn from the 
study UNLESS they withdraw their consent Where possible, they should continue attending 
site visits for the assessments indicated in Section 1.3 Schedule of Activities. 
If the Participant does not wish to attend any further visits, the participants would return to site 
for early exit visit.This visit is suggested to be scheduled at least 30 days after last injection. If 
not possible, to set an EOS visit as soon as possible is also acceptable. 
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the 
participant. This telephone contact should preferably be done according to the study visit 
schedule. 
After discontinuation from study treatment, at a minimum, in abbreviated visits, the following 
data should be collected at clinic visits or via telephone/email contact: 
• New / concomitant treatments 
• Adverse Events / Serious Adverse Events 
The Investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 
7.2 
Participant discontinuation from the study 
Discontinuation from study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason. 
If the participant agrees, he/ she should then return to the study site to complete Early Exit visit 
as detailed in Section 1.3 Schedule of Activities.  This Early Exit visit is suggested to be 
scheduled at least 30 days after last injection. If not possible, to set an Early Exit visit as soon 
as possible is also acceptable. 
7.3 
Withdrawal of informed consent and exercise of participants’ 
data privacy rights 
Withdrawal of consent/opposition to use of data and/or biological samples occurs in countries 
where the legal justification to collect and process the data is consent and when a participant: 
• Explicitly requests to stop use of their data 
and 
• No longer wishes to receive study treatment 
and 
• Does not want any further visits or assessments (including further study-related contacts) 


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This request should be as per local regulations (e.g. in writing) and recorded in the source 
documentation. 
Withdrawal of consent impacts ability to further contact the participant, collect follow-up data 
(e.g. to respond to data queries) and potentially other country-specific restrictions. It is therefore 
very important to ensure accurate recording of withdrawal vs. discontinuation based on the 
protocol definitions of these terms. 
In this situation, the Investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw their 
consent/exercise data privacy rights and record this information. The Investigator shall clearly 
document if the participant has withdrawn his/her consent for the use of data in addition to a 
study discontinuation. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/exercise data privacy rights should be made as detailed in Section 1.3 Schedule of 
Activities. 
Further details on withdrawal of consent or the exercise of participants' data privacy rights are 
included in the corresponding informed consent form. 
7.4 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits or fail to 
respond to any site attempts to contact them without stating an intention to discontinue from 
study treatment or discontinue from study or withdraw consent (or exercise other participants’ 
data privacy rights), the Investigator must show "due diligence" by documenting in the source 
documents steps taken to contact the participant, e.g. dates of telephone calls, registered letters, 
etc. A participant should not be considered as lost to follow-up until due diligence has been 
completed or until the end of the study. 
7.5 
Early study termination by the Sponsor 
The study can be terminated by Novartis at any time. 
Reasons for early termination (but not limited to) 
• Unexpected, significant, or unacceptable safety risk to participants enrolled in the study 
• Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
• Discontinuation of study treatment development 
In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible and treated 
as a participant who discontinued from study treatment: provide instruction for contacting the 
participant, when the participant should stop taking drug, when the participant should come in 


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for a final visit(s) that the safety follow up period must be completed if applicable and which 
visits to be performed. The Investigator may be informed of additional procedures to be 
followed in order to ensure that adequate consideration is given to the protection of the 
participant’s interests. The Investigator or Novartis depending on local regulation will be 
responsible for informing Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) of the early termination of the trial. 
8 
Study Assessments and Procedures 
Study procedures and their timing are summarized in Section 1.3 Schedule of Activities. 
Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with Novartis upon occurrence or awareness to 
determine if the participant should continue or discontinue study treatment. 
Adherence to the study design requirements, including those specified in Section 1.3 Schedule 
of Activities, is essential and required for study conduct. 
Except the screening visit, all lipid parameter measurements results and PCSK9 results that 
could unblind the study will not be reported to investigative sites or other blinded personnel 
until core part database lock. After core part database has been locked, all lipid parameter 
measurements results and PCSK9 results should still remain blind to the participants and 
investigators/site staff until final database lock. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
8.1 
Screening 
Screening activities must be initiated only after the ICF has been signed. 
If a safety laboratory assessment during the screening period is outside of the range specified 
in the exclusion criteria, the assessment may be repeated one time prior to randomization. If the 
repeat value remains outside of the specified ranges, the participant will be considered as screen 
failure. 
The investigator may consider re-screening the participant at a later time if he/she believes that 
the participant's condition has changed and they may potentially be eligible. A participant may 
be re-screened up to 1 time. A minimum of 4 weeks from the Screening visit must elapse before 
re-screening. 
Re-screened participants must provide new written informed consent. A new participant 
number will be assigned to the re-screened participants and the site must record the re-screening 
information in the corresponding eCRF and in IRT. All screening procedures will need to be 
re-performed. 
8.2 
Participant demographics/other baseline characteristics 
China specific regulations should be considered for the collection of demographic and baseline 
characteristics in alignment with CRF. 


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Participant demographics: full date (only if required and permitted) or year of birth or age, sex, 
race/predominant ethnicity (if permitted) and relevant medical history/current medical 
conditions (until date of signature of informed consent) will be recorded in the eCRF. 
Participant race/ethnicity data are collected and analyzed to identify any differences in the 
safety and/or efficacy profile of the treatment due to these characteristics. In addition, these data 
are necessary to assess the diversity of the study population as required by health authorities. 
All prescription medications, over-the-counter drugs and significant non-drug therapies within 
30 days prior to the screening visit must be documented. See the protocol Section 6.8.1 
Concomitant Therapy for further details on what information must be recorded on the 
appropriate page of the eCRF. 
Investigators will have the discretion to record abnormal test findings on the medical history 
eCRF whenever, in their judgement, the test abnormality occurred prior to the informed consent 
signature. 
8.3 
Efficacy assessments 
Planned time points and requirements for all efficacy assessments are provided in Section 1.3 
Schedule of Activities. 
All efficacy assessments 
 will be analyzed at a central lab. Participants must be 
in a fasted state for all of these laboratory assessments. 
The results from all lipid parameter measurements and PCSK9 results will not be reported to 
the site except the screening visit and will be blinded to the participants, investigator, site staff, 
persons performing the assessment, monitors and the Novartis Clinical Trial Team (CTT) until 
the core part database lock. After core part database has been locked, all lipid parameter 
measurements results and PCSK9 results should still remain blind to the participants and 
investigators/site staff until after final database lock. 
8.3.1 
LDL-C 
The primary efficacy assessment will be LDL-C, which will be collected at the frequency shown 
in Table 1-2. 
LDL-C value assessed during Screening visit will be reported to the site for the eligibility 
decision. The following visits' results of the assessments after randomization must be blinded 
to participants, investigators, site staff, persons performing the assessment, monitors and the 
CTT until the core part database lock.  After core part database lock, LDL-C value should 
remain blind to the participants and investigators/site staff until after final database lock. 
Investigators and site staff involved in the conduct of this trial and all medical personnel 
involved in the participant's care and management should refrain from obtaining LDL-C value 
locally between the time from randomization to final database lock. If an LDL-C value is 
inadvertently obtained, all reasonable actions must be taken to ensure the study participant 
and/or study personnel are not informed of the results. 


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8.3.2 
Additional efficacy assessments 
Additional efficacy assessments will include Total cholesterol, triglycerides, HDL-C, non-
HDL-C, ApoA-1, Apo B, Lp(a) and PCSK9, which will be collected at the time points in 
Table 1-2. 
Similar to LDL-C values, the results of the total cholesterol, triglycerides, HDL-C, non-HDL-
C, ApoA-1, Apo B, Lp(a) and PCSK9 will not be reported to the site except the screening visit, 
and will be blinded for the participants, investigator, site staff, persons performing the 
assessment, monitors and the CTT until the core part database lock. After core part database 
has been locked, all above lipid parameter measurements results and PCSK9 results should still 
remain blind to the participants and investigators/site staff until final database lock. 
Investigators and site staff involved in the conduct of this trial and all medical personnel 
involved in the participant's care and management should refrain from obtaining lipid panels 
locally between the time from randomization to final database lock. If a lipid panel is 
inadvertently obtained, all reasonable actions must be taken to ensure the study participant 
and/or study personnel are not informed of the results. 
8.3.3 
Appropriateness of efficacy assessments 
Inclisiran is a siRNA which acts to inhibit the synthesis of PCSK9 protein, which consequently 
reduces LDL-C in circulation. LDL-C is a well-defined and validated laboratory parameter and 
is routinely assessed in clinical trials. LDL-C reduction is an accepted surrogate for CV risk 
reduction, e.g., for statins and PCSK9- blocking monoclonal antibodies. While multiple factors 
contributing to the development of ASCVD have been described, strong and consistent 
evidence from genetics, epidemiology, Mendelian randomization studies, and randomized trials 
have established that LDL-C is not only a laboratory parameter of increased risk, but also a 
causal and modifiable factor in ASCVD (Mach et al 2020). Laboratory tests related to the 
primary and secondary endpoints are in line with the expected efficacy of inclisiran. 
8.4 
Safety assessments 
Safety assessments are specified below with Section 1.3 Schedule of Activities detailing when 
each assessment is to be performed. 
For details on AE collection and reporting, refer to Section 8.6. 
As per Section 4.5, during a public health emergency as declared by local authorities i.e. 
pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, regular phone 
or virtual calls can occur (every 4 weeks or more frequently if needed) for safety monitoring 
and discussion of the participant´s health status until it is safe for the participant to visit the site 
again. 
8.4.1 
Physical examinations 
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular, and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed. 


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A short physical exam will include the examination of general appearance and vital signs (blood 
pressure (BP) [Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)] and pulse). 
A short physical exam will be conducted at all visits starting from visit 1 except where a 
complete physical examination is required (see above). 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in indoor clothing, 
but without shoes) will be measured as specified in Table 1-2. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
Information for all physical examinations must be included in the source documentation at the 
study site. Clinically relevant findings that are present prior to signing informed consent must 
be recorded on the appropriate CRF that captures medical history. Significant findings made 
after signing informed consent which meet the definition of an Adverse Event must be recorded 
as an adverse event. 
8.4.2 
Vital signs 
Vital signs include BP and pulse measurements. After the participant has been sitting for five 
minutes, with the back supported and both feet placed on the floor, pulse and systolic and 
diastolic blood pressure will be measured three times using an automated validated device, e.g. 
OMRON, with an appropriately sized cuff. The repeat sitting measurements will be made at 1 
- 2 minute intervals and the mean of the three measurements will be used. In case the cuff sizes 
available are not large enough for the participant's arm circumference, a sphygmomanometer 
with an appropriately sized cuff may be used. 
Clinically notable vital signs are defined in Section 10.3. 
8.4.3 
Electrocardiograms 
Not applicable. 
8.4.4 
Clinical safety laboratory tests 
Clinically notable laboratory findings are defined in Section 10.3.1. 
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse events as appropriate. 
Table 8-1 
Safety Laboratory Assessments 
Test Category 
Test Name 
Hematology 
Mean Corpuscular Hemoglobin (MCH), Mean Corpuscular HGB 
Concentration (MCHC), MCV, Erythrocytes, Hematocrit, Hemoglobin, 
Leukocytes, Platelets, Differential (% of Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils), HbA1c 
Chemistry (full panel) 
Albumin, ALP, ALT, Amylase, AST, Blood Urea Nitrogen (BUN) Calcium, 
Chloride, Creatine kinase (CK), Creatinine, Direct Bilirubin, eGFR, Fasting 
Plasma Glucose (FPG), GGT, Indirect Bilirubin, Lipase, Magnesium, 
Phosphate, Potassium, Sodium, Total Bilirubin, Uric Acid 
Chemistry (limited panel) 
AST, ALT, ALP, GGT, TBL, Creatinine, eGFR, FPG, CK 


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Test Category 
Test Name 
Urinalysisa 
Macroscopic Panel (Dipstick) (Color, Bilirubin, Occult Blood, Macroscopic 
Blood, Glucose, Ketones, Leukocytes esterase, Nitrite, pH, Protein, Specific 
Gravity, Urobilinogen) 
Coagulation 
PT, INR, Activated partial thromboplastin time (APTT) 
Liver Event Testing and Liver 
Follow-Up Testing 
Albumin, ALP, ALT, AST, CK, GGT, GLDH, INR, PT, and Total Bilirubin 
(TBL). Test for hemolysis (haptoglobin, reticulocytes, unconjugated [indirect] 
bilirubin. 
These tests are in addition to routine testing, to be performed only in follow-
up to safety events when indicated in Section 10.5 Liver safety monitoring 
Renal follow-up 
Urine Albumin and Albumin (for Albumin:creatinine ratio (ACR)), Serum 
Creatinine. Repeat standard chemistry testing and standard urinalysis 
(Microscopic Panel (Casts, Crystals, Bacteria, Epithelial cells, Erythrocytes, 
Leukocytes.) and Macroscopic panel (Dipstick) (Color, Bilirubin, Glucose, 
Ketones, Leukocytes esterase, Macroscopic Blood, Nitrite Occult Blood, pH, 
Protein, Specific Gravity, Urobilinogen)) 
These tests are in addition to routine testing, to be performed only in follow-
up to safety events when indicated in Section 10.6, Renal safety monitoring 
Pregnancy Test and 
Assessments of Fertility 
Serum pregnancy test 
Urine pregnancy test 
Follicle Stimulating Hormone 
(refer to Section 8.4.5) 
a. In case of abnormal results, microscopic urinalysis will be performed at the central lab. Microscopic 
Panel: Erythrocytes, Leukocytes, Casts, Crystals, Bacteria, Epithelia cells. 
8.4.5 
Pregnancy testing 
All pre-menopausal women who are not surgically sterile will have a serum pregnancy testing 
at the screening visit and urine pregnancy testing at other study visits, the time points refer to 
Table 1-2. 
Additional pregnancy testing might be performed if requested by local requirements. 
As per Section 4.5, during a public health emergency as declared by local authorities' i.e. 
pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, if participants 
cannot visit the site to have serum pregnancy tests, urine pregnancy test kits may be used. 
Relevant participants can perform the urine pregnancy test at home and report the result to the 
site. A communication process should be established with the participant so that the site is 
informed and can verify the pregnancy test results (e.g. following country specific measures). 
Assessments of fertility 
A woman is considered of childbearing potential from menarche and until becoming post 
menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy and bilateral oophorectomy. Medical documentation of oophorectomy, 
hysterectomy, or tubal ligation must be retained as source documents. 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause and an appropriate clinical profile. 
In absence of the medical documentation confirming permanent sterilization, or if the post-
menopausal status is not clear, the investigator should use his medical judgment to appropriately 
evaluate the fertility state of the woman and document it in the source document. In such cases, 


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FSH testing is required of any female participant regardless of reported reproductive/ 
menopausal status at screening visit. 
8.4.6 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/participant population. 
8.5 
Additional assessments 
No additional tests will be performed on participants entered into this study. 
8.6 
Adverse events (AEs), serious adverse events (SAEs), and other 
safety reporting 
The definitions of adverse events (AEs) and serious adverse events (SAEs) can be found in 
Section 8.6.1and Section 8.6.2. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up (see Section 7). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 8.6.3. 
8.6.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The Investigator has the responsibility for managing the safety of individual participant and 
identifying adverse events. Novartis qualified medical personnel will be readily available to 
advise on trial-related medical questions or problems. 
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments 
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 8.6.2): 
1. The severity grade: 
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 


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2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant 
3. Its duration (start and end dates or ongoing) and the outcome must be reported 
4. Whether it constitutes a SAE (see Section 8.6.2 for definition of SAE) and which 
seriousness criteria have been met 
5. Action taken regarding with study treatment. 
All adverse events must be treated appropriately. Treatment may include one or more of 
the following: 
• Dose not changed 
• Dose Reduced/increased 
• Drug interrupted/permanently discontinued 
6. Its outcome (i.e. recovery status or whether it was fatal) 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for at least 30 days following the last study 
treatment visit. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be not recovered/not resolved (e.g. continuing at the end of the study), and assessment must be 
made at each visit (or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB). 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease. Alert ranges for laboratory and other test abnormalities are included 
in Section 10.3. 


