Conditions: Atherosclerotic Cardiovascular Disease Atherosclerotic Cardiovascular Disease Risk Equivelents Elevated Low Density Lipoprotein Cholesterol
Keywords: Atherosclerotic Cardiovascular Disease Atherosclerotic Cardiovascular Disease Risk Equivalents Elevated Low Density Lipoprotein Cholesterol ASCVD LDL-C
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 892
Healthy volunteers: no

Brief summary:
The purpose of this study was to evaluate the implementation of inclisiran in a regional primary care setting in the UK

Inclisiran, also known as KJX839, is a medication made to reduce the level of "bad" cholesterol (LDL-cholesterol) in the blood. Inclisiran works in a way that makes the liver produce less of a substance called 'PCSK9'. PCSK9 reduces the ability of the liver to remove LDL-cholesterol from the blood. By lowering the production of PCSK9, Inclisiran leads to more LDL-cholesterol being removed by the liver from the blood, thereby reducing LDL-cholesterol overall.

Detailed description:
A phase IIIb, multicenter, randomized controlled study to evaluate the implementation, preference, and utility for administration of inclisiran sodium in participants on established lipid lowering medication or, have been recommended lipid lowering therapy by their healthcare provider but are unable to tolerate treatment, with elevated low density lipoprotein cholesterol (LDL-C) in a primary care population. This study was an implementation research study that utilized implementation science methodology and use of the electronic medical record (EMR).

Using implementation science methodology, the study intended to assess the effect of 9 months treatment with inclisiran with/without behavioural support, compared to standard of care + behavioural support, on LDL-C reduction, total lipid profile, assessments of patient and healthcare professional (HCP) satisfaction, health-care resource utilization and healthcare service process evaluation.

The primary focus of this study was implementation and 'transactability' - how to organize, deliver and maintain an innovative treatment for Atherosclerotic Cardiovascular Disease (ASCVD) in a primary care setting in a sustainable way.

Patients taking part in the study were randomised to one of three groups:

* Control + BS: Participants continued to receive their background lipid lowering therapy plus behavioural support. Subjects in treatment group 1 were referred to as the control group in this study
* Inclisiran: Participants continue to receive their background lipid lowering therapy, plus inclisiran for injection (delivered in an injection-only model).
* Inclisiran + BS: Participants continued to receive their background lipid lowering therapy, plus inclisiran for injection, plus behavioural support.

Participants who were randomized to Inclisiran or Inclisiran + BS received one injection of inclisiran on Day 1 and a second injection of inclisiran on Day 90.

Participants in Control + BS and Inclisiran + BS received a monthly telephone call from a health advisor, providing support to enable participants to make positive behaviour changes to reduce their cardiovascular risk.

Arms:
arm 1: Participants continued to receive their background lipid lowering therapy plus behavioural support (BS). arm 2: Participants continue to receive their background lipid lowering therapy, plus inclisiran for injection (delivered in an injection-only model). arm 3: Participants continued to receive their background lipid lowering therapy, plus inclisiran for injection, plus behavioural support.

Interventions: intervention 1: Inclisiran intervention 2: Behavioural Support intervention 3: Background lipid lowering therapy
Intervention descriptions: intervention 1: Inclisiran Sodium 300mg on Day 1 and Day 90 by subcutaneous injection intervention 2: Regular telephone based behavioural support programme delivered throughout the study period, as measured by point of care testing device. intervention 3: lipid-lowering therapy (such as a statin and/or ezetimibe) as background therapy

Protocol document:
Prot_000.pdf: 
Novartis Research and Development 
KJX839/Inclisiran  
Clinical Trial Protocol CKJX839A1GB01 / NCT04807400
Title: A phase IIIb, multicentre, randomised controlled 
study to evaluate the implementation, preference and utility 
for administration of inclisiran sodium in participants with 
Atherosclerotic Cardiovascular Disease (ASCVD) or 
ASCVD-risk equivalents and elevated Low Density 
Lipoprotein Cholesterol (LDL-C) using a primary care 
models in the NHS 
Short Title: VICTORION-Spirit - Study in Primary care evaluating 
Inclisiran deliveRy Implementation + enhanced SupporT (Spirit) 
Document type: 
Clinical Trial Protocol 
EUDRACT number:  2020-004401-31 
Version number: 
02 (Amended Protocol) 
Clinical Trial Phase: 
IIIb 
Release date: 
12 Sep 2022 
Property of Novartis  
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 10 
Amendment 1 .................................................................................................................... 12 
Protocol summary .............................................................................................................. 18 
1 
Introduction ....................................................................................................................... 23 
1.1 
Background ............................................................................................................ 23 
1.1.1 
Cardiovascular benefits of lowering LDL cholesterol .......................... 23 
1.1.2 
Inhibition of PCSK9 as a therapeutic target .......................................... 23 
1.1.3 
Inhibition of PCSK9 with siRNA has potential advantages over 
antibodies .............................................................................................. 24 
1.1.4 
Clinical efficacy and safety ................................................................... 24 
1.1.5 
Background to the research framework ................................................ 28 
2 
Purpose and rationale ........................................................................................................ 29 
3 
Objectives .......................................................................................................................... 29 
3.1 
Primary Objective .................................................................................................. 29 
3.2 
Secondary Objectives ............................................................................................ 29 
3.3 
 
4 
Study design ...................................................................................................................... 30 
4.1 
Overview of Implementation Science ................................................................... 30 
4.2 
The structure of this study and use of the EMR .................................................... 32 
4.3 
The Process Evaluation Sub-Study ........................................................................ 32 
4.3.1 
Level 1: Feasibility and acceptability of delivery models for 
inclisiran to patients .............................................................................. 33 
4.3.2 
Level 2: Feasibility and acceptability of delivery models for 
inclisiran to providers ............................................................................ 34 
4.3.3 
Level 3: Exploring wider system readiness for inclisiran ..................... 35 
4.3.4 
Standards of reporting ........................................................................... 36 
4.4 
Patient identification and recruitment process ....................................................... 36 
4.4.1 
Cohort finding solutions ........................................................................ 36 
4.4.2 
Patient identification in this study ......................................................... 37 
4.5 
Treatment groups and outcome assessments ......................................................... 38 
4.5.1 
Rationale for choice of background therapy ......................................... 39 
4.5.2 
Rationale for dose/regimen and duration of treatment .......................... 39 
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4.5.3 
Rationale for choice of comparator arm ................................................ 40 
4.6 
Risks and benefits .................................................................................................. 40 
4.6.1 
Blood sample volume ............................................................................ 41 
5 
Study Population ............................................................................................................... 41 
5.1 
Inclusion criteria .................................................................................................... 42 
5.2 
Exclusion criteria ................................................................................................... 42 
6 
Treatment ........................................................................................................................... 43 
6.1 
Study treatment ...................................................................................................... 43 
6.1.1 
Investigational drug ............................................................................... 43 
6.1.2 
Additional study treatments .................................................................. 43 
6.1.3 
Treatment groups .................................................................................. 43 
6.1.4 
Post-Trial Access .................................................................................. 44 
6.1.5 
Concomitant therapy ............................................................................. 44 
6.2 
Participant numbering, treatment assignment, randomisation ............................... 45 
6.2.1 
Participant numbering ........................................................................... 45 
6.2.2 
Treatment assignment, randomisation .................................................. 45 
6.2.3 
Recruitment cap .................................................................................... 45 
6.3 
Dose escalation and dose modification .................................................................. 45 
6.4 
Additional treatment guidance ............................................................................... 45 
6.4.1 
Treatment compliance ........................................................................... 45 
6.4.2 
Recommended treatment of adverse events .......................................... 46 
6.5 
Preparation and dispensation ................................................................................. 46 
6.5.1 
Handling of study treatment and additional treatment .......................... 46 
6.5.2 
Instruction for prescribing and taking study treatment ......................... 47 
7 
Informed consent procedures ............................................................................................ 47 
7.1 
Participants who will be asked for consent ............................................................ 47 
7.2 
Remote consent ...................................................................................................... 48 
7.3 
Informed consent procedures for the process evaluation ...................................... 48 
7.3.1 
Confidentiality and anonymity .............................................................. 48 
8 
Visit schedule and assessments ......................................................................................... 49 
8.1 
Domiciliary visits ................................................................................................... 49 
8.2 
Screening ............................................................................................................... 51 
8.2.1 
Information to be collected on screening failures ................................. 52 
8.3 
Participant demographics/other baseline characteristics ....................................... 52 
8.4 
Efficacy Assessments ............................................................................................ 53 
8.4.1 
Efficacy assessment - Primary .............................................................. 53 