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8.6.2 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the International Council for Harmonization 
of Technical Requirements for Pharmaceuticals for Human Use (ICH)-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect, fetal death  
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (primary hypercholesterolemia) 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment 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 participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” 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 (please refer to the ICH-
E2D Guidelines). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
events irrespective of whether a clinical event has occurred. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 


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If an SAE occurs, investigators is encouraged to take any appropriate actions immediately based 
on their judgments and relevant clinical guidance. 
8.6.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days after the last study visit (or 90 days after the 
last administration of study drug, whichever is longer) must be reported to Novartis safety 
immediately, without undue delay, but under no circumstances later than within 24 hours of 
obtaining knowledge of the events (Note: If more stringent, local regulations regarding 
reporting timelines prevail). Detailed instructions regarding the submission process and 
requirements are to be found in the Investigator folder provided to each site. Information about 
all SAEs is collected and recorded on the eSAE with paper backup Serious Adverse Event 
Report Form; all applicable sections of the form must be completed in order to provide a 
clinically thorough report. 
Consider the following 2 categories to determine SAE reporting timeframes: 
1. Screen Failures (e.g. a participant who is screened but is not treated or randomized): SAEs 
occurring after the participant has provided informed consent until the time the participant 
is deemed a Screen Failure must be reported to Novartis. 
2. Randomized OR Treated Participants: SAEs collected between time participant signs ICF 
until 30 days after the last study visit (or 90 days after the last administration of study 
drug, whichever is longer) 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, but under no circumstances later than within 24 hours of the 
Investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail). An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a Chief Medical Office and 
Patient Safety (CMO&PS) Department associate may urgently require further information from 
the Investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all Investigators involved in any study with the same study treatment 
that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with Novartis 
procedures and applicable global regulations or as per national regulatory requirements in 
participating countries. 
Any SAEs experienced after the 30-day period following the last study visit (or 90 days after 
the last administration of study drug, whichever is longer) should only be reported to Novartis 
Safety if the Investigator suspects a causal relationship to study treatment, unless otherwise 
specified by local law/regulations. 


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8.6.4 
Pregnancy 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
pregnancy consent form should be presented to the trial participant. The participant must be 
given adequate time to read, review and sign the pregnancy consent form. This consent form is 
necessary to allow the Investigator to collect and report information regarding the pregnancy. 
To ensure participant safety, each pregnancy occurring after signing the informed consent must 
be reported to Novartis within 24 hours of learning of its occurrence. 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. 
Pregnancy should be recorded and reported by the Investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported. 
After consent is provided, the pregnancy reporting will occur up to one year after the estimated 
date of delivery. 
8.6.5 
Disease-related events and/or disease-related outcomes not qualifying 
as AEs or SAEs 
Not Applicable. 
8.6.6 
Adverse events of special interest 
Not Applicable. 
8.7 
Pharmacokinetics 
PK parameters are not evaluated in this study. 
 
 
 
 
 
 
 
 
 
 
 
 


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8.9 
Immunogenicity assessments 
Immunogenicity is not evaluated in this study. 
8.10 
Health economics OR Medical resource utilization and health 
economics 
Not Applicable. 
9 
Statistical considerations 
The primary analyses will be conducted after the database lock for the core part, when all 
randomized participants have completed the visit at Day 180 (or have discontinued from the 
study before EOC). The final analyses will be conducted when the trial ended. 
Details of the statistical analysis and data reporting will be summarized in the statistical analysis 
(SAP) document finalized before database lock. 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
9.1 
Analysis sets 
The following analysis sets will be used for statistical analyses: 
The screened set (SCR) consists of all participants who signed the informed consent. The SCR 
includes only unique screened participants, i.e., in the case of re-screened participants only the 
chronologically last screening data is counted. 
The Randomized Analysis Set (RAS) consists of all participants who received a randomization 
number, regardless of receiving trial medication. 
The Full Analysis Set (FAS) consists of all randomized participants with the exception of those 
participants who have not been qualified for randomization and have not received study drug, 
but have been inadvertently randomized into the study. Following the intent-to-treat (ITT) 
principle, participants will be analyzed according to the treatment they have been assigned to at 
randomization. 
The Safety Analysis Set (SAF) includes all participants who received at least one dose of study 
drug. Participants will be analyzed according to the study treatment actually received. 
Note: The last part of the definition of the FAS is what is often referred to as mis-randomized 
participants i.e. participants for whom IRT calls were made by the site either prematurely or 
inappropriately prior to confirmation of the participant’s final randomization eligibility and 
double-blind medication was not administered to the participant. These participants would 
subsequently not continue to take part in the study or be followed-up. Mis-randomized 
participants will not be included in the FAS, but they will be included in the RAS. Further 


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exclusions from the FAS may only be justified in exceptional circumstances (e.g., serious Good 
Clinical Practice (GCP) violations). 
9.2 
Statistical analyses 
Details of the statistical analysis and data reporting will be summarized in the Statistical 
Analysis Plan (SAP) document finalized before the database lock. 
9.2.1 
General considerations 
Efficacy variables will be analyzed based on the FAS. The SAF will be used for the analyses of 
safety variables. 
9.2.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data will be summarized descriptively by treatment group for 
the FAS. Categorical data will be presented as frequencies and percentages by treatment group. 
For continuous data, number of non-missing observations, mean, standard deviation, median, 
minimum, and maximum will be presented by treatment group. For selected parameters, 25th 
and 75th percentiles will also be presented by treatment group. 
Relevant medical histories will be summarized by system organ class and preferred term, 
separately by treatment group. 
9.2.3 
Treatments 
The SAF will be used for the analyses in this section. 
Study treatment 
The number and percentage of participants receiving study dose at each dosing visit will be 
summarized by treatment group. The number of doses received during the core part (excluding 
Day 180 dose) and during the extension part (including Day 180 dose) will also be summarized 
by treatment group. 
Prior and concomitant therapies 
Prior or concomitant medications will be summarized for the SAF in separate tabulations based 
on the coding dictionary used. Medications will be presented in alphabetical order, by 
Anatomical Therapeutic Chemical (ATC) class and preferred terms. Tables will show the 
overall number and percent of participants receiving at least one drug of a particular ATC class 
and at least one drug in a particular preferred term. 
Prior medications and significant non-drug therapies will be summarized by treatment group. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized by treatment group and by part. 
9.3 
Primary endpoint(s)/estimand(s) analysis 
The primary aim of the study is to demonstrate the superiority of inclisiran as monotherapy, 
compared to placebo, in reducing LDL-C. 


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The FAS will be used for the primary efficacy analysis. 
9.3.1 
Definition of primary endpoint(s) 
The primary endpoint of the study is the percentage change from baseline at Day 150 in LDL-
C. 
9.3.2 
Statistical model, hypothesis, and method of analysis 
The primary objective is to demonstrate the superiority of inclisiran as monotherapy, compared 
to placebo, in reducing LDL-C as measured by percentage change from baseline at Day 150. 
The justification of the corresponding primary estimand is detailed in Section 3.1. 
The primary statistical hypothesis is stated as below. 
• H0: the mean difference (inclisiran minus placebo) in percentage change from baseline at 
Day 150 in LDL-C is no less than zero. 
• H1: the mean difference (inclisiran minus placebo) in percentage change from baseline at 
Day 150 in LDL-C is less than zero. 
The study can be claimed a success if the null hypothesis (H0) is rejected at the one-sided 
significance level of 0.025. 
The primary efficacy endpoint will be analyzed using an Analysis of Covariance (ANCOVA) 
model, in which the response variable will be the percentage change from baseline at Day 150 
in LDL-C, treatment will be included as fixed-effect factor and baseline LDL-C will be included 
as a covariate. 
Based on the ANCOVA model, the estimate and the 95% confidence interval will be provided 
for the adjusted mean difference between inclisiran and placebo, and for the adjusted mean for 
both inclisiran and placebo groups. The one-sided p-value will be provided for the primary null 
hypothesis. 
9.3.3 
Handling of intercurrent events of primary estimand (if applicable) 
The primary analysis will account for different intercurrent events as explained in the following: 
• Discontinuation of study treatment: Retrieved drop out (RDO) data collected after 
discontinuation from study treatment will be used for the analysis (treatment policy). 
Missing data after discontinuation from study treatment will be multiply imputed based on 
RDO data, and when there are no sufficient RDO data, a control-based Pattern-Mixture 
Model (PMM) will be used for multiple imputation. 
• Use of prohibited LLT: Use of prohibited LLT (PCSK9 monoclonal antibodies taken 
before Day 150 visit assessment or other LLT taken within 30 days before Day 150 visit 
assessment) will be treated in a hypothetical scenario of what would happen had those 
LLT not been taken and those participants behaved like other participants in the same 
treatment group (hypothetical strategy). Data after those intercurrent events will be 
excluded for the analysis and will be multiply imputed under missing at random 
assumption. 
• Death: Death due to CV or non-CV causes is considered as an unfavorable outcome 
(composite strategy). Data after death will be set using the subject's baseline values. 


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 The primary analysis will be conducted on each multiply imputed dataset, and the treatment 
effects estimated from each of those imputed datasets will be combined using Rubin's rule. The 
details will be described in the SAP. 
9.3.4 
Handling of missing values not related to intercurrent event 
Missing values not related to intercurrent event will be multiply imputed under missing at 
random assumption. The primary analysis will be conducted on each multiply imputed dataset, 
and the treatment effects estimated from each of those imputed datasets will be combined using 
Rubin's rule. Details will be given in the SAP. 
9.3.5 
Multiplicity adjustment (if applicable) 
Not applicable. 
9.3.6 
Sensitivity analyses 
Sensitivity analyses will be planned and described in the SAP. 
9.3.7 
Supplementary analysis 
Two sets of supplementary analyses will be conducted. 
For the first one, all three intercurrent events, including discontinuation of study treatment, use 
of prohibited LLT under certain conditions and death due to CV or non-CV causes, will be 
handled with a hypothetical strategy. Data after all these intercurrent events will be multiply 
imputed under missing at random assumption. Missing values not related to intercurrent events 
will also be multiply imputed under missing at random assumption. 
For the second one, the intercurrent events of discontinuation of study treatment and death due 
to CV or non-CV causes will be handled in the same way as in the primary analysis. Use of 
prohibited LLT under certain conditions will be treated with a treatment policy strategy, keeping 
treatment labels as assigned at randomization. Retrieved drop out (RDO) data collected after 
use of prohibited LLT under certain conditions will be used for the analysis. If no RDO data 
was collected, missing data will be multiply imputed using a control-based PMM. Missing 
values not related to intercurrent events will also be multiply imputed using a control-based 
PMM. 
Details of supplementary analyses will be described in the SAP. 
Subgroup analyses 
Subgroup analyses to assess the homogeneity of the treatment effect across demographic and 
baseline characteristics may be performed. All subgroup analyses will be defined in the SAP 
prior to database lock. 
9.4 
Secondary endpoint(s)/estimand(s) analysis 
9.4.1 
Efficacy and/or pharmacodynamic endpoint(s) 
The FAS will be used for all below efficacy analyses. 


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9.4.1.1 
Efficacy and/or pharmacodynamic endpoints for core part 
The secondary efficacy endpoints for core part are listed as follows: 
• Absolute change in LDL-C from baseline at Day 150 
• Percentage and absolute change in PCSK9, TC, HDL-C, non-HDL-C, ApoB, ApoA-1, 
Lp(a) and TG from baseline at Day 150 
All secondary efficacy endpoints for core part will be analyzed using the same ANCOVA model 
as for the primary efficacy endpoint. Lipoprotein (a) will be log-transformed before modeling. 
The model will include treatment as fixed effect, and baseline value as a covariate. The adjusted 
mean difference between inclisiran and placebo and corresponding two-sided 95% CIs will be 
provided separately. 
Details of the analyses for secondary efficacy endpoints for core part and sensitivity analyses if 
necessary will be specified in the SAP. 
9.4.1.2 
Efficacy and/or pharmacodynamic endpoints for extension part 
The secondary efficacy endpoints for extension part are listed as follows: 
• Percentage change in LDL-C from baseline at Day 330 for inclisiran group 
• Absolute change in LDL-C from baseline at Day 330 for inclisiran group 
The secondary efficacy endpoints for extension part will be analyzed descriptively. Mean 
percentage and absolute change from baseline at Day 330 in inclisiran group will be provided, 
respectively, as well as the 95% confidence intervals. 
The secondary analysis for extension part will account for different intercurrent events as 
explained in the following: 
• Discontinuation of study treatment: Retrieved drop out (RDO) data collected after 
discontinuation from study treatment will be used for the analysis (treatment policy). 
Missing data after discontinuation from study treatment will be multiply imputed based on 
RDO data, and when there are no sufficient RDO data, a control-based PMM (using the 
core part data) will be used for multiple imputation. 
• Use of prohibited LLT: Use of prohibited LLT (PCSK9 monoclonal antibodies taken 
before Day 330 visit assessment or other LLT taken within 30 days before Day 330 visit 
assessment) will be treated in a hypothetical scenario of what would happen had those 
LLT not been taken and those participants behaved like other participants in the same 
treatment group (hypothetical strategy). Data after those intercurrent events will be 
excluded for the analysis and will be multiply imputed under missing at random 
assumption. 
• Death: Death due to CV or non-CV causes is considered as an unfavorable outcome 
(composite strategy). Data after death will be set using the subject's baseline value. 
 Missing values not related to intercurrent events will also be multiply imputed under missing 
at random assumption. The details will be described in SAP. 


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9.4.2 
Safety endpoints 
For safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group. Baseline data will be summarized where appropriate (for change from baseline 
summaries). 
Adverse events 
The adverse events will be coded using the MedDRA dictionary and will be allocated into each 
study part according to the event start date. All information obtained on adverse event CRFs 
will be summarized by treatment group and by part as described below. 
The number (and percentage) of participants with treatment emergent adverse events (events 
started after the first dose of study medication or events present prior to start of double-blind 
treatment but increased in severity based on preferred term) will be summarized in the following 
ways: 
• by treatment, study part, primary system organ class and preferred term; 
• by treatment, study part, primary system organ class, preferred term and maximum 
severity; 
• by treatment, study part,  and preferred term. 
Separate summaries by treatment, study part, primary system organ class and preferred term 
will be provided for study medication related adverse events, death, serious adverse events, 
other significant adverse events leading to discontinuation. 
A participant with multiple adverse events within a primary system organ class will be only 
counted once towards the total of the primary system organ class. 
Vital signs 
All vital signs data will be listed by treatment group, participant, and visit and if ranges are 
available, abnormalities will be flagged. Summary statistics will be provided by treatment and 
visit. 
Clinical laboratory evaluations 
Summary statistics will be provided by treatment group and visit. Shift tables using the low, 
normal, or high classification will be used to compare baseline to the worst on-treatment value 
by treatment group and by part. The number (and percentage) of participants meeting clinically 
significant criteria will be provided by treatment group and by part. 
 
 
 
 
 
 
 


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9.6 
(Other) Safety analyses 
Not applicable. 
9.7 
Other analyses 
Not applicable. 


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9.8 
Interim analysis 
Not applicable. 
9.9 
Sample size determination 
9.9.1 
Primary endpoint(s) 
This study is designed to randomize approximately 200 Participants (with randomization ratio 
of 1:1 to inclisiran and placebo arms) in order to provide adequate information to characterize 
the safety profile of inclisiran as well as to have sufficient power for the primary efficacy 
endpoint. 
 
 
 
 
9.9.2 
Secondary endpoint(s) 
Statistical power will not be assessed for secondary endpoints. 


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10 
Supporting documentation and operational considerations 
10.1 
Appendix 1: Regulatory, ethical, and study oversight 
considerations 
10.1.1 
Regulatory and ethical considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) international ethical guidelines 
• Applicable ICH Good Clinical Practice (GCP) guidelines 
• Applicable laws and regulations 
The protocol, protocol amendments, ICF, Investigator’s Brochureand other relevant documents 
(e.g. advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
Protocols and any substantial amendments/modifications to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
The Investigator will be responsible for the following: 
Signing a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Quality Assurance representatives, designated agents of Novartis, IRBs/IECs, and 
regulatory authorities as required 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures 
Providing oversight of the conduct of the study at the site and adherence to requirements of 21 
CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable)and all other applicable local regulations 
Inform Novartis immediately if an inspection of the clinical site is requested by a regulatory 
authority 


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10.1.2 
Informed consent process 
The Investigator or his/her representative will explain the nature of the study, including the risks 
and benefits, to the participant or their legally authorized representative  and answer all 
questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representatives will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, privacy and data protection 
requirements, where applicable, and the IRB/IEC or study center. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the participant source documents. 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
A copy of the ICF(s) must be provided to the participant or their legally authorized 
representative. 
Participants who are rescreened are required to sign a new ICF. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional additional research. The Investigator or authorized designee will explain to each 
participant the objectives of the additional research. Participants will be told that they are free 
to refuse to participate and may withdraw their consent at any time and for any reason during 
the storage period. A separate signature will be required to document a participant’s agreement 
to allow any remaining specimens to be used for additional research. Participants who decline 
to participate in this optional additional research will document this. 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her level of understanding. If the participant is capable of doing so, he/she 
must indicate agreement by personally signing and dating the written informed consent 
document. 
Information about common side effects already known about the investigational treatment can 
be found in the Investigator's Brochure (IB) . This information will be included in the participant 
informed consent and should be discussed with the participant upon obtaining consent and also 
during the study as needed. Any new information regarding the safety profile of the 
investigational drug that is identified between IB updates will be communicated as appropriate, 
for example, via an Investigator notification or an aggregate safety finding. New information 
might require an update to the informed consent and then must be discussed with the participant. 
The following informed consents are included in this study: 
• Main study consent, which also included: 


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• A subsection that requires a separate signature for the ‘Optional Consent for 
Additional Research’ to allow future research on data/samples collected during this 
study 
• As applicable, Pregnancy Outcomes Reporting Consent for female participants who took 
study treatment 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
As per Section 4.5, during a public health emergency as declared by local authorities i.e. 
pandemic, epidemic or natural disaster, that may challenge the ability to obtain a standard 
written informed consent due to limits that prevent an on-site visit, Investigator may conduct 
the informed consent discussion remotely (e.g. telephone, videoconference) if allowable by a 
local health authority. 
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g. the presence of an impartial witness, sign/dating separate ICFs 
by trial participant and person obtaining informed consent, etc.). 
10.1.3 
Data protection 
Participants will be assigned a unique identifier by Novartis. Any participant records or datasets 
that are transferred to Novartis will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by 
Novartis in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by Novartis, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
Novartis has appropriate processes and policies in place to handle personal data breaches 
according to applicable privacy laws. 
10.1.4 
Committees structure 
10.1.4.1 Steering Committee 
The Steering Committee (SC) will be established comprising Investigators participating in the 
study, i.e. not being Novartis representatives from the Clinical Trial Team. 
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with clinical trial team, the SC will also develop 
recommendations for publications of study results including authorship rules. The details of the 
role of the SC will be defined in the steering committee charter. 


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10.1.5 
Data quality assurance 
Monitoring details describing strategy, including definition of study critical data items and 
processes (e.g. risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan or other equivalent 
documents. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of Novartis. No records may be transferred to 
another location or party without written notification to Novartis. 
10.1.5.1 Data collection 
Designated Investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the Investigator staff. 
The Investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate. 
After final database lock, the Investigator will receive copies of the participant data for 
archiving at the investigational site. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
10.1.5.2 Database management and quality control 
Novartis personnel will review the data entered by investigational staff for completeness and 
accuracy. Electronic data queries stating the nature of the problem and requesting clarification 
will be created for discrepancies and missing values and sent to the investigational site via the 
EDC system. Designated Investigator site staff are required to respond promptly to queries and 
to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Dates of screenings, randomizations, screen failures and study completion, as well as 
randomization codes and data about all study treatment (s) dispensed to the participant and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 


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will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated Contract Research Organization (CRO)) at specific 
timelines. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of 
Novartis. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis. Any changes to the database after that time can only be made after 
written agreement by Novartis development management. 
10.1.6 
Source documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending on the 
study. Also, current medical records must be available. 
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. The Investigator must also keep the original 
informed consent form signed by the participant (a signed copy is given to the participant). 
Definition of what constitutes source data and its origin can be found in, e.g. monitoring 
guidelines. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. Study monitors will perform ongoing source data verification 
to confirm that data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently approved 
protocol and any other study agreements, ICH GCP, and all applicable regulatory requirements. 
Key study personnel must be available to assist the field monitor during these visits. Continuous 
remote monitoring of each site’s data may be performed by CRA . Additionally, a central 
analytics organization may analyze data & identify risks & trends for site operational 
parameters, and provide reports to Novartis clinical teams to assist with trial oversight. 
10.1.7 
Publication policy 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT or CTIS public website. In addition, after study completion (defined as 
last participant last visit) and finalization of the study report the results of this trial will be 
submitted for publication and posted in a publicly accessible database of clinical trial results, 
such as the Novartis clinical trial results website and all required health authority websites (e.g. 
Clinicaltrials.gov, EudraCT or CTIS public website etc.). 


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For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial Investigator 
meetings. 
Any data analysis carried out independently by the Investigator should be submitted to Novartis 
before publication or presentation. 
10.1.8 
Protocol adherence and protocol amendments 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an Investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the Investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
Investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented. 
10.1.8.1 Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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10.2 
Appendix 2: Abbreviations and definitions 
10.2.1 
List of abbreviations 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANA 
Antinuclear Antibodies 
ANCOVA 
Analysis of covariance 
ApoA-1 
Apolipoprotein A-1 
ApoB 
Apolipoprotein B 
APTT 
Activated Partial Thromboplastin time 
ASCVD 
Atherosclerotic Cardiovascular Disease 
ASGPR 
Asialoglyco Protein Receptors 
ASMA 
Anti-smooth muscle antibody 
ASO 
Antisense Oligonucleotide 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BP 
Blood pressure 
BUN 
Blood Urea Nitrogen 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
Creatine Kinase 
cm 
centimeter(s) 
CMO&PS 
Chief Medical Office and Patient Safety 
CMV 
Cytomegalovirus 
CO 
Country Organization 
COA 
Clinical Outcome Assessment 
CRA 
Clinical Research Associate 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CTIS 
Clinical Trials Information System 
CTT 
Clinical Trial Team 
CV 
Cardiovascular 
CVD 
Cardiovascular Disease 
DBP 
Diastolic Blood Pressure 
DHA 
Docosahexaenoic acid 
DILI 
Drug-Induced Liver Injury 
dL 
deciliter(s) 
DLT 
Dose Limiting Toxicity 
DNA 
Deoxyribonucleic acid 
EBV 
Epstein-Barr virus 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Forms 
EDC 
Electronic Data Capture 
eGFR 
Estimated glomerular filtration rate 


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EMA 
European Medicines Agency 
EOC 
End of core part 
EOS 
End of Study 
EPA 
Eicosapentaenoic acid 
ERCP 
Endoscopic retrograde cholangiopancreatography 
eSAE 
Electronic Serious Adverse Event 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials Database 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FPG 
Fasting Plasma Glucose 
FSH 
Follicle Stimulating Hormone 
GalNAc 
N-Acetylgalactosamine 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
GGT 
Gamma-glutamyl transferase 
GLDH 
Glutamate Dehydrogenase 
h 
Hour 
HAV 
Hepatitis A Virus 
HbA1c 
Glycated hemoglobin (hemoglobin A1c) 
HBsAg 
Hepatitis B virus surface antigen 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HDL-C 
High-Density Lipoprotein Cholesterol 
HeFH 
Heterozygous Familial Hypercholesterolemia 
HEV 
Hepatitis E Virus 
HIV 
Human immunodeficiency virus 
HSV 
Herpes simplex virus 
HTN 
Hypertension 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for Pharmaceuticals for 
Human Use 
IEC 
Independent Ethics Committee 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent-To-Treat 
IUD 
Intrauterine Device 
IUS 
Intrauterine System 
LDL-C 
Low-Density Lipoprotein Cholesterol 
LDLR 
Low Density Lipoprotein Receptor 
LFT 
Liver function test 
LLT 
Lipid-Lowering Therapy 
Lp(a) 
Lipoprotein (a) 
LPLV 
Last participant last visit 


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MACE 
Major adverse cardiovascular event 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical dictionary for regulatory activities 
mg 
milligram(s) 
mL 
milliliter(s) 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
non-HDL-C 
non-High-Density Lipoprotein Cholesterol 
PCR 
Protein-creatinine ratio 
PCSK9 
Proprotein Convertase Subtilisin/Kexin type 9 
PD 
Pharmacodynamic(s) 
PDC 
Proportion of days covered 
PFS 
Prefilled syringe 
PMM 
Pattern-Mixture Model 
PT 
prothrombin time 
R Value 
ALT/ALP x ULN 
RAS 
Randomized Set 
RDO 
Retrieved Drop Out 
RISC 
Ribonucleic acid-Induced Silencing Complex 
RNA 
Ribonucleic acid 
s.c. 
subcutaneous 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SARS-CoV- 2 
Severe acute respiratory syndrome coronavirus 2 also referred to as COVID-19 
SBP 
Systolic Blood Pressure 
SCR 
Screened Set 
siRNA 
small interfering RNA 
SoA 
Schedule of Activities 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBL 
Total bilirubin 
TC 
Total cholesterol 
TEAE 
Treatment-Emergent Adverse Event 
TG 
Triglycerides 
ULN 
upper limit of normal 
WHO 
World Health Organization 
10.2.2 
Definitions 
Additional 
treatment 
Medicinal products that may be used during the clinical trial as described in the protocol, 
but not as an investigational medicinal product (e.g. any background therapy) 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, 
urine, stool, etc. taken from a study participant 
Clinical Trial Team 
A group of people responsible for the planning, execution and reporting of all clinical trial 
activities. Examples of team members include the Study Lead, Medical Monitor, Trial 
Statistician etc. 


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Coded Data 
Personal Data which has been de-identified by the investigative center team by replacing 
personal identifiers with a code. 
Control drug 
A study intervention (active or placebo) used as a comparator to reduce assessment 
bias, preserve blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug 
Discontinuation 
from study 
Point/time when the participant permanently stops receiving the study treatment and 
further protocol required assessments or follow-up, for any reason. No specific request is 
made to stop the use of their samples or data. 
Discontinuation 
from study 
treatment 
Point/time when the participant permanently stops receiving the study treatment for any 
reason (prior to the planned completion of study intervention administration, if any). 
Participant agrees to the other protocol required assessments including follow-up. No 
specific request is made to stop the use of their samples or data. 
Dosage 
Dose of the study treatment given to the participant in a time unit (e.g. 100 mg once a 
day, 75 mg twice a day) 
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study data using 
data collection systems, such as Web-based applications, interactive voice response 
systems and clinical laboratory interfaces. EDC includes the use of Electronic Case 
Report Forms (eCRFs) which are used to capture data transcribed from source 
data/documents used at the point of care 
End of the clinical 
trial 
The end of the clinical trial is defined as the last visit of the last participant. 
Enrollment 
Point/time of participant entry into the study at which informed consent must be obtained. 
The action of enrolling one or more participants 
Estimand 
As defined in the ICH E9(R1) addendum, estimand is a precise description of the 
treatment effect reflecting the clinical question posed by the trial objective. It summarizes 
at a population-level what the outcomes would be in the same participants under 
different treatment conditions being compared. Attributes of an estimand include the 
population, variable (or endpoint) and treatment of interest, as well as the specification of 
how the remaining intercurrent events are addressed and a population-level summary for 
the variable. 
Intercurrent events 
Events occurring after treatment initiation that affect either the interpretation or the 
existence of the measurements associated with the clinical question of interest. 
Investigational 
drug/ treatment 
The drug whose properties are being tested in the study 
Investigational 
Medical Device 
Medical Device being assessed for safety or performance in a clinical investigation. This 
includes devices already on the market and being evaluated for new intended uses, new 
populations, new materials, or design changes 
Medication number 
A unique identifier on the label of medication kits 
Mis-randomized 
participants 
Mis-randomized participants are those who were not qualified for randomization and who 
did not take study treatment, but have been inadvertently randomized into the study or 
the participant allocated to an invalid stratification factor 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e. concomitant 
or rescue therapy) 
Participant 
A trial participant (can be a healthy volunteer or a patient). "Participant" terminology is 
used in the protocol whereas term "Subject" is used in data collection 
Participant number 
A unique number assigned to each participant upon signing the informed consent. This 
number is the definitive, unique identifier for the participant and should be used to 
identify the participant throughout the study for all data collected, sample labels, etc. 
Period 
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) which are 
described in the Protocol. Periods define the study phases and will be used in clinical 
trial database setup and eventually in analysis 
Personal data 
Participant information collected by the Investigator that is coded and transferred to 
Novartis for the purpose of the clinical trial. This data includes participant identifier 
information, study information and biological samples. 


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Randomization 
The process of assigning trial participants to investigational drug or control/comparator 
drug using an element of chance to determine the assignments in order to reduce bias. 
Randomization 
number 
A unique identifier assigned to each randomized participant 
Remote 
Describes any trial activities performed at a location that is not the investigative site. 
Rescreening 
If a participant fails the initial screening and is considered as a Screen Failure, he/she 
can be invited once for a new Screening visit after medical judgment and as specified by 
the protocol 
Screen Failure 
A participant who did not meet one or more criteria that were required for participation in 
the study 
Source 
Data/Document 
Source data refers to the initial record, document, or primary location from where data 
comes. The data source can be a database, a dataset, a spreadsheet or even hard-
coded data, such as paper or eSource 
Start of the clinical 
trial 
The start of the clinical trial is defined as the signature of the informed consent by the 
first participant 
Study treatment 
Any drug or combination of drugs or intervention administered to the study participants 
as part of the required study procedures; includes investigational drug(s), control(s) or 
background therapy 
Tele-visit 
Procedures or communications conducted using technology such as telephone or video-
conference, whereby the participant is not at the investigative site where the Investigator 
will conduct the trial. 
Treatment 
arm/group 
A treatment arm/group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts. 
Treatment of 
interest 
The treatment of interest and, as appropriate, the alternative treatment to which 
comparison will be made. These might be individual interventions, combinations of 
interventions administered concurrently, e.g. as add-on to standard of care, or might 
consist of an overall regimen involving a complex sequence of interventions. This is the 
treatment of interest used in describing the related clinical question of interest, which 
might or might not be the same as the study treatment. 
Variable (or 
endpoint) 
The variable (or endpoint) to be obtained for each participant that is required to address 
the clinical question. The specification of the variable might include whether the 
participant experiences an intercurrent event. 
Withdrawal of 
consent 
Withdrawal of consent from the study occurs when the participant explicitly requests to 
stop use of their data and/or biological samples AND no longer wishes to receive study 
treatment, AND does not agree to further protocol required assessments. This request 
should be in writing (depending on local regulations) and recorded in the source 
documentation. 
This request should be distinguished from a request to discontinue the study. Other 
study participant's privacy rights are described in the corresponding informed consent 
form. 


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10.3 
Appendix 3: Clinical laboratory tests 
10.3.1 
Clinically notable laboratory values and vital signs 
The central laboratory will flag laboratory values falling outside of the normal ranges on the 
central laboratory reports. Investigators are responsible for reviewing these abnormal values for 
clinical significance, signing the laboratory reports to indicate their review, and reporting values 
considered clinically significant in the appropriate eCRF. 
Any clinically significant abnormal laboratory value should be evaluated and followed-up by 
the investigator until normal or a cause for the abnormality is determined. 