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8.4.2 
Efficacy assessment - Secondary .......................................................... 53 
8.5 
Safety ..................................................................................................................... 54 
8.5.1 
Pregnancy .............................................................................................. 54 
8.5.2 
SAEs ...................................................................................................... 54 
8.6 
Laboratory assessments ......................................................................................... 54 
9 
Study discontinuation and completion .............................................................................. 54 
9.1 
Discontinuation and completion ............................................................................ 54 
9.1.1 
Study treatment discontinuation and study discontinuation.................. 54 
9.1.2 
Withdrawal of informed consent ........................................................... 55 
9.1.3 
Lost to follow-up ................................................................................... 56 
9.1.4 
Early study termination by the sponsor ................................................. 56 
9.2 
Study completion and post-study treatment .......................................................... 56 
10 Safety monitoring and reporting ........................................................................................ 57 
10.1 
Definition of adverse events .................................................................................. 57 
10.1.1 
Adverse events ...................................................................................... 57 
10.1.2 
Serious adverse events .......................................................................... 57 
10.2 
Reporting requirements for adverse events ........................................................... 58 
10.3 
Collection and assessment of adverse events ........................................................ 58 
10.3.1 
Adverse event severity .......................................................................... 58 
10.3.2 
Relationship to study treatment ............................................................. 58 
10.3.3 
SAE reporting........................................................................................ 59 
10.3.4 
Pregnancy reporting .............................................................................. 60 
10.3.5 
Reporting of study treatment errors including misuse/abuse ................ 60 
11 Data Collection and Database management ...................................................................... 61 
11.1 
Data collection ....................................................................................................... 61 
11.2 
Database management and quality control ............................................................ 62 
11.3 
Site monitoring ...................................................................................................... 62 
11.3.1 
Remote study initiation and monitoring visits ...................................... 63 
12 Data analysis and statistical methods ................................................................................ 63 
12.1 
Analysis sets .......................................................................................................... 63 
12.2 
Participant demographics and other baseline characteristics ................................. 64 
12.3 
Treatments ............................................................................................................. 64 
12.4 
Analysis of the primary endpoint(s)/estimand(s) .................................................. 64 
12.4.1 
Definition of primary endpoint(s)/estimand(s) ..................................... 64 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 65 
12.4.3 
Handling of remaining intercurrent events of primary estimand .......... 66 


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12.4.4 
Handling of missing values not related to intercurrent event ............... 66 
12.4.5 
Sensitivity analyses for primary endpoint/estimand ............................. 66 
12.4.6 
Supplementary analysis ......................................................................... 66 
12.4.7 
Supportive analyses ............................................................................... 66 
12.5 
Analysis of secondary endpoints/estimands .......................................................... 66 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) .................................... 66 
12.5.2 
Safety endpoints .................................................................................... 67 
12.6 
 