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10.4 
Appendix 4: Participant Engagement 
The following participant engagement initiatives are included in this study and will be provided, 
as available, for distribution to study participants at the time points indicated. If compliance is 
impacted by cultural norms or local laws and regulations, sites may discuss modifications to 
these requirements with Novartis. 
• Thank You letter 
• Plain language trial summary - after Clinical study report (CSR) publication 
• Individual study results - after CSR publication 


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10.5 
Appendix 5: Liver safety monitoring 
To ensure participant safety and enhance reliability in determining the hepatotoxic potential of 
an investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
Please refer to Table 10-1 in Section 10.5 for complete definitions of liver laboratory triggers. 
Once a participant is exposed to study treatment, every liver event defined in Table 10-1 should 
be followed up by the Investigator or designated personnel at the trial site, as summarized 
below. Additional details on actions required in case of liver events are outlined in Table 10-2 
Repeat liver chemistry tests (i.e. ALT, AST, TBL, PT/INR, ALP and G-GT) to confirm 
elevation. 
• These liver chemistry repeats will be performed using the central laboratory. If results will 
not be available from the central laboratory, then the repeats can also be performed at a 
local laboratory to monitor the safety of the participant. If a liver event is subsequently 
reported, any local liver chemistry tests previously conducted that are associated with this 
event should have results recorded on the appropriate CRF. 
• If the initial elevation is confirmed, close observation of the participant will be initiated, 
including consideration of treatment interruption if deemed appropriate. 
• Discontinuation of the investigational drug (refer to the Discontinuation of study treatment 
section), if appropriate 
• Hospitalization of the participant if appropriate 
• Causality assessment of the liver event 
• Thorough follow-up of the liver event should include 
• These investigations can include based on Investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy; obtaining more 
detailed history of symptoms and prior or concurrent diseases, history of concomitant 
drug use, exclusion of underlying liver disease 
All follow-up information and procedures performed must be recorded as appropriate in the 
CRF. 
10.5.1 
Liver event and laboratory trigger definitions & follow-up requirements 
Table 10-1 
Liver event and laboratory trigger definitions 
 
Definition/ threshold 
Liver laboratory triggers 
If ALT, AST and total bilirubin 
normal at baseline: 
● ALT or AST > 5 × ULN 
● ALP > 2 × ULN (in the absence of known bone pathology) 
● Total bilirubin > 3 × ULN (in the absence of known Gilbert syndrome) 
● ALT or AST > 3 × ULN and INR > 1.5 
● Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and 
Total bilirubin > 2 × ULN [mainly conjugated fraction] without notable 
increase in ALP to > 2 × ULN) 
● Any clinical event of jaundice (or equivalent term) 
● ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia 
● Any adverse event potentially indicative of a liver toxicity 
If ALT or AST abnormal at baseline: 
● ALT or AST > 3x baseline or > 300 U/L (whichever occurs first) 


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Table 10-2 
Follow up requirements for liver laboratory triggers - ALT, AST, TBL  
 
ALT 
TBL 
Liver 
Symptoms 
Action 
ALT increase without bilirubin increase: 
 
 
If normal at baseline: 
ALT > 3 x ULN 
Normal 
For participants 
with Gilbert’s 
syndrome: No 
change in 
baseline TBL 
None 
• 
No change to study 
treatment 
Measure ALT, AST, ALP, 
GGT, TBIL, INR, albumin, 
CK, and GLDH in 48-72 
hours. 
Follow-up for symptoms. 
If elevated at baseline: 
ALT > 2 x baseline 
or > 300 U/L (whichever occurs 
ﬁrst) 
 
If normal at baseline: 
ALT > 5 x ULN for more than 
two weeks 
Normal 
For participants 
with Gilbert’s 
syndrome: No 
change in 
baseline TBL 
None 
• 
Interrupt study treatment 
Measure ALT, AST, ALP, 
GGT, TBIL, INR, albumin, 
CK, and GLDH in 48-72 
hours. 
Follow-up for symptoms. 
Initiate close monitoring and 
workup for competing 
etiologies. 
Study treatment can be 
restarted only if another 
etiology is identiﬁed and 
liver enzymes return to 
baseline. 
If elevated at baseline: 
ALT > 3 x baseline 
AND >5x ULN  for more than 
two weeks 
 
If normal at baseline: 
ALT > 8 x ULN 
Normal 
None 
ALT increase with bilirubin increase: 
 
If normal at baseline: 
ALT > 3 x ULN 
TBL > 2 x ULN 
(or INR > 1.5) 
For participants 
with Gilbert’s 
syndrome: 
Doubling of direct 
bilirubin 
None 
If elevated at baseline: 
ALT > 2 x baseline 
AND >3x ULN 
 
If normal at baseline: 
ALT > 3 x ULN 
Normal or 
elevated 
Severe fatigue, 
nausea, 
vomiting, right 
upper quadrant 
pain 
If elevated at baseline: 
ALT > 2 x baseline 
AND >3x ULN, 
OR ALT  > 300 U/L 
Table 10-3 
Follow up requirements for liver laboratory triggers - Isolated 
Hyperbilirubinemia  
Criteria 
Actions required 
Follow-up monitoring 
Total Bilirubin (isolated) 
>1.5 – 3.0 ULN 
● Maintain treatment 
● Repeat LFTs within 48-72 hours 
Monitor LFTs weekly until resolution to 
≤ Grade 1 or to baseline 
> 3 - 10 × ULN (in 
the absence of 
known Gilbert 
syndrome) 
● Interrupt treatment 
● Repeat LFT within 48-72 hours 
● Hospitalize if clinically appropriate 
● Establish causality 
● Record the AE and contributing factors 
(e.g. conmeds, med hx, lab) in the 
appropriate CRF 
Monitor LFTs weekly until resolution to 
≤ Grade 1 or to baseline (ALT, AST, 
total bilirubin, Alb, PT/INR, ALP and 
GGT) 
Test for hemolysis (e.g. reticulocytes, 
haptoglobin, unconjugated [indirect] 
bilirubin) 
> 10 x ULN 
● Discontinue the study treatment 
immediately 
● Hospitalize the participant 
● Establish causality 
● Record the AE and contributing factors(e.g. 
ALT, AST, total bilirubin, Alb, PT/INR, 
ALP and GGT until resolution 
(frequency at Investigator discretion) 


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Criteria 
Actions required 
Follow-up monitoring 
conmeds, med hx, lab)in the appropriate 
CRF 
Any AE potentially 
indicative of a liver 
toxicity 
● Consider study treatment interruption or 
discontinuation 
● Hospitalization if clinically appropriate 
● Establish causality 
● Record the AE and contributing factors(e.g. 
conmeds, med hx, lab)in the appropriate 
CRF 
Investigator discretion 
Based on Investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: Serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease. 


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10.6 
Appendix 6: Renal safety monitoring 
Once a participant is exposed to study treatment, the following two categories of abnormal renal 
laboratory alert values should be assessed during the study period: 
• Serum creatinine increase ≥ 25% compared to baseline during normal hydration status 
• Any one of the following: 
• Urine protein-creatinine ratio (PCR) ≥1g/g or ≥100 mg/mmol, OR 
• New onset dipstick proteinuria ≥ 3+, OR 
• New onset dipstick hematuria ≥ 3+ (after excluding menstruation, UTI, extreme 
exercise, or trauma) 
Abnormal renal event findings must be confirmed after ≥24 hours but ≤ 5 days after first 
assessment 
Once a participant is exposed to study treatment, renal laboratory alerts or renal safety events 
should be monitored and followed up by the Investigator or designated trial staff. 
10.7 
Appendix 7: Diagnostic Criteria for Low or Moderated ASCVD 
risk 
Diagnosis of low or moderate ASCVD risk in this study follows the ASCVD Risk Assessment 
Flowchart recommended by 2016 Chinese Guideline for the Management of Dyslipidemia in 
Adults （Zhao et al 2016）. 
Table 10-4 
ASCVD Risk Assessment Flowchart 
Those who meet any of the following conditions can be directly classified as Very High Risk or High Risk: 
Very High Risk: Established ASCVD 
High Risk: 
1) LDL-C≥ 4.9 mmol/L or TC≥ 7.2 mmol/L 
2) Diabetes patients over 40 years old with 1.8 mmol/L≤LDL-C<4.9 mmol/L (or) 3.1 mmol/L≤TC<7.2 mmol/L 
If not meet above condition, need to further assess 10-year ASCVD risk as follows. 
No. of Risk Factors* 
Serum Cholesterol Level Classification (mmol/L) 
3.1 ≤ TC <4.1 (or) 
1.8 ≤ LDL<-C <2.6 
4.1 ≤ TC <5.2 (or) 
2.6 ≤ LDL-C <3.4 
5.2 ≤ TC <7.2 (or) 
3.4 ≤ LDL-C <4.9 
Without hypertension 
0~1 
Low Risk 
Low Risk 
Low Risk 
2 
Low Risk 
Low Risk 
Moderate Risk 
3 
Low Risk 
Moderate Risk 
Moderate Risk 
With hypertension 
0 
Low Risk 
Low Risk 
Low Risk 
1 
Low Risk 
Moderate Risk 
Moderate Risk 
2 
Moderate Risk 
High Risk 
High Risk 
3 
High Risk 
High Risk 
High Risk 
For Moderate Risk patients under 55 years old, assess lifetime residual risk 
• 
Those who meet any 2 of the following risk factors can be classified as High Risk: 
SBP  ≥ 160 mmHg or DBP ≥ 100 mmHg 
Non-HDL-C ≥ 5.2 mmol/L (200 mg/dL) 
HDL-C < 1.0 mmol/L (40 mg/dL) 


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BMI  ≥ 28 kg/m3 
Smoking 
*Risk Factors: Smoking, low HDL-C, Male≥45 years old or Female≥55 years old 


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11 
References 
References are available upon request 
Baigent C, Blackwell L, Emberson L et al (2010) Efficacy and safety of more intensive 
lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 
randomised trials. Lancet; 376(9753):1670-81. 
Ference BA, Ginsberg HN, Graham I, et al (2017) Low-density lipoproteins cause 
atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical 
studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. 
Eur Heart J; 38(32):2459-72. 
Fitzgerald K, White S, Borodovsky A, et al (2017) A Highly Durable RNAi Therapeutic 
Inhibitor of PCSK9. N Engl J Med; 376(1):41-51. 
Foreman KJ, Marquez N, Dolgert A, et al (2018) Forecasting life expectancy, years of life 
lost, and all-cause and cause-specific mortality for 250 causes of death: reference and 
alternative scenarios for 2016-40 for 195 countries and territories. Lancet; 392(10159):2052-
90. 
Mach F, Baigent C, Catapano AL, et al (2020) 2019 ESC/EAS Guidelines for the 
management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J; 
41(1):111-88. 
Mousavi SA, Berge KE, Leren TP (2009) The unique role of proprotein convertase 
subtilisin/kexin 9 in cholesterol homeostasis. J Intern Med; 266:507-19. 
Raal FJ, Kallend D, Ray KK, et al (2020) Inclisiran for the Treatment of Heterozygous 
Familial Hypercholesterolemia. N Engl J Med; 382(16):1520-30. 
Ray KK, Wright RS, Kallend D, et al (2020) Two Phase 3 Trials of Inclisiran in Patients with 
Elevated LDL Cholesterol. N Engl J Med;382(16):1507-19. 
Silverman MG, Ference BA, Im K, et al (2016) Association Between Lowering LDL-C and 
Cardiovascular Risk Reduction Among Different Therapeutic Interventions: A Systematic 
Review and Meta-analysis. JAMA; 316(12):1289-97. 
Slejko JF, Ho M, Anderson HD, et al (2014) Adherence to statins in primary prevention: 
yearly adherence changes and outcomes. J Manag Care Pharm; 20(1):51-7. 
Yusuf S, Hawken S, Ounpuu S, et al Effect of potentially modifiable risk factors associated 
with myocardial infarction in 52 countries (the INTERHEART study): case-control study. 
Lancet; 364(9438):937-52. 
Zhang M, Deng Q, Wang L, et al (2018) Prevalence of dyslipidemia and achievement of low-
density lipoprotein cholesterol targets in Chinese adults: A nationally representative survey of 
163,641 adults. Int J Cardiol; 260:196-203. 
Zhao B, He X, Wu J, et al (2020) Adherence to statins and its impact on clinical outcomes: a 
retrospective population-based study in China. BMC Cardiovasc Disord; 20(1):282. 


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Clinical Trial Protocol (Version No. v00) 
 
Protocol No. CKJX839D12305 
 
Zhao SP, Lu GP, Zhao D (2016) 2016 Chinese Guideline for the Management of 
Dyslipidemia in Adults. Zhonghua Xin Xue Guan Bing Za Zhi; 44(10):833-53 
Zhou M, Wang H, Zhu J, et al (2016) Cause-specific mortality for 240 causes in China during 
1990-2013: a systematic subnational analysis for the Global Burden of Disease Study 2013. 
Lancet; 387:251-72. 

SAP_001.pdf: 
Clinical Development 
KJX839/Inclisiran/Leqvio® 
CKJX839D12305 / NCT05888103
A 6 month randomized, double-blind, placebo-controlled study 
followed by a 6 month open-label extension to assess the efficacy 
and safety of inclisiran as monotherapy in Chinese adults with low 
or moderate ASCVD risk and elevated low-density lipoprotein 
cholesterol   
Statistical Analysis Plan (SAP)  
Document type: 
SAP Documentation 
Document status: 
Final 
Release date: 
29-Oct-2024
Number of pages: 
43 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Template Version 6.0, Effective from 23-Nov-2022 


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Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and 
title impacted 
(Current) 
19-
June-
2023 
Prior 
to 
core 
part 
DB 
lock 
N/A - First version 
NA 
22-
April-
2024 
Prior 
to 
core 
part 
DB 
lock 
SAP Amendment 1 
Section 2.2.1 
Section 2.5.6 
 
 
 
Section 2.3.2 
 
 
 
 
Section 2.4.2 
 
 
 
Section 2.7.1 
 
 
 
Section 
2.7.1.1 
 
 
 
 
 
 
Appendix 
5.1.3 


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Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and 
title impacted 
(Current) 
21-
August-
2024 
Prior 
to 
final 
DB 
lock 
SAP Amendment 2 
Section 2.2 
Section 2.3.1 
Section 2.4.1 
Section 2.4.2 
Section 2.7 
Section 2.8 
Appendix 5.5 
 
 
 
Section 2.4 
Section 2.7.1 
Section 2.8 
 
 
 
Section 2.7.3 
 
 
 
Section 2.4.1 
 
 
 
Section 2.7.1 
Section 
2.7.1.1 


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Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and 
title impacted 
(Current) 
 
 
Section 2.7.1 
 
 
Section 2.3.1 
 
 
Section 5.4.2 
 


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Table of contents 
Table of contents ................................................................................................................. 5 
List of tables ........................................................................................................................ 7 
List of figures ...................................................................................................................... 7 
List of abbreviations ............................................................................................................ 8 
1 
Introduction ....................................................................................................................... 10 
1.1 
Study design .......................................................................................................... 10 
1.2 
Study objectives, endpoints and estimands ........................................................... 12 
1.2.1 
Primary estimand(s) .............................................................................. 13 
1.2.2 
Secondary estimand(s) .......................................................................... 14 
2 
Statistical methods ............................................................................................................. 15 
2.1 
Data analysis general information ......................................................................... 15 
2.1.1 
General definitions ................................................................................ 16 
2.2 
Analysis sets .......................................................................................................... 18 
 
 19 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 20 
2.3.1 
Patient disposition ................................................................................. 20 
2.3.2 
Demographics and other baseline characteristics ................................. 21 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ........................................................................................................... 22 
2.4.1 
Study treatment / compliance ................................................................ 22 
2.4.2 
Prior and concomitant therapies ............................................................ 22 
2.5 
Analysis supporting primary objective(s) .............................................................. 23 
2.5.1 
Primary endpoint(s) ............................................................................... 24 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 24 
2.5.3 
Handling of intercurrent events ............................................................. 24 
2.5.4 
Handling of missing values not related to intercurrent event ............... 25 
2.5.5 
Sensitivity analyses ............................................................................... 25 
2.5.6 
Supplementary analyses ........................................................................ 25 
2.6 
Analysis supporting secondary efficacy objectives ............................................... 26 
2.6.1 
Secondary endpoint(s). .......................................................................... 26 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 27 
2.6.3 
Handling of intercurrent events ............................................................. 27 
2.6.4 
Handling of missing values not related to intercurrent event ............... 28 
2.6.5 
Sensitivity analyses ............................................................................... 28 
2.6.6 
Supplementary analyses ........................................................................ 28 


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2.7 
Safety analyses ...................................................................................................... 28 
2.7.1 
Adverse events (AEs) ............................................................................ 28 
2.7.2 
Deaths .................................................................................................... 31 
2.7.3 
Laboratory data ..................................................................................... 31 
2.7.4 
Other safety data ................................................................................... 32 
2.8 
Impact of COVID-19 ............................................................................................. 32 
2.9 
Pharmacokinetic endpoints .................................................................................... 32 
2.10 
PD and PK/PD analyses ........................................................................................ 33 
2.11 
Patient-reported outcomes ..................................................................................... 33 
 
 33 
 
 33 
2.14 
Interim analysis ...................................................................................................... 34 
3 
Sample size calculation ..................................................................................................... 34 
4 
Change to protocol specified analyses .............................................................................. 34 
5 
Appendix ........................................................................................................................... 34 
5.1 
Imputation rules ..................................................................................................... 34 
5.1.1 
Study drug ............................................................................................. 34 
5.1.2 
AE date imputation ............................................................................... 34 
5.1.3 
Concomitant medication date imputation ............................................. 35 
5.2 
AEs coding/grading ............................................................................................... 35 
5.3 
Laboratory parameters derivations ........................................................................ 35 
5.4 
Statistical models ................................................................................................... 38 
5.4.1 
Analysis supporting primary objective(s) ............................................. 38 
5.4.2 
Analysis supporting secondary objective(s) ......................................... 41 
5.5 
Rule of exclusion criteria of analysis sets ............................................................. 42 
6 
Reference ........................................................................................................................... 43 
 


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List of tables 
Table 1-1 
Objectives and Endpoints ...................................................................... 12 
Table 2-1 
Early exit (EE) visit mapping ................................................................ 17 
 
 19 
Table 5-1 
Clinically notable laboratory abnormalities for selected tests .............. 35 
Table 5-2 
Notable liver function test criteria......................................................... 37 
Table 5-3 
Protocol deviation criteria leading to exclusion from the analysis 
sets ......................................................................................................... 42 
Table 5-4 
Patient classification.............................................................................. 42 
 
List of figures 
Figure 1-1 
Study design .......................................................................................... 11 


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List of abbreviations 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AGB 
ADaM Governance Board 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
ApoA-1 
Apolipoprotein A-1 
ApoB 
Apolipoprotein B 
ASCVD 
Atherosclerotic Cardiovascular Disease 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical classification system 
BILI 
Total Bilirubin 
BMI 
Body Mass Index 
CI 
Confidence Interval 
COVID-19 
Coronavirus Disease 2019 
CRS 
Case Retrieval Strategy 
CSR 
Clinical Study Report 
DBL 
Database Lock 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
eGFR 
Estimated Glomerular Filtration Rate 
EOC 
End of Core Part 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
HbA1c 
Glycated hemoglobin (hemoglobin A1c) 
HDL-C 
High-Density Lipoprotein Cholesterol 
ICF 
Informed Consent Form 
IRT 
Interactive Response Technology 
ITT 
Intent-To-Treat 
LDL-C 
Low-Density Lipoprotein Cholesterol 
LFT 
Liver Function Test  
LLQ 
Lower Limit of Quantification 
LLT 
Lipid Lowering Therapy 
Lp(a) 
Lipoprotein (a) 
MACE 
Major Adverse Cardiovascular Event 
MAR 
Missing-at-Random 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
non-HDL-C 
non-High-Density Lipoprotein Cholesterol 
PCSK9 
Proprotein Convertase Subtilisin/Kexin type 9 
PD 
Pharmacodynamics 
PDS 
Programming Datasets Specifications 


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PK 
Pharmacokinetics 
PMM 
Pattern-Mixture Model 
PT 
Preferred Term 
Q1 
First Quartile 
Q3 
Third Quartile 
RAS 
Randomized Analysis Set 
RDO 
Retrieved Drop Out 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SBP 
Systolic Blood Pressure 
s.c. 
subcutaneous(ly) 
SCR 
Screened Set 
SD 
Standard Deviation 
SOC 
System Organ Class 
TC 
Total Cholesterol 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
ULN 
Upper Limit of Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1 
Introduction 
This document contains a detailed statistical analysis plan to describe the implementation of the 
statistical analysis planned in Section 9 of the CKJX839D12305 study protocol version 00 and 
to support the completion of both the core part clinical study report (CSR) and the Final CSR 
for the study CKJX839D12305. 
The core part analyses will be conducted after the core part database lock (DBL), when all 
randomized participants have completed the Day 180 visit (or have discontinued from the study). 
The results from the core part analyses will be summarized in the core part CSR. 
The final analyses will be conducted when the trial ended. The results from final analyses will 
be summarized in the final CSR. 
1.1 
Study design 
This study is designed as a randomized, double-blind, multi-center phase 3 trial, with a placebo-
controlled period and an open label treatment period, to evaluate the efficacy and safety of 
inclisiran sodium 300mg s.c. in participants aged 18~75 years with low or moderate ASCVD 
risk and fasting low-density lipoprotein cholesterol (LDL-C) value of ≥ 130 mg/dL but < 190 
mg/dL who are not on any lipid lowering therapy. 
The study design is depicted in Figure 1-1. The study consists of 3 parts: 
• Screening: a screening period of up to 14 days for all participants 
• Core Part: a double-blind, placebo-controlled treatment period of 180 days in which 
eligible participants will be randomized 1:1 to receive either inclisiran sodium 300mg s.c. 
(Inclisiran Group) or matching placebo s.c. (Control Group) on Day 1 and Day 90. The 
end of core part (EOC) visit will be conducted on Day 180. The database lock for the core 
part is planned to occur after all randomized participants have completed the EOC visit (or 
have discontinued from the study before EOC). The primary endpoint analysis will be 
conducted after the database lock for the core part. 
• Extension Part: an extended treatment period of 180 days. After all "Core part" study 
assessments are completed on Day 180, the extension part starts. In the extension, all 
patients randomized to inclisiran in the core part will continue on inclisiran while patients 
initially randomized to placebo will transit to inclisiran therapy. The extension part starts 
from a dose of study treatment on Day 180 (placebo in the inclisiran group and inclisiran 
for patients originally randomized to the control group). Thereafter, all participants will 
receive inclisiran sodium 300mg s.c. on Day 270. Treatment on Day 270 will be open-
label. Participants and investigators/site staff will remain blinded to the original 
randomized treatment group assignment (inclisiran vs placebo) until final database lock. 
The EOS visit (Day 360) will be the last visit of the study. 
 


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Figure 1-1 
Study design  
 
1. Participants who discontinue from study treatment should continue to attend the rest of the 
scheduled visits. 
2. Participants randomized to Inclisiran Group will be treated with inclisiran sodium 300mg s.c. on Day 
1 and Day 90 and Day 270, and with matching placebo s.c. on Day 180. Participants randomized 
to Control Group will be treated with matching placebo s.c. on Day 1 and Day 90, and with 
inclisiran sodium 300mg on Day 180 and Day 270. 
3. The end of core part visit. The database lock for the core part is planned to occur after all 
randomized participants have completed the EOC visit (or have discontinued from the study 
before EOC). The primary endpoint analysis will be conducted after the database lock for the core 
part. 
4. Participants who discontinue from study should be scheduled for an Early Exit visit if they agree. 
This Early Exit visit is suggested to be scheduled at least 30 days after last injection. If not 
possible, to set an Early Exit visit as soon as possible is also acceptable. 
On Day 1 (Baseline), approximated 200 eligible participants who meet all inclusion and not 
meet any exclusion criteria will be randomized 1:1 to Inclisiran Group and Control Group. 
Study visits of core part will occur on Day 1 (baseline visit), Day 30, Day 90, Day 150, and 
Day 180. On Day 1 and Day 90 visits, inclisiran s.c. or placebo s.c. will be administered at the 
site by a healthcare professional. The primary endpoint will be assessed at Day 150. The EOC 
visit will be conducted on Day 180. 
The extension part starts with a dose on Day 180 after all core part assessment are completed. 
In order to maintain the blind for the treatment group assignment, participants randomized to 
Control Group will receive inclisiran, while participants randomized to Inclisiran Group will 
receive placebo on Day 180. All participants will then receive inclisiran sodium 300 mg on Day 
270, which will be the third dose of inclisiran for Inclisiran Group, and the second dose of 
inclisiran for Control Group. All injections will be administered at the site by a healthcare 
professional. The EOS visit (Day 360) will be the last visit of the study. 
The randomization will not be stratified. 


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The core part analyses will be conducted when all randomized participants have completed the 
visit at Day 180 (or have discontinued from the study). The final analyses will be conducted 
when the trial ended. No interim analyses are planned. 
1.2 
Study objectives, endpoints and estimands  
Table 1-1 
Objectives and Endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
● To demonstrate the superiority of inclisiran as 
monotherapy, compared to placebo, on mean 
percentage change from baseline in LDL-C at Day 
150, in Chinese adults with low or moderate ASCVD 
risk and elevated LDL-C who are not on any lipid 
lowering therapy. 
● Percentage change in LDL-C from baseline at Day 
150 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
● To demonstrate the efficacy of inclisiran as 
monotherapy, compared to placebo on absolute 
change from baseline in LDL-C at Day 150. 
● Absolute change in LDL-C from baseline at Day 150 
● To demonstrate the efficacy of inclisiran as 
monotherapy, compared to placebo on percentage 
and absolute change from baseline in Proprotein 
Convertase Subtilisin/Kexin type 9 (PCSK9), total 
cholesterol (TC), high-density lipoprotein (HDL-C), 
non-high-density lipoprotein cholesterol (non-HDL-C), 
apolipoprotein B (ApoB), apolipoprotein A-1 (ApoA-1), 
lipoprotein (a) (Lp(a)) and triglycerides (TG) at Day 
150. 
● Percentage change from baseline at Day 150 in 
PCSK9 
● Absolute change from baseline at Day 150 in 
PCSK9 
● Percentage change from baseline at Day 150 in TC, 
HDL-C, non-HDL-C, ApoB, ApoA-1, Lp(a) and TG 
● Absolute change from baseline at Day 150 in TC, 
HDL-C, non-HDL-C, ApoB, ApoA-1, Lp(a) and TG 
● To evaluate the effect of inclisiran as monotherapy 
on percentage and absolute change in LDL-C from 
baseline at Day 330. 
● Percentage change in LDL-C from baseline at Day 
330 for inclisiran group 
● Absolute change in LDL-C from baseline at Day 330 
for inclisiran group 
● To evaluate the safety and tolerability of inclisiran 
as monotherapy compared to placebo during core 
part. 
● Adverse Events (AEs), vital signs and safety 
laboratory values 
● To evaluate the safety and tolerability of inclisiran 
as monotherapy during extension part. 
● Adverse Events (AEs), vital signs and safety 
laboratory values 


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1.2.1 
Primary estimand(s) 
The estimand is the precise description of the treatment effect and reflects strategies to address 
events occurring during trial conduct which could impact the interpretation of the trial results 
(e.g. premature discontinuation of treatment). 
The clinical question of primary interest is: what is the reduction in LDL-C, quantified by 
difference of mean percentage change from baseline at Day 150, in Chinese adults with low or 
moderate ASCVD risk and elevated LDL-C who are not on any lipid-lowering therapy, who 
receive inclisiran as monotherapy, compared to placebo, regardless of discontinuation from 
study treatment, if other lipid-lowering therapy were not taken, and where death due to CV or 
non-CV causes is considered an unfavorable outcome. 
The primary estimand is described by the following attributes: 
Population: Chinese adults with low or moderate ASCVD risk and elevated LDL-C who are 
not on any lipid-lowering therapy. 
Endpoint: Percentage change from baseline at Day 150 in LDL-C. 
Treatments of interest: Inclisiran as monotherapy compared to the use of placebo, regardless of 
study treatment discontinuation. 
Handling of intercurrent events: 
• Permanent discontinuation of study treatment will be handled with a treatment policy 
strategy, keeping treatment labels as assigned at randomization. 


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• Use of prohibited LLT (PCSK9 monoclonal antibodies taken before Day 150 visit 
assessment or other LLT taken within 30 days before Day 150 visit assessment) will be 
treated with a hypothetical strategy of what would happen had those LLT not been taken 
and those participants behaved like other participants in the same treatment group. 
• Participants who died will be handled with a composite strategy; death is considered an 
unfavorable outcome. 
Summary measure: the summary measure to be used is the difference of mean percentage 
changes. 
Complete details on the statistical methods and inference, including missing data handling and 
sensitivity analyses are provided in Section 2.5.   
1.2.2 
Secondary estimand(s) 
1.2.2.1 
Secondary estimands for core part 
The secondary estimands for core part address the same clinical question as the primary 
estimand, albeit for different endpoints. They share the same population, intercurrent events,  
summary measure, as well as the same treatments as the primary estimand. They differ by the 
definition of the endpoints, these being: 
• Absolute change in LDL-C from baseline at Day 150 
• Percentage and absolute change in PCSK9, TC, HDL-C, non-HDL-C, ApoB, ApoA-1, 
Lp(a) and TG from baseline at Day 150 
Complete details on the statistical methods and inference, including missing data handling and 
sensitivity analyses are provided in Section 2.6. 
1.2.2.2 
Secondary estimands for extension part 
The clinical question of interest in extension part is: what is the reduction in LDL-C, quantified 
by mean percentage or absolute change from baseline at Day 330, in Chinese adults with low 
or moderate ASCVD risk and elevated LDL-C who are not on any lipid-lowering therapy, who 
receive inclisiran as monotherapy, regardless of discontinuation from study treatment, if other 
lipid-lowering therapy were not taken, and where death due to CV or non-CV causes is 
considered an unfavorable outcome. 
The secondary estimand for extension part is described by the following attributes: 
Population: Chinese adults with low or moderate ASCVD risk and elevated LDL-C who are 
not on any lipid-lowering therapy. 
Endpoint: Percentage or absolute change from baseline at Day 330 in LDL-C for inclisiran 
group. 
Treatments of interest: Inclisiran as monotherapy, regardless of study treatment discontinuation. 
Handling of intercurrent events: 
• Permanent discontinuation of study treatment will be handled with a treatment policy 
strategy, keeping treatment labels as assigned at randomization. 


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• Use of prohibited LLT (PCSK9 monoclonal antibodies taken before Day 330 visit 
assessment or other LLT taken within 30 days before Day 330 visit assessment) will be 
treated with a hypothetical strategy of what would happen had those LLT not been taken, 
and those participants behaved like other participants in the same treatment group. 
• Participants who died will be handled with a composite strategy; death is considered an 
unfavorable outcome. 
Summary measure: the summary measure to be used is the mean percentage or absolute change. 
Complete details on the statistical methods and inference, including missing data handling and 
sensitivity analyses are provided in Section 2.6. 
2 
Statistical methods 
2.1 
Data analysis general information 
All analyses will be performed by Novartis or a designated CRO. The most recent version of 
SAS available in the statistical programming environment of Novartis or the designated CRO 
will be used for the analyses.  
The core part analyses will be conducted after the core part database lock, when all randomized 
participants have completed the Day 180 visit (or have discontinued from the study). The data 
snapshot at the time of the core part database lock will be used for these analyses. The analysis 
cutoff date will be determined and documented prior to the core part database lock, and will be 
chosen based on the operational feasibility, as a calendar date on or after the last core part visit 
date from all participants and prior to the core part database lock date. The analysis cutoff date 
will be applied to include relevant extension part assessments / events in the core part analyses. 
All events with start date before or on the cut-off date, and end date after the cut-off date will 
be reported as ‘ongoing’. The same rule will be applied to events starting before or on the cut-
off date and not having documented end date. The results from the core part analyses will be 
summarized in the core part CSR. 
The final analyses will be conducted after the final database lock at the end of the study, when 
all randomized participants have completed the Day 360 visit (or have discontinued from the 
study). The data snapshot at the time of the final database lock will be used for the final analyses. 
The analysis cutoff date for the final analyses will be the final database lock date, such that, all 
collected data will be included in the final analyses. The results from the final analyses will be 
summarized in the final CSR. 
For overall study analyses in core part analyses, available data on or prior to the analysis cutoff 
date will be used, unless otherwise specified. For by-part analyses, analyses using core part data 
and extension part data will be performed in core part analyses and final analyses, respectively, 
unless otherwise specified.  If there were any major changes in core part data after the core part 
DBL, some analyses including only core part data may be repeated in final analyses. This will 
be recorded in the TFL shell before the final DBL. 


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In general, continuous data will be summarized using number of non-missing observations (n), 
mean, standard deviation, median, minimum, the 25th percentile (Q1), the 75th percentile (Q3), 
and maximum; categorical data will be summarized using frequencies and percentages. 
2.1.1 
General definitions   
Study treatment 
The term “study drug” or “study treatment” refers to the study drug (inclisiran sodium 300 mg 
s.c. or inclisiran-matching placebo) dispensed during the study.  
For each participant and each dosing visit, the participant will be considered to have received 
the study treatment if the date of dose is non-missing and the answer to ‘was dose administered’ 
is yes. 
For each participant, the first dose date and the last dose date of the study treatment are defined 
as the earliest date and the latest date on which the participant received the study treatment. 
Study day  
Study day will be defined as the number of days since the date of first dose of study treatment. 
The date of first dose of study treatment will be defined as Day 1 and the day before the first 
dose of study treatment will be defined as Day -1.  
Therefore, for a particular date, study day will be calculated as follows: 
For dates on or after the date of first dose of study treatment, 
Study day = Assessment date – Date of first dose of study treatment + 1; 
For dates prior to the date of first dose of study treatment, 
Study day = Assessment date – Date of first dose of study treatment. 
In case a participant has been randomized but has not received any study treatment then 
randomization visit day will be considered as Day 1. 
Baseline assessment 
For each variable, the baseline assessment is defined as the last non-missing assessment 
(scheduled or unscheduled) collected on or prior to the first dose of study treatment, unless 
otherwise specified. If a participant has never started any study treatment, then the last non-
missing assessment (scheduled or unscheduled) collected on or prior to the study Day 1 will be 
used as baseline assessment. 
Post-baseline assessment 
Post-baseline assessments are defined as those assessments that were collected after the first 
dose of study treatment. 
When change from baseline is of interest the following formula will be used for each scheduled 
visit and time-point where baseline and post-baseline values are both available: 


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Absolute change from baseline = post-baseline value – baseline value. 
Percentage change from baseline = (absolute change from baseline / baseline value)*100. 
Unscheduled assessment 
Unscheduled assessments will not be included in by-visit summary but will be included in the 
derivation of over-period minimum and maximum values. 
All scheduled or unscheduled assessments will be included in the listings. 
Early Exist (EE) visit mapping 
For participants who discontinued from the study and come to the site for the early exit (EE) 
visit, the EE visit will be mapped to the next scheduled visit. 
Table 2-1 
Early exit (EE) visit mapping 
Study status 
Last Attended Scheduled 
Visit Prior to EE 
Mapped Visit for Visit EE 
Visit Day 
Visit Name 
Visit Day 
Visit Name 
Discontinued 
1 
Visit 1 
30 
Visit 2 
Discontinued 
30 
Visit 2 
90 
Visit 3 
Discontinued 
90 
Visit 3 
150 
Visit 4 
Discontinued 
150 
Visit 4 
180 
Visit 5/EOC 
Discontinued 
180 
Visit 5/EOC 
210 
Visit 6 
Discontinued 
210 
Visit 6 
270 
Visit 7 
Discontinued 
270 
Visit 7 
330 
Visit 8 
Discontinued 
330 
Visit 8 
360 
Visit 9/EOS 
Completed 
--- 
--- 
--- 
--- 
Switching date 
The switching date will be defined using the following algorithm. 
• For participants with non-missing Day 180 study treatment dose date, the switching date 
will be set to the Day 180 study treatment dose date. 
• For participants with missing Day 180 study treatment dose date and non-missing Day 180 
visit date, the switching date will be set to the Day 180 visit date. 
• For participants with missing Day 180 study treatment dose date and missing Day 180 
visit date, the switching date will be set to the study day 195 date. 
If the resulting switching date locates after the study discontinuation date or the analysis cutoff 
date (if any), the switching date will be set to missing and the participant will be considered to 
have not switched until the study discontinuation or the analysis cutoff. 