12.7 
Interim analyses ..................................................................................................... 68 
12.8 
Sample size calculation .......................................................................................... 68 
13 Ethical considerations and administrative procedures ...................................................... 68 
13.1 
Regulatory and ethical compliance ........................................................................ 68 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 69 
13.3 
Publication of study protocol and results............................................................... 69 
13.4 
Quality Control and Quality Assurance ................................................................. 69 
14 Protocol adherence ............................................................................................................ 69 
14.1 
Protocol amendments ............................................................................................. 70 
15 References (available upon request) .................................................................................. 71 
16 Appendices ........................................................................................................................ 75 
16.1 
Appendix 1: Behavioural Support Programme ...................................................... 75 
16.2 
Appendix 2: The CSQ-8 PROMs Questionnaire ................................................... 76 
16.3 
Appendix 3: The PAM PROMs Questionnaire ..................................................... 78 
16.4 
Appendix 4: 
 
16.5 
Appendix 5: Generalisability of the Greater Manchester Population to the UK ... 83 
16.5.1 
Key indicators of generalisability of the Greater Manchester 
population to the UK ............................................................................. 83 
16.5.2 
Greater Manchester population by ethnicity, compared with 
England and Wales ................................................................................ 83 
16.5.3 
Greater Manchester population by Age, compared with England 
and Wales .............................................................................................. 84 
16.5.4 
Greater Manchester male population, compared with England and 
Wales ..................................................................................................... 84 
16.6 
Appendix 6: Calculating the 4-level Physical Activity Index (PAI) ..................... 85 
 
 
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List of tables 
Table 6-1 
Investigational drug ............................................................................... 43 
Table 6-2 
Therapy derived data ............................................................................. 44 
Table 8-1 
Assessment schedule ............................................................................. 49 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 61 
 
List of figures 
Figure 1-1 
Mean percentage change from baseline LDL-C in patients with 
primary hypercholesterolaemia and mixed dyslipidaemia treated 
with inclisiran compared to placebo (pooled analysis) ......................... 25 
Figure 4-1 
Types of research design (adapted from Lane-Fall et al, 2019) ............ 31 
Figure 4-2 
Schematic of study design ..................................................................... 40 
Figure 8-1 
FARSITE System Overview ................................................................. 51 
 


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List of abbreviations  
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ASCVD 
Atherosclerotic Cardiovascular Disease 
ASGPR 
asialoglycoprotein receptor 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
 
 
CFIR 
Consolidated Framework for Implementation Research 
CI 
Confidence Interval  
CDM 
Clinical Data Management  
CHD 
Coronary Heart Disease 
CK 
Creatinine Kinase 
CMO&PS  
Chief Medical Office and Patient Safety 
COA 
Clinical Outcome Assessment 
CQA 
Clinical Quality Assurance 
CRA 
Clinical Research Associate  
CRO 
Contract Research Organisation 
CSR 
Clinical study report 
CSQ-8 
Client Satisfaction Questionnaire 
CT 
Computerised tomography scan  
CTC 
Common Terminology Criteria 
CV 
coefficient of variation 
DMC 
Data Monitoring Committee 
 
 
eCRF 
Electronic Case Report Form  
EHR 
Electronic Health Record 
EMA 
European Medicines Agency  
EMR 
Electronic Medical Record 
EOS 
End of study 
EQUATOR 
Enhancing the QUAlity and Transparency Of health Research 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials Database 
FARSITE 
NWEH’s Feasibility Assessment and Recruitment System for Improving Trial 
Efficiency system 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FH  
Familial Hypercholesterolaemia  
GalNAc 
N-acetylgalactosamine 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
GGT 
Gamma-glutamyl transferase 
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GLDH 
Glutamate dehydrogenase 
GM 
Greater Manchester 
GP 
General Practitioner  
HCP 
Health Care Professional 
 
  
 