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Assessments and events allocation 
In general, assessments and events will be allocated into the screening period, the core part and 
the extension part using the following rules. 
• For non-randomized participants, all assessments / events will be considered as screening 
period assessments / events. 
• For randomized participants, assessments / events with assessment date / event date prior 
to the randomization visit date will be considered as screening period assessments / 
events. 
• For randomized participants with missing switching date, assessments / events with 
assessment date / event date on or after the randomization visit date will be considered as 
core part assessments / events. 
• For randomized participants with non-missing switching date, assessments / events with 
assessment date / event date on or after the randomization visit date and on or prior to the 
switching date will be considered as core part assessments / events. 
• For randomized participants with non-missing switching date, assessments / events with 
assessment date / event date after the switching date will be considered as extension part 
assessments / events. 
Study treatment allocation 
In general, study treatments will be allocated using the following algorithm. 
• Study treatments at the randomization visit and Day 90 will be considered as core part 
study treatments. 
• Study treatments at Day 180 and Day 270 will be considered as extension part study 
treatments. 
Reflexive LDL-C 
The LDL-C will be collected through the central laboratory, using the Friedewald formula and 
the ultracentrifugation method as appropriate. The calculated LDL-C (Friedewald formula) and 
the directly measured LDL-C (ultracentrifugation) will be loaded from the central laboratory. 
The LDL-C endpoint will be derived using a reflexive LDL-C approach: either calculated LDL-
C (based on the Friedewald formula) will be used, or if the calculated LDL-C is less than 70 
mg/dL or triglycerides are greater than 400 mg/dL, or calculated LDL-C is missing, directly 
measured (using ultracentrifugation) LDL-C will be used if it is available. 
2.2 
Analysis sets  
The following analysis sets will be used for statistical analyses: 
The Screened Set (SCR) consists of all participants who signed the informed consent. The SCR 
includes only unique screened participants, i.e., in the case of re-screened participants only the 
chronologically last screening data is counted. 


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The Randomized Analysis Set (RAS) consists of all participants who received a randomization 
number, regardless of receiving trial medication. 
The Full Analysis Set (FAS) consists of all randomized participants with the exception of those 
participants who have not been qualified for randomization and have not received study drug 
but have been inadvertently randomized into the study. Following the intent-to-treat (ITT) 
principle, participants will be analyzed according to the treatment they have been assigned to at 
randomization. Efficacy variables will be analyzed based on the FAS. 
The Safety Analysis Set (SAF) includes all participants who received at least one dose of study 
drug. Participants will be analyzed according to the study treatment actually received. The SAF 
will be used for the analyses of safety variables. 
The Open-label Set (OLS) includes all participants who entered the extension part and received 
at least one dose of study drug during extension part (at Day 180 or Day 270). OLS will be used 
to analyze the non-efficacy data in extension part, unless otherwise specified.  
Participants without valid written informed consent will be excluded from all analysis sets. 
Further exclusions from the FAS are only justified in exceptional circumstances (e.g., site 
closed down for GCP reasons). The determination of which participants were excluded from 
the FAS is made in a blinded manner before the database lock for the Core Part. 
Rules leading to exclusion from the analysis sets are given in Appendix 5.5. 
Note: The last part of the definition of the FAS is what is often referred to as mis-randomized 
participants i.e. participants for whom IRT calls were made by the site either prematurely or 
inappropriately prior to confirmation of the participant’s final randomization eligibility and 
study medication was not administered to the participant. These participants would 
subsequently not continue to take part in the study or be followed-up. Mis-randomized 
participants will not be included in the FAS, but they will be included in the RAS.  


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2.3 
Patient disposition, demographics and other baseline 
characteristics 
2.3.1 
Patient disposition 
Core part analyses 
The screening period completion status and the corresponding reason for non-completion will 
be collected for all participants with informed consent signed as the screening disposition and 
will be summarized using the number of screened participants, the number and the percentage 
of screened participants, who completed the screening period, and who discontinued during the 
screening period. In addition, the reason for discontinuation will also be summarized, using the 
number and the percentage of screened participants discontinued due to each reason. The SCR 
will be used for screening disposition. 
The study completion status and the corresponding reason for non-completion will be collected 
for all randomized participants as the study disposition. The study disposition for core part will 
be summarized by treatment group separately using the number of randomized participants, the 
number and the percentage of participants who completed core part, and who discontinued from 
the study during core part. The reason for discontinuation during the core part will be 
summarized by treatment group separately, using the number and the percentage of participants 
discontinued due to each reason. The RAS will be used. Listing for study disposition will also 
be provided for core part. 
The study treatment completion status and the corresponding reason for non-completion for 
core part will be summarized by treatment group, using SAF. 
Duration on study is defined as: date of last known visit on study – date of study Day 1 + 1. For 
core part analyses, duration on study will be truncated at switching date. The duration on study 
will be summarized by treatment group for core part, using FAS. 
Number of participants with protocol deviations will be tabulated by category (e.g., selection 
criteria not met, subject not withdrawn as per protocol, treatment deviation, prohibited 


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concomitant medication, other), deviation for core part, using RAS. Listing of participants with 
protocol deviation will be provided for core part. 
The number of participants included in each analysis set will be tabulated by treatment group 
using SCR. Participants exclusion from analysis sets will be summarized for all participants 
with reasons for exclusion (i.e. including both protocol and non-protocol deviations) and 
corresponding listing will be provided. 
Final analyses 
The study disposition for extension part will be summarized by treatment group separately using 
the number of randomized participants, the number of completed core part participants, the 
number and the percentage of participants who completed extension part, and who discontinued 
from the study during extension part. The reason for discontinuation during the extension part 
will be summarized by treatment group separately, using the number and the percentage of 
participants discontinued due to each reason. The RAS will be used. Listing for study 
disposition will also be provided for overall study. 
The study treatment completion status and the corresponding reason for non-completion for 
extension part will be summarized by treatment group, using OLS. 
Duration on study is defined as: date of last known visit on study – date of study Day 1 + 1. The 
duration on study will be summarized by treatment group for overall study using FAS. 
Number of participants with protocol deviations will be tabulated by category, deviation for 
extension part and for overall study, using OLS and RAS, respectively. Listing of participants 
with protocol deviation will be provided for overall study. 
The number of participants included in each analysis set will be tabulated by treatment group 
using SCR. Participants exclusion from analysis sets will be summarized for all participants 
with reasons for exclusion (i.e. including both protocol and non-protocol deviations) and 
corresponding listing will be provided. 
2.3.2 
Demographics and other baseline characteristics 
Summary statistics will be provided by treatment group for demographics and for other baseline 
characteristics, including age (years), age group (< 65 years, >= 65 years), sex, race, ethnicity, 
smoking history, alcohol history, protocol solicited medical history, ASCVD risk level, height, 
weight, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), 
pulse rate, eGFR, eGFR group ( >=30 mL/min/1.73 m2 to < 60 mL/min/1.73 m2, >= 60 
mL/min/1.73 m2), LDL-C, PCSK9, TG, TC, HDL-C, non-HDL-C, ApoB, ApoA-1, Lp(a), 
where the BMI will be calculated as weight (kg) / [height (m)]2 from the height and the weight 
at screening. For variables only scheduled at screening, the scheduled assessment at screening 
will be summarized. For other variables, the baseline assessment will be summarized. Listings 
will also be provided. 
The FAS will be used for the above summaries. 
The above summaries for demographics and baseline characteristics will be conducted only in 
the core part analyses. 


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Medical histories will be collected using the medical history case report form (CRF) and coded 
using the Medical Dictionary for Regulatory Activities terminology (MedDRA). The collected 
medical histories will be summarized by treatment group, primary system organ class (SOC), 
and preferred term (PT), using the number and the percentage of participants with each medical 
history. 
The FAS will be used for the above summaries. 
The above summaries for medical histories will be conducted only in the core part analyses. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
The SAF will be used for the analyses below, unless otherwise specified. 
2.4.1 
Study treatment / compliance 
The number and percentage of participants receiving study dose and the injection site location 
will be summarized by study visit and treatment group for both core part analyses and final 
analyses. For core part analyses, the summary tables including Day 1 and Day 90 visit and for 
overall study will be provided. For final analyses, the summary table will include Day 180, and 
Day 270 visit using OLS. 
The number of doses received during the core part (at Day 1 and Day 90), duration of exposure, 
patient year of exposure will be summarized by treatment group for core part analyses. Such 
summary table of exposure to study treatment and listing for overall study will also be provided 
in core part analyses. The number of doses received during the whole study, duration of 
exposure for overall study and patient year of exposure will be summarized by treatment group 
for final analyses. Listings for overall study will also be provided in final analyses. 
Duration of exposure for overall study will be calculated as: minimum of (Date of last dose of 
treatment – Date of first dose of treatment + 1 + 180, Date of last known visit – Date of first 
dose of treatment + 1). Duration of exposure to study treatment for overall study will be 
truncated at the analysis cutoff date for core part analyses. 
The number of doses received during the extension part (at Day 180 and Day 270), duration of 
exposure in extension part and patient year of exposure will also be summarized by treatment 
group using OLS for final analyses. Duration of exposure for extension part will be calculated 
as: minimum of (Date of last dose of treatment in extension part – Date of treatment at Day 180 
+ 1 + 180, Date of last known visit in extension part – Date of treatment at Day 180 + 1). If the 
Day 180 treatment was not taken, then the date of Day 180 visit will be used. 
Patient-year of exposure will be calculated as duration of exposure/365.25. 
2.4.2 
Prior and concomitant therapies 
Prior / concomitant medications / non-drug therapies will be collected in the corresponding CRF 
and will be coded using the WHO dictionary and the MedDRA dictionary accordingly. The 
medications / non-drug therapies will be classified into prior, core part concomitant, and 
extension part concomitant. 


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• The prior (pre-baseline) medications / non-drug therapies will be defined as medications / 
non-drug therapies with the end date prior to the first dose date of study treatment. 
• The core part concomitant medications / non-drug therapies will be defined as medications 
/ non-drug therapies with the end date on or after the first dose date of study treatment (or 
no documented end date) and the start date on or prior to the switching date. 
• The extension part concomitant medications / non-drug therapies will be defined as 
medications / non-drug therapies with the end date after the switching date (or no 
documented end date). 
The prior medications will be summarized by treatment group, anatomical therapeutic chemical 
(ATC) class and PT for core part analyses only. The concomitant medications will be 
summarized by study part, treatment group, ATC class and PT. For the extension part, the 
summary will be provided using OLS. 
The prior non-drug therapies will be summarized by treatment group, SOC and PT for core part 
analyses only. The concomitant non-drug therapies will be summarized by study part, treatment 
group, SOC and PT. For the extension part, the summary will be provide using OLS. 
The following lipid-lowering therapies will be identified from the medications, using the ATC 
class and the PT. Detailed specifications will be provided separately. 
• Statins 
• Cholesterol absorption inhibitor 
• PCSK9 inhibitor monoclonal antibody 
• Inclisiran 
• Other lipid lowering therapy 
Any above lipid-lowering therapy added after study Day 1 will be summarized by treatment 
group and medication, using the numbers and the percentages of participants who received the 
corresponding medication on or prior to the following select time points. 
• Study day 1 
• Study day 90 
• Study day 150 
• Study day 180 
• Study day 270 
• Study day 330 
• Study day 360 
In core part analyses, the above new added LLT summary table will include time points up to 
study Day 180 only. In final analyses, summary table of new added LLT will be provided 
including the time points from study Day 180 up to study Day 360 using OLS.  
2.5 
Analysis supporting primary objective(s) 
The FAS will be used for the primary efficacy analysis. 


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2.5.1 
Primary endpoint(s) 
The primary objective of this study is to demonstrate the superiority of inclisiran as 
monotherapy, compared to placebo, on mean percentage change from baseline in LDL-C at Day 
150, in Chinese adults with low or moderate ASCVD risk and elevated LDL-C who are not on 
any lipid lowering therapy. 
The primary endpoint is the percentage change from baseline at Day 150 in LDL-C. 
2.5.2 
Statistical hypothesis, model, and method of analysis  
The primary efficacy endpoint will be analyzed using an Analysis of Covariance (ANCOVA) 
model, in which the response variable will be the percentage change from baseline at Day 150 
in LDL-C, treatment will be included as fixed-effect factor and baseline LDL-C will be included 
as a covariate.  
The primary statistical hypothesis is stated as below. 
• 
H0: the mean difference (inclisiran minus placebo) in percentage change from baseline at 
Day 150 in LDL-C is no less than zero. 
• 
H1: the mean difference (inclisiran minus placebo) in percentage change from baseline at 
Day 150 in LDL-C is less than zero. 
The study can be claimed a success if the null hypothesis (H0) is rejected at the one-sided 
significance level of 0.025. 
The statistical test will be performed at the one-sided significance level of 0.025 based on the 
ANCOVA model. The estimate and the 95% confidence interval will be provided for the 
adjusted mean difference between inclisiran and placebo, and for the adjusted mean for both 
inclisiran and control groups, based on the ANCOVA model. The one-sided p-value will be 
provided for the primary null hypothesis. 
2.5.3 
Handling of intercurrent events  
The primary efficacy analysis will account for different intercurrent events as explained in the 
following: 
• Discontinuation of study treatment: Retrieved drop out (RDO) data collected after 
discontinuation from study treatment will be used for the analysis (treatment policy). 
Missing data after discontinuation from study treatment will be multiply imputed based on 
RDO data within each treatment group, and when there are no sufficient RDO data, a 
control-based Pattern-Mixture Model (PMM) will be used for multiple imputation. In the 
PMM, missing not at random (MNAR) assumption will be used for inclisiran group. The 
detailed information is specified in Appendix 5.4.1.1. 
• Use of prohibited LLT: Use of prohibited LLT (PCSK9 monoclonal antibodies taken 
before Day 150 visit assessment or other LLT taken within 30 days before Day 150 visit 
assessment) will be treated in a hypothetical scenario of what would happen had those 
LLT not been taken, and those participants behaved like other participants in the same 
treatment group (hypothetical strategy). Data after those intercurrent events will be 


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excluded for the analysis and will be multiply imputed within each treatment group under 
MAR assumption. 
• Death: Death due to CV or non-CV causes is considered as an unfavorable outcome 
(composite strategy). The LDL-C values at Day 150 after death will be set using the 
participant’s baseline values. 
In the case of multiple intercurrent events, death will be the dominant one in the analysis (if 
present). If a participant experiences only two other intercurrent events and usage of prohibited 
LLT occurs first, s/he will be handled by the event of usage of LLT (hypothetical strategy). If 
treatment discontinuation occurs prior to usage of prohibited LLT, then data after usage of LLT 
will be set missing and s/he will be handled by the event of treatment discontinuation (treatment 
policy). The detailed imputation model and algorithm are specified in Appendix 5.4.1.1. 
Number and percentage of participants by each intercurrent event will be summarized by 
treatment group in core part analyses. Listing will also be provided. 
 
2.5.4 
Handling of missing values not related to intercurrent event 
Missing values not related to intercurrent event will be multiply imputed within each treatment 
group under MAR assumption. The detailed imputation model and algorithm are specified in 
Appendix 5.4.1.1. The primary efficacy analysis will be conducted on each multiply imputed 
dataset, and the treatment effects estimated from each of those imputed datasets will be 
combined using Rubin’s rule. 
2.5.5 
Sensitivity analyses  
The following sensitivity analysis will be conducted to assess the robustness of the inferences 
to various assumptions about the hypothetical strategy for handling usage of prohibited LLT. 
• 
Tipping point analyses: a tipping point analysis will be performed to search for the tipping 
point that reverses the study conclusion. In the tipping point analysis, scale-adjustment to 
the MAR assumptions will be applied multiplicatively to the imputed values, where the 
multiplicative factor is allowed to vary for inclisiran group only.  
2.5.6 
Supplementary analyses 
A plot displaying descriptive mean percentage change in LDL-C from baseline up to Day 180 
visit for both treatment groups will be provided, using the observed data. 
Subgroup analyses to assess the homogeneity of the treatment effect across demographic and 
baseline characteristics will be performed in subgroups as specified in Section 2.2.1. The 
subgroup analyses will use the same ANCOVA model as specified above. The difference in the 
adjusted means between treatment groups, corresponding two-sided 95% CI and one-sided p-
value will also be provided for each of the subgroups. The adjusted means in both treatment 
groups, corresponding two-sided 95% CI will also be provided for each of the subgroups. The 
subgroup analysis results will be left blank if the subgroup analysis model did not converge. 
Forest plot will be provided for subgroup analyses. The multiply imputed datasets created from 
primary analysis will be used in the subgroup analyses. The results from the subgroup analysis 
models will be combined using the Rubin’s rule. 


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Two sets of supplementary analyses under different estimand will also be conducted. 
For the first one, all three intercurrent events, including discontinuation of study treatment, use 
of prohibited LLT under certain conditions and death due to CV or non-CV causes, will be 
handled with a hypothetical strategy. Data after all these intercurrent events will be multiply 
imputed under missing at random assumption. Missing values not related to intercurrent events 
will also be multiply imputed under missing at random assumption. Details are specified in 
Appendix 5.4.1.2. 
For the second one, the intercurrent events of discontinuation of study treatment and death due 
to CV or non-CV causes will be handled in the same way as in the primary analysis. Use of 
prohibited LLT under certain conditions will be treated with a treatment policy strategy, keeping 
treatment labels as assigned at randomization. Retrieved drop out (RDO) data collected after 
use of prohibited LLT under certain conditions will be used for the analysis. Missing data after 
usage of prohibited LLT will be multiply imputed using a control-based PMM. Missing values 
not related to intercurrent events will also be multiply imputed using a control-based PMM. 
Details are specified in Appendix 5.4.1.3. 
2.6 
Analysis supporting secondary efficacy objectives  
The FAS will be used for all below efficacy analyses. 
2.6.1 
Secondary endpoint(s). 
2.6.1.1 
Secondary efficacy endpoints for core part  
The secondary efficacy endpoints for core part are listed as follows: 
• Absolute change in LDL-C from baseline at Day 150 
• Percentage and absolute change in PCSK9, TC, HDL-C, non-HDL-C, ApoB, ApoA-1, 
Lp(a) and TG from baseline at Day 150 
All secondary efficacy endpoints for core part will be analyzed using the same ANCOVA model 
as for the primary efficacy endpoint. Lp(a) will be log-transformed before modeling. The model 
will include treatment as fixed effect, and baseline value as a covariate. The adjusted mean 
difference between inclisiran and placebo and corresponding two-sided 95% CIs will be 
provided separately. Nominal two-sided p-values will also be provided. 
2.6.1.2 
Secondary efficacy endpoints for extension part 
The secondary efficacy endpoints for extension part are listed as follows: 
• Percentage change in LDL-C from baseline at Day 330 for inclisiran group 
• Absolute change in LDL-C from baseline at Day 330 for inclisiran group 
The secondary efficacy endpoints for extension part will be analyzed descriptively. Mean 
percentage and absolute change from baseline at Day 330 in inclisiran group will be provided, 
respectively, as well as the 95% confidence intervals.  


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2.6.2 
Statistical hypothesis, model, and method of analysis 
No multiple comparisons including primary and secondary efficacy endpoints will be made. 
2.6.3 
Handling of intercurrent events  
2.6.3.1 
Estimands for core part  
The same methods as specified in Section 2.5.3 will be applied to all secondary efficacy 
endpoints for core part. Multiple imputation will be conducted for log-transformed Lp(a) values. 
The details are specified in Appendix 5.4.2. 
2.6.3.2 
Estimands for extension part  
The secondary efficacy analysis for extension part will account for different intercurrent events 
as explained in the following: 
• Discontinuation of study treatment: Retrieved drop out (RDO) data collected after 
discontinuation from study treatment will be used for the analysis (treatment policy). 
Missing data after discontinuation from study treatment will be multiply imputed based on 
RDO data, and when there are no sufficient RDO data, a control-based PMM (using the 
Core Part data) will be used for multiple imputation. The detailed information is specified 
in Appendix 5.4.2. 
• Use of prohibited LLT: Use of prohibited LLT (PCSK9 monoclonal antibodies taken 
before Day 330 visit assessment or other LLT taken within 30 days before Day 330 visit 
assessment) will be treated in a hypothetical scenario of what would happen had those 
LLT not been taken, and those participants behaved like other participants in the same 
treatment group (hypothetical strategy). Data after those intercurrent events will be 
excluded for the analysis and will be multiply imputed under MAR assumption. 
• Death: Death due to CV or non-CV causes is considered as an unfavorable outcome 
(composite strategy). The LDL-C values at Day 330 after death will be set using the 
participant’s baseline values. 
In the case of multiple intercurrent events, death will be the dominant one in the analysis (if 
present). If a participant experiences only two other intercurrent events and usage of prohibited 
LLT occurs first, s/he will be handled by the event of usage of LLT (hypothetical strategy). If 
treatment discontinuation occurs prior to usage of prohibited LLT, then data after usage of LLT 
will be set missing and s/he will be handled by the event of treatment discontinuation (treatment 
policy). The detailed imputation model and algorithm are specified in Appendix 5.4.2. Number 
and percentage of participants by each intercurrent event will be summarized by treatment 
group in final analyses. Listing will also be provided. 


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2.6.4 
Handling of missing values not related to intercurrent event 
2.6.4.1 
Estimands for core part  
The same methods as specified in Section 2.5.4 will be applied to all secondary efficacy 
endpoints for core part. Multiple imputation will be conducted for log-transformed Lp(a) values. 
The details are specified in Appendix 5.4.2. 
2.6.4.2 
Estimands for extension part  
Missing values not related to intercurrent event will be multiply imputed under MAR 
assumption. The detailed imputation model and algorithm are specified in Appendix 5.4.2. The 
secondary efficacy analysis for extension part will be conducted on each multiply imputed 
dataset, and the results from each of those imputed datasets will be combined using Rubin’s 
rule. 
2.6.5 
Sensitivity analyses 
The same sensitivity analysis as specified in Section 2.5.5 will be conducted for LDL-C 
endpoint at Day 150.  
2.6.6 
Supplementary analyses 
The same subgroup analyses as specified in Section 2.5.6 will be performed for absolute change 
in LDL-C at Day 150 and percentage change in PCSK9, TC, non-HDL-C and ApoB at Day 150. 
The difference in the adjusted means between treatment groups, corresponding two-sided 95% 
CI and two-sided p-value will be provided for each of the subgroups. The adjusted means in 
both treatment groups, corresponding two-sided 95% CI will also be provided for each of the 
subgroups. 
A plot displaying descriptive mean percentage change in LDL-C from baseline up to Day 360 
visit for both treatment groups will be provided, using the observed data. 
2.7 
Safety analyses 
For all safety analyses, the SAF will be used, unless otherwise specified. All listings and tables 
will be presented by treatment group. Baseline data will be summarized where appropriate (for 
change from baseline summaries).  
2.7.1 
Adverse events (AEs) 
An AE will be counted as a treatment emergent AE (TEAE) if the AE started after the first dose 
of study treatment or the AE present prior to start of study treatment but increased in severity 
based on preferred term. 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 start date is on or after 
date of first dose of study treatment. All TEAEs will be classified into core part TEAEs and 
extension part TEAEs. 
• The core part TEAEs will be defined as TEAEs with the start date on or prior to the 
switching date. 


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• The extension TEAEs will be defined as TEAEs with the start date after the switching 
date. 
Overall summary of TEAE will be displayed by treatment group and study part. The number 
(and percentage) of participants with TEAEs will be summarized: 
• By study part, treatment group, primary system organ class (SOC) and preferred term 
(PT). 
• By study part, treatment group, SOC, PT and maximum severity. 
• By study part, treatment group, PT. 
• By study part, treatment group, SOC and PT for TEAEs leading to study drug 
discontinuation. 
• By study part, treatment group, SOC and PT for TEAEs related to study drug. 
The number (and percentage) of participants with treatment emergent serious adverse events 
(TESAE) will be summarized: 
• By study part, treatment group, SOC and PT. 
• By study part, treatment group, SOC and PT for TESAEs related to study drug. 
In core part analyses, the number (and percentage) of participants with TESAE will also be 
summarized for overall study: 
• By treatment group, SOC and PT. 
• By treatment group, SOC and PT for TESAEs related to study drug. 
Unless otherwise specified, SOCs will be sorted alphabetically and, within each SOC, the PTs 
will be sorted in descending order of frequency. If a participant reported more than one adverse 
event with the same PT, the AE will be counted only once. A participant with multiple adverse 
events within a SOC is only counted once towards the total of the SOC. In case of summary by 
severity or relationship to study drug, summary will be done using the most severe or related 
occurrence respectively. Listing of all AEs and SAEs will be provided in both core part analyses 
and final analyses, regardless of whether they are treatment emergent. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by study part, treatment group, 
SOC and PT. 
For above by-part summary tables, OLS will be used for extension part data in final analyses. 
Besides, above summary tables for overall study will also be provided using SAF in final 
analyses.  Subgroup analyses for safety will be performed in subgroups as specified in Section 
2.2.1. Overall summary of TEAE by subgroup will be provided by treatment group in core part 
analyses. Subgroup analyses of all treatment emergent adverse events (TEAE) will also be 
displayed by treatment group, SOC and PT in core part analyses. The number (and percentage) 
of participants with TEAEs will be provided for each category of subgroup.  
AE reporting for CT.gov 
For the legal requirements of clinicaltrials.gov, two required tables on treatment emergent 
adverse events which are not serious adverse events with an incidence greater than X% (X will 


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be selected prior to final database lock)* and on treatment emergent serious adverse events and 
SAE suspected to be related to study treatment will be provided by SOC and PT on the safety 
set population. 
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness, and severity) occurred with the same SOC and PT: 
• a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
These summaries will be provided only after full study completion. 
*Note: the X% has been chosen as 5% before the final database lock. 
2.7.1.1 
Adverse events of special interest / grouping of AEs 
The number and percentage of participants with adverse event of special interest (AESI) will 
be summarized for each topic for: 
• TEAE by study part, treatment group and PT 
In final analyses, OLS will be used for the summary tables of extension part data. Besides, 
summary tables for overall study will also be provided using SAF. In core part analyses, 
summary of TEAE by treatment group, PT and maximum severity and of TESAE by treatment 
group and PT will also be provided. PTs will be sorted in descending order of frequency in the 
total column. If a participant reported more than one adverse event with the same PT, the AE 
will be counted only once. If a participant reported more than one AE within the same AESI, 
the participant will be counted only once at that AESI.  
Adverse event of special interest will include the following: 
• Hepatotoxicity 
• Injection site reaction 
For injection site reaction, separate listing will be provided for participants with injection site 
reaction AE in both core part analyses and final analyses. The time to the first injection site 
reaction TEAE will also be summarized by treatment group and study part using the following 
categories: No ISR, ≤4h, >4h to ≤12h, >12h. The time (hours) to the event will be calculated 
from the most recent administration of study drug. The duration of the first injection site 
reaction TEAE will also be summarized by treatment group and study part using the following 
categories: No ISR, ≤4h, >4h to ≤7 days, >7 days to ≤14 days, >14 days. Total number of TEAE 
at the injection site per participants will be summarized in categories (e.g. 1, 2, 3, and >3 etc.) 


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by treatment group and study part. In final analyses, OLS will be used for the summary tables 
of extension part data. Besides, all summary tables of injection site reaction will also be 
provided for overall study using SAF. 
Case Retrieval Strategy (CRS) will be used to determine the MedDRA search criteria to be used 
to identify the AESI. The CRS listing will be provided. 
2.7.2 
Deaths 
As stated in Section 2.7.1, summary for deaths will be provided by SOC, PT of death cause and 
treatment. Specifically, the summary tables for core part and for overall study will be provided 
in core part analyses using SAF. Besides, the summary tables for extension part (using OLS) 
and for overall study (using SAF) will also be provided in final analyses. Listing of all deaths 
will be provided in both core part analyses and final analyses. 
2.7.3 
Laboratory data 
Laboratory data consists of hematology, biochemistry, and urinalysis measurements. Observed 
value, absolute change, and percent change from baseline in continuous laboratory parameters 
will be summarized descriptively by visit and by treatment group. Frequency table of results 
for categorical laboratory parameters will be presented by visit. For some parameters, only 
screen tests are planned. Thus, summaries of post-baseline values will not be provided. For core 
part analyses, the summary tables will include Day 1 visit up to Day 180 visit. For final analyses, 
the summary table will include Day 1 visit up to Day 360 visit. 
Shift tables using the low, normal, or high classification based on the normal range will be used 
to compare baseline to the worst post-baseline value by treatment group and study part for 
hematology and biochemistry measurements. All data collected after first dose of study 
treatment, from scheduled, unscheduled, and premature discontinuation visits will be used. For 
some parameters, if only screen tests are planned and there are no scheduled post-baseline 
values, then the shift table will not be provided. In final analyses, OLS will be used for the shift 
tables of extension part data. Besides, shift tables for overall study will also be provided using 
SAF. 
The following ranges will be used for shift tables of eGFR, fasting glucose and HbA1c 
• For eGFR, the categories will be: 
Severe = <30 mL/min/1.73m2;  
Moderate = ≥ 30 to <60 mL/min/1.73m2;  
Mild = ≥ 60 to <90 mL/min/1.73m2;  
Normal = ≥90 mL/min/1.73m2. 
• For fasting glucose, the categories will be < 100 mg/dL, ≥ 100 mg/dL to < 126 mg/dL, and 
≥ 126 mg/dL. 
• For HbA1c, the categories will be <5.7%, ≥5.7% to <6.5%, and ≥6.5%. 
For selected laboratory tests, the number and percentage of patients meeting the clinically 
notable criteria at any time, considering all data collected after first dose of study treatment, 
from scheduled, unscheduled, and premature discontinuation visits, will be summarized by 


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laboratory parameter and treatment group and study part. The worst post-baseline value will be 
used for this analysis. In final analyses, OLS will be used for the summary of worst post-
baseline value from extension part. Besides, such summary of worst post-baseline from overall 
study will also be provided using SAF. Notable criteria are defined in Appendix 5.3. Clinically 
notable criteria will be considered to be met when both of the following occur: 
• Post-baseline value meets the thresholds listed in Appendix 5.3. 
• Baseline value and any prior post-baseline values do not meet the thresholds listed in 
Appendix 5.3. 
Furthermore, the number and percentage of participants meeting notable criteria in liver 
function tests (LFT) will be summarized by treatment group and study part considering post-
baseline data from scheduled, unscheduled, and premature discontinuation visit. LFT criteria 
are defined in Appendix 5.3. In final analyses, OLS will be used for the summary of post-
baseline value from extension part. Besides, such summary of post-baseline from overall study 
will also be provided using SAF. 
All laboratory data will be listed by treatment group, participant, and visit/date and if ranges are 
available, abnormalities will be flagged. 
2.7.4 
Other safety data 
2.7.4.1 
ECG and cardiac imaging data 
NA 
2.7.4.2 
Vital signs 
Observed values, absolute change from baseline and percentage change from baseline will be 
summarized descriptively for vital sign parameters (SBP, DBP and pulse) by visit and treatment 
group. At each assessment, average of 3 readings will be used for analysis while all 3 readings 
will be provided in listing. For core part analyses, the summary tables will include Day 1 visit 
up to Day 180 visit. For final analyses, the summary table will include Day 1 visit up to Day 
360 visit. 
2.8 
Impact of COVID-19 
Below analysis about impact of COVID-19 may be performed, if needed. 
The number and percentage of participants with any and each of the following COVID-19 
impacted criteria will be provided for all randomized participants by treatment group and study 
part: (1) missed visit due to COVID-19; (2) treatment not given due to COVID-19; (3) study 
treatment discontinuation due to COVID-19; (4) premature study discontinuation related to 
COVID-19; (5) death related to COVID-19. OLS will be used for summary of extension part 
data in final analyses. 
2.9 
Pharmacokinetic endpoints   
NA  


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2.10 
PD and PK/PD analyses 
NA 
2.11 
Patient-reported outcomes 
NA 


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2.14 
Interim analysis 
NA 
3 
Sample size calculation 
This study is designed to randomize approximately 200 Participants (with randomization ratio 
of 1:1 to inclisiran and placebo arms) in order to provide adequate information to characterize 
the safety profile of inclisiran as well as to have sufficient power for the primary efficacy 
endpoint. 
 