 
HeFH 
Heterozygous Familial Hypercholesterolaemia 
IB 
Investigator’s Brochure 
EU 
European Union  
IDMC 
Independent Data Monitoring Committee 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IN 
Investigator Notification 
INR 
International Normalised Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LDL-C 
Low-density Lipoprotein associated Cholesterol 
LDLR 
LDL Receptors 
LFT 
Liver function test  
LLN 
lower limit of normal 
MDCO 
The Medicines Company 
MedDRA 
Medical Dictionary for Regulatory Activities  
mg 
Milligram(s) 
mL 
Milliliter(s) 
MRI 
Magnetic resonance imaging  
NCDS 
Novartis Clinical Data Standards 
NHS 
UK National Health Service 
NHS-E 
National Health Service- England 
NWEH 
NorthWest EHealth 
PAI 
Physical Activity Index 
PAM 
Patient Activation Measure 
PCR 
Polymerase Chain Reaction  
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PFS 
Pre-filled Syringe 
PI 
Principal Investigator 
PIS 
Patient Information Sheet 
PROM 
Patient Reported Outcome Measure 
PSSRU 
Personal Social Services Research Unit 
QMS  
Quality Management System 
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QOPH 
Quality and Outcomes in Primary Healthcare clinical indicators  
RAP 
The Report and Analysis Plan  
REB 
Research Ethics Board 
 
  
RISC 
RNA-induced silencing complex 
RNAi 
Ribonucleic acid interference 
s.c. 
Subcutaneous 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
siRNAs 
small interfering RNAs 
SOP 
Standard Operating Procedure  
Spirit 
Study in Primary care evaluating Inclisiran deliveRy Implementation + enhanced 
SupporT 
SRQR 
Standards for Reporting Qualitative Research 
SDTM 
Structured Data Tabular Model 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAEs 
Treatment Emerged Adverse Events  
TIDieR 
Template for Intervention Description and Replication 
TD 
Study Treatment Discontinuation 
TBL 
Total bilirubin 
 
 
 
 
UK 
United Kingdom  
ULN 
upper limit of normal 
ULQ 
upper limit of quantification 
US 
Ultra Sound  
UTI 
Urinary Tract Infection 
WHO 
World Health Organisation  
WoC 
Withdrawal of Consent 
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Glossary of terms 
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  
Cohort 
A specific group of participants fulfilling certain criteria and generally treated at 
the same time 
ConneXon 
A suite of software applications developed by NWEH to support the operation 
of Real World Evidence clinical trials. 
Control drug 
A study drug (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 
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) 
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  
Estimand  
A precise description of the treatment effect reflecting the clinical question 
posed by the trial objective. It summarises at a population-level what the 
outcomes would be in the same patients 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. 
Healthy volunteer 
A person with no known significant health problems who volunteers to be a 
study participant  
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 (e.g. treatment discontinuation, use of prohibited medications, 
deviation in background treatment or death). 
Investigational 
drug/ treatment 
The drug whose properties are being tested in the study - KJX839/Inclisiran 
for Injection (sub-cutaneous use), is a sterile formulation of inclisiran sodium 
in water for injection packaged in vial or glass pre-filled syringe (PFS) 
presentations; also referred to as study drug 
Medication number 
A unique identifier on the label of medication kits 
Mis-randomised 
participants 
Mis-randomised participants are those who were not qualified for 
randomisation and who did not take study treatment, but have been 
inadvertently randomised into the study  
Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy) 
Part  
A sub-division of a study used to evaluate specific objectives or contain 
different populations. For example, one study could contain a single dose part 
and a multiple dose part, or a part in participants with established disease and 
in those with newly-diagnosed disease 
Participant 
A trial participant (can be a healthy volunteer or a patient) 


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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. 
Premature 
participant 
withdrawal 
Point/time when the participant exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned 
Randomisation 
number 
A unique identifier assigned to each randomised participant 
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 
The study treatment, KJX839/Inclisiran for Injection (sub-cutaneous use), is a 
sterile formulation of inclisiran sodium in water for injection packaged in vial or 
glass pre-filled syringe (PFS) presentations 
Study treatment 
discontinuation 
When the participant permanently stops taking any of the study drug(s) prior 
to the defined study treatment completion date (if any) for any reason; may or 
may not also be the point/time of study discontinuation  
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 
study consent 
(WoC) 
Withdrawal of consent from the study occurs only when a participant does not 
want to participate in the study any longer and does not allow any further 
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Amendment 2 
Amendment rationale 
The study CKJX839A1GB01 was initiated in July 2021 with the first patient enrolled on 07 
July 2021.  As of 15th July 2022, 900 patients have been randomised. 
The main purpose of the amendment is to: 
a. 
Updated the definition of investigational treatment and intercurrent events 
b. 
Corrected typographical errors some of which had been notified to the ethics committee 
previously  
c. 
Corrected the use of the word placebo to standard of care + behavioural support 
d. 
Confirmed the inclisiran group is inclisiran (+/-  behavioural support)  
e. 
Confirmed that if questionnaires are not returned they will be followed up twice at 2-
weekly intervals 
f. 
Confirmed that patients will be monitored for safety events for 30 days after their EOS 
visit and not administration of study treatment 
g. 
Confirmed that the data analysis in the protocol summary will be from baseline to Day 
270 and not Day 90, this now matches section 12.4.1 
 
 
 


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Changes to the protocol 
The changes made to the protocol, and sections affected are listed below 
 
Section 
Changes made 
Glossary of terms 
Update to investigational drug/ treatment and intercurrent events 
Amendment 1 - changes to the 
protocol - exclusion criteria 
Key exclusion criteria for triglycerides updated 
Amendment 1 - changes to the 
protocol - section 5.2 
Exclusion criteria for triglycerides updated 
Amendment 1 - changes to the 
protocol - section 6.1 
Corrected that patients do not need to wait 15 mins after receiving 
the Inclisiran dose at Day 1 
Protocol summary – treatment 
of interest 
Updated ratio to confirm this is 1:1:1 
Protocol summary – data 
analysis 
Corrected inclisiran and placebo to inclisiran (+/- behavioural 
support) and standard of care + behavioural support and 
confirmed we are looking at changes from baseline to Day 270 
4.5 – treatment groups and 
outcome assessments 
Confirmed patients will attend 3 study visits 
Confirmed visits will be planned in accordance with the 
assessment schedule 
Confirmed the behavioural support programme is delivered 
monthly 
Confirmed – Unreturned questionnaires will be followed up twice 
at 2-weekly intervals. 
6.1.3 – Treatment groups  
Confirmed the ratio is 1:1:1 
6.4.1 - treatment compliance 
confirmed participants will receive monthly telephone based 
behavioural support 
8.1 - Domiciliary visits 
Confirmed these will be conducted by experienced HCPs 
Table 8.1 
Confirmed the behavioural support will be a scheduled 
programme of delivery 
9.2 - Study completion and 
post-study treatment 
Confirmed that patients will be remotely monitored for safety 
events for 30 days after their EOS visit 
10.3.3 SAE reporting 
Confirmed that SAEs will be reported for 30 days after their EOS 
visit 
11.2 - Database Management 
and quality control 
Confirmed that IRT data will be sent electronically to Novartis and 
NWEH at specific timelines 
12.4.1 - Definition of primary 
endpoint 
Confirmed test treatment inclisiran (+/- behavioural support) and 
standard of care + behavioural support and not versus placebo   
Confirmed the strategy for handling intercurrent events 
12.4.2 - Statistical model, 
hypothesis, and method of 
analysis 
Confirmed test treatment inclisiran (+/- behavioural support) and 
standard of care + behavioural support and not versus placebo 
 
12.8 - Sample size calculation 
Confirmed the sample size would inclisiran group (+/- behavioural 
support) and standard of care + behavioural support and not 
placebo 
 