 
 
 
4 
Change to protocol specified analyses 
NA 
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
NA 
5.1.2 
AE date imputation 
The partially missing AE start/end date will be imputed using the Novartis ADaM Governance 
Board (AGB) global standard approach. Details will be provided in the study programming 
datasets specifications (PDS). 


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5.1.3 
Concomitant medication date imputation 
For LLT, the end date will be imputed using below rules. 
Year missing 
Set the earliest of (last visit date, date of death, 
analysis cutoff date) 
Month missing 
Set the earliest of (last visit date, 31DecYYYY, 
date of death, analysis cutoff date) 
Day missing 
Set the earliest of (last visit date, last date of 
reported month, date of death, analysis cutoff 
date) 
If imputed end date is prior to start date, set the end date using start date. 
 
For other medications, the partially missing concomitant medication start/end date will be 
imputed using the Novartis ADaM Governance Board (AGB) global standard approach. Details 
will be provided in the study PDS. 
5.2 
AEs coding/grading 
The MedDRA version which will be available at the time of database lock, will be used for the 
coding purpose of the adverse events. 
5.3 
Laboratory parameters derivations 
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 
For fasting glucose, only measurements taken in a fasting state will be used. Baseline glucose 
is defined as the average of the last two non-missing fasting glucose values on or prior to Day 
1. If only one non-missing fasting glucose value is available on or prior to Day 1, the available 
value will be used as baseline. 
Notable laboratory values are defined in Table 5-1: 
Table 5-1 
Clinically notable laboratory abnormalities for selected tests 
HbA1c criteria is explicitly stated in the table below. 
All other criteria are met when both of the following occur: 
• Post-baseline values meet the thresholds below 
• Baseline values or any previous post-baseline values do not meet the thresholds 
below 
Parameters 
Criteria 
Hemoglobin 
≤ 10 g/dL 
Hematocrit 
≤ 0.8 × LLN 
WBC(total) 
≤ 2.8 ×103 / μL, ≥ 16 ×103 / μL 


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Parameters 
Criteria 
Platelet count 
≤ 75 ×103 / μL, ≥ 700 ×103 / μL 
HbA1c 
≥ 6.5% and ≥0.5% increase from baseline 
Creatinine 
> 2 mg/dL 
CK 
> 1 and ≤ 3 × ULN 
CK 
> 3 and ≤ 5 × ULN 
CK 
> 5 and ≤ 10 × ULN 
CK 
> 10 × ULN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Notable liver function test criteria are defined in Table 5-2. 
Table 5-2 
Notable liver function test criteria 
Peak post-baseline value 
ALT >3x ULN 
ALT >5x ULN 
ALT >10x ULN 
ALT >20x ULN 
AST >3x ULN 
AST >5x ULN 
AST >10x ULN 
AST >20x ULN 
ALT or AST >3x ULN 
ALT or AST >5x ULN 
ALT or AST >8x ULN 
ALT or AST >10x ULN 
ALT or AST >20x ULN 
ALP > 2x ULN 
Total bilirubin (BILI) >2x ULN 
Total bilirubin (BILI) >3x ULN 
Combined elevations post-baseline 
For participants with AST and ALT =< ULN at baseline   
    Elevated ALT or AST ($) & BILI >2x ULN 
    Elevated ALT or AST ($) & BILI >2x ULN & ALP >=2x ULN 
    Elevated ALT or AST ($) & BILI >2x ULN & ALP <2x ULN 
For participants with ALT or AST > ULN at baseline 
    Elevated ALT or AST (*) & BILI (>2x Bsl and 2x ULN) 
    Elevated ALT or AST (*) & BILI (>2x Bsl and 2x ULN) & ALP >=2x ULN 
    Elevated ALT or AST (*) & BILI (>2x Bsl and 2x ULN) & ALP <2x ULN 
ALT = alanine aminotransferase, AST = aspartate aminotransferase, ALP = alkaline phosphatase 
Combined elevations based on the peak post-baseline values (considering all post-baseline data 
from scheduled, unscheduled and premature discontinuation visit) for each parameter for each 
participant. 
* Elevated AST or ALT for participants with > ULN at baseline is defined as >3x Baseline or 8x 
ULN. 
$ Elevated AST or ALT for participants with =< ULN at baseline is defined as >3x ULN. 
 


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5.4 
Statistical models 
5.4.1 
Analysis supporting primary objective(s)  
5.4.1.1 
Primary efficacy analysis 
In handling of intercurrent events and missing data not related to intercurrent events, multiple 
imputation will be used to account for uncertainty in the imputation process and there will be 
100 multiply imputed datasets. The results from these 100 imputed datasets will be combined 
using Rubin’s method. Further details are provided below. 
For control-based PMM, the missing data after specific intercurrent events in inclisiran group 
will be imputed using data from control group. The covariates and baseline characteristics 
which can be predictive of the response will be included in a multiple imputation procedure 
(SAS PROC MI) and will include the following: 
• Baseline value of efficacy measurement (continuous) 
• Observed/imputed value of efficacy measurement at Day 30 (continuous) 
• Observed/imputed value of efficacy measurement at Day 90 (continuous) 
• Observed/imputed value of efficacy measurement at Day 150 (continuous) 
• Observed/imputed value of efficacy measurement at Day 180 (continuous) 
For RDO based imputation model, the missing data after treatment discontinuation will be 
imputed based on RDO data within each group. The covariates, baseline characteristics and on- 
or off- treatment status at the same visit with the response which can be predictive of the 
response will be included in a multiple imputation procedure (SAS PROC MI) and will include 
the following: 
• Baseline value of efficacy measurement (continuous) 
• Observed/imputed value of efficacy measurement at Day 30 (continuous) 
• Observed/imputed value of efficacy measurement at Day 90 (continuous) 
• Observed/imputed value of efficacy measurement at Day 150 (continuous) 
• Indicator of on- or off- treatment status at Day 180 (binary) 
• Observed/imputed value of efficacy measurement at Day 180 (continuous) 
The indicator variable will vary with the imputed response from visit to visit.  
1. For those participants who experienced the intercurrent event of using prohibited LLT, set 
the LDL-C values on or after the usage of LLT missing (out_step1). 
2. Missing data will be imputed under MAR assumption in this step. The same imputation 
model as specified for control-based PMM will be used except that the missing data will be 
multiply imputed using data within each treatment group. SAS PROC MI will be utilized 
using the FCS REG statement, where only previous measurements will be included for each 
imputed variable.  A total of 100 datasets (out_step2) will be created. These fully imputed 
datasets will be utilized in step 3.  


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3. For participants handled by intercurrent events of treatment discontinuation, if the 
measurement is missing in (out_step1) and after treatment discontinuation, set this value 
back to missing (out_step3). These datasets (out_step3) will be utilized in step 4. 
4. If there are enough RDO data, the RDO based imputation model will be used in this step. 
SAS PROC MI will be utilized using the FCS REG statement, where previous 
measurements and an indicator of on- or off-treatment status at the same visit with the 
response will be included for each imputed variable. This imputation will be implemented 
based on data within each group. If there are not enough RDO data, the control-based 
PMM will be used in this step. With this imputation model, the missing value in the 
inclisiran group will not be constructed from the observed data in the inclisiran group but 
rather from the observed and imputed data in the control group. SAS PROC MI will be 
utilized using the FCS REG statement, where only previous measurements will be 
included for each imputed variable. The MNAR statement in SAS PROC MI will also be 
used under MNAR assumption for inclisiran group. After this step, the 100 
datasets(out_step4) will be fully imputed. These datasets will be utilized in step 5. (Which 
model will be used in this step will be determined before Core Part database lock) 
5. For participants who died, set the values after death using his/hers baseline value. (out_step5) 
6. Datasets (out_step5) will be used in this step. The absolute change and the percentage 
change values will be calculated in each of the imputed datasets.  
7. These 100 datasets will be analyzed using the ANCOVA model for the LDL-C endpoints. 
8. The results from the 100 datasets will be combined using Rubin’s method via SAS PROC 
MIANALYZE procedure. 
 
 
 
 
 
 
 
5.4.1.2 
Supplementary analysis under estimand 1 
The same imputation model as specified in Appendix 5.4.1.1 will be used in supplementary 
analysis 1. Again, multiple imputation will be used to account for uncertainty in the imputation 
process and there will be 100 multiply imputed datasets. The results from these 100 imputed 
datasets will be combined using Rubin’s method. Further details are provided below. 
1. For those participants handled by any intercurrent event, set the LDL-C values on or after 
the intercurrent event missing (out_step1). 
2. Missing data will be imputed under MAR assumption in this step. The same imputation 
model as specified for control-based PMM will be used except that the missing data will 
be multiply imputed using data within each treatment group. SAS PROC MI will be 
utilized using the FCS REG statement, where only previous measurements will be 


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included for each imputed variable.  A total of 100 datasets (out_step2) will be created. 
These fully imputed datasets will be utilized in step 3.   
3. The absolute change and the percentage change values will be calculated in each of the 
imputed datasets.  
4. These 100 datasets will be analyzed using the ANCOVA model for the LDL-C endpoints. 
5. The results from the 100 datasets will be combined using Rubin’s method via SAS PROC 
MIANALYZE procedure. 
5.4.1.3 
Supplementary analysis under estimand 2 
The same imputation model as specified in Appendix 5.4.1.1 will be used in supplementary 
analysis 1. Again, multiple imputation will be used to account for uncertainty in the imputation 
process and there will be 100 multiply imputed datasets. The results from these 100 imputed 
datasets will be combined using Rubin’s method. Further details are provided below. 
1. In this step, the control-based PMM will be used. With this imputation model, the missing 
value in the inclisiran group will not be constructed from the observed data in the inclisiran 
group but rather from the observed and imputed data in the control group. SAS PROC MI 
will be utilized using the FCS REG statement, where only previous measurements will be 
included for each imputed variable. The MNAR statement in SAS PROC MI will also be 
used under MNAR assumption for inclisiran group. After this step, the 100 
datasets(out_step1) will be fully imputed.  
2. Datasets (out_step1) will be used in this step. If there are enough RDO data, the RDO based 
imputation model will be utilized in this step. Thus, for participants handled by intercurrent 
events of treatment discontinuation, if the LDL-C value is missing before step 1 and after 
treatment discontinuation, set this value back to missing. Then, SAS PROC MI will be 
utilized using the FCS REG statement, where previous measurements and an indicator of 
on- or off-treatment status at the same visit with the response will be included for each 
imputed variable. This imputation will be implemented based on data within each group. 
After this step, the 100 datasets (out_step2) will be fully imputed. 
3. If step 2 is conducted, then datasets (out_step2) will be used in this step. Otherwise, datasets 
(out_step1) will be used. For participants who died, set the values after death using his/hers 
baseline value. (out_step3) 
4. Datasets (out_step3) will be used in this step. The absolute change and the percentage 
change values will be calculated in each of the imputed datasets.  
5. These 100 datasets will be analyzed using the ANCOVA model for the LDL-C endpoints. 
6. The results from the 100 datasets will be combined using Rubin’s method via SAS PROC 
MIANALYZE procedure. 


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5.4.2 
Analysis supporting secondary objective(s) 
Objectives for core part  
The same imputation models and procedure as specified in Appendix 5.4.1.1 will be applied to 
all secondary efficacy endpoints for core part. For Lp(a), log-transformation will be taken 
before the imputation and the imputation model will exclude variables at Day 30 and Day 90 
visits. 
Objectives for extension part 
The RDO based imputation model is the same as specified in Appendix 5.4.1.1 except that the 
model here is extended to include more measurements at Day 210, Day 270, Day 330 and Day 
360. 
For the control-based PMM, the same model as specified in Appendix 5.4.1.1 will be used for 
fitting the imputation model based on data from control group (i.e., the measurements at 
baseline, Day 30, 90, 150 and 180 from control group will be used to fit the imputation model). 
Based on the fitted regression model, the imputation model for missing measurements at Day 
330 after specific intercurrent events in inclisiran group will only include following as 
covariates: 
• Baseline value of efficacy measurement (continuous) 
• Observed/imputed value of efficacy measurement at Day 30 (continuous) 
• Observed/imputed value of efficacy measurement at Day 90 (continuous) 
• Observed/imputed value of efficacy measurement at Day 150 (continuous) 
In other words, the imputed Day 180 values in inclisiran group under the control-based PMM 
will be carried forward as imputations for missing measurements at Day 330 in inclisiran 
group. 
1. Only inclisiran group data will be included. For those participants who experienced the 
intercurrent event of using prohibited LLT, set the LDL-C values on or after the usage of 
LLT missing (out_step1). 
2. Missing data will be imputed under MAR assumption in this step. The same imputation 
model as specified for fitting purpose in the control-based PMM will be used. SAS PROC 
MI will be utilized using the FCS REG statement, where only previous measurements will 
be included for each imputed variable. A total of 100 datasets (out_step2) will be created. 
These fully imputed datasets will be utilized in step 3.  
3. For participants handled by intercurrent events of treatment discontinuation, if the 
measurement is missing in (out_step1) and after treatment discontinuation, set this value 
back to missing (out_step3). These datasets (out_step3) will be utilized in step 4. 
4. If there are enough RDO data, the RDO based imputation model as specified will be used 
in this step. SAS PROC MI will be utilized using the FCS REG statement, where previous 
measurements and an indicator of on- or off-treatment status at the same visit with the 
response will be included for each imputed variable. This imputation will be implemented 
based on data in inclisiran group. If there are not enough RDO data, the control-based 


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PMM will be used in this step. With this imputation model, the missing value in the 
inclisiran group will not be constructed from the observed data in the inclisiran group but 
rather from the observed (excluding data after usage of LLT) and imputed data in the 
control group. SAS PROC MI will be utilized using the FCS REG statement. The MNAR 
statement in SAS PROC MI will also be used under MNAR assumption for inclisiran 
group. These datasets(out_step4) will be utilized in step 5.  
5. For participants who died, set the values after death using his/hers baseline value. (out_step5) 
6. Datasets (out_step5) will be used in this step. The absolute change and the percentage 
change values will be calculated in each of the imputed datasets.  
7. These 100 datasets will be analyzed descriptively for the LDL-C endpoints. 
8. The results from the 100 datasets will be combined using Rubin’s method via SAS PROC 
MIANALYZE procedure. 
5.5 
Rule of exclusion criteria of analysis sets  
The protocol deviation criteria are listed in the sheet “Protocol Deviations” in the data review 
plan. The protocol deviation criteria leading to exclusion from the analysis sets are provided in 
below table, which may be updated prospectively and will be finalized before database lock. 
Table 5-3 
Protocol deviation criteria leading to exclusion from the analysis sets 
Protocol Deviation 
Excluding from Analysis 
Set 
 
ID 
Description 
SCR 
RAS 
FAS SAF OLS 
INCL01A 
Written informed consent not obtained. 
X 
X 
X 
X 
X 
TRT03 
Subject was not randomized but took study drug 
 
X 
X 
X 
X 
OTH07 
Participant was randomized in error but did not 
receive IMP 
 
 
X 
X 
X 
OTH01A 
Site closed down for GCP reasons during Core 
part. 
 
 
X 
 
 
OTH01B 
Site closed down for GCP reasons during 
Extension. 
 
 
X 
 
 
Below table presents patient classification criteria including protocol deviation criteria and non-
protocol-deviation criteria leading to exclusion from analysis sets. 
Table 5-4 
Patient classification 
Analysis 
Set 
Protocol Deviation ID leading 
to exclusion of patients 
Non-protocol deviation criteria leading 
to exclusion from analysis sets 
SCR 
INCL01A 
Not applicable 
RAS 
INCL01A, TRT03 
• Patient without a randomization number 
FAS 
INCL01A, TRT03, OTH07, 
OTH01A,OTH01B 
• Patient without a randomization number 
SAF 
INCL01A, TRT03,  OTH07 
• Patient without a randomization number 
OLS 
INCL01A, TRT03,  OTH07 
• Patient without a randomization number 


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6 
Reference 
ICH E9(R1) Harmonized Guideline: addendum on estimands and sensitivity analysis in clinical 
trials to the guideline on statistical principles for clinical trials. Final version on 20 November 
2019.