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Amendment 1 
Amendment rationale 
The study CKJX839A1GB01 was initiated in July 2021 with the first patient enrolled on 07 
July 2021.  As of 9th Sep 2021, 47 patients have been randomised. 
The main purpose of the amendment is to: 
a. 
Remove the DMC and need for interim analysis 
• When the study was written we did not have a licence for the IMP therefore a DMC 
was a requirement at the time.  We are administering the IMP as it should be given 
and within its license. 
b. 
Addition of exclusion for patients with triglycerides greater than or equal to 4.52 
• We are unable to calculate LDL-C values using the Friedewald formula if triglyceride 
value is high 
c. 
Added that patients randomised to Group 1 will not be required to attend the Day 1 visit 
but can receive a phone call instead.  Visit schedule has also been updated 
• Group 1 patients do not receive IMP and no additional assessments are required at 
this visit 
d. 
Reworded primary objective as this was not very clear 
• The primary objective of this study is to demonstrate superiority of inclisiran +/- 
behavioural support compared to standard of care + behavioural support in a primary 
care setting, in terms of the percentage change in LDL-C from baseline to Day 270 
in adults with elevated LDL-C. 
e. 
 
 
f. 
If patients receive the study medication at home the lipid profile test will also need to 
be performed at Day 90 
• This is to ensure all study assessments are performed as per protocol 
g. 
COVID-19 vaccine should not be given within 7 days of receiving IMP. 
• Delivery of COVID-19 vaccine is a change in Novartis policy 
h. 
 
 
 
 
i. 
The site of injection is the abdomen, alternative injection sites include the upper arm or 
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• When the protocol was written the IMP was not licensed so this information was not 
available 
j. 
The Behavioural Support Programme consists of a telephone based support service 
providing advice on diet, lifestyle, medication adherence and CV risk management. 
Patients will have access to this service throughout the study  
• This has been updated as it is not when patients choose but a scheduled programme 
of delivery  
k. 
Update on requirements for adverse events 
• In this study, only SAEs will be detected, documented and reported. AEs leading to 
treatment discontinuation will be documented only and do not need to be reported as 
per normal practice 
l. 
Reference to safety management plan removed 
• This is an internal document that will not be given to sites and is not part of the 
protocol 
m. 
Pregnancy reporting section updated 
• This now reflects the legally approved wording as per the pregnancy PICF 
n. 
 
 
 
 
 
o. 
Confirmation that the behavioural support programme will be delivered by health 
advisors and not healthcare professionals 
p. 
 
 
 
q. 
Removal of liver events 
• This is consistent with the design of the study being to understand the effects of the 
innovation within the real world conditions of everyday clinical practice,  there was 
no requirement to include testing in the study or monitoring of renal or hepatic 
function required in accordance with our SPC.   
r. 
Update to the number of interviews that may be required 
• This is to give some more scope in case we haven’t reached data saturation by the 
30/10 interviews 
s. 
Update to lipid profile in schedule of events 
• To match section 8.4 of the protocol 
t. 
Confirmation that study treatment refers to Inclisiran 
 
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Changes to the protocol 
The changes made to the protocol, and sections affected are listed below 
 
Section 
Changes Made 
Title page 
Short title updated so the underlined letters spell SPIRIT 
Glossary  
Definition of study treatment updated 
Protocol summary – 
primary objective 
Updated wording 
Protocol summary-  
Key exclusion 
criteria 
Exclusion added for patients with triglycerides value greater than or 
equal to 4.52 mmol/l 
Protocol Summary - 
Data Analysis 
Wording updated  
Section 3.1 
Wording updated 
Section 4.2 
 
 
 
  
Section 4.3.1.2 
Updated the number of interviews 
Section 4.3.2.2 
Updated the number of interviews 
Section 4.3.3.2 
Updated the number of interviews 
Section 4.5 
Added that Patient’s randomised to Group 1 do not need to attend the 
Day 1 visit but can receive a phone call instead 
Typo corrected 
References to DMC have been removed 
If patients receive the study medication at home the lipid profile test 
will also need to be performed at Day 90 
Section 5.2 
Exclusion added for patients with triglycerides value greater than or 
equal to 4.52 mmol/l 
Section 6.1 
Added clarification on time between receiving COVID-19 Vaccine 
and study medication 
 
Section 6.1.5 
Updated with regards how the automated data will be collected 
Section 6.5.2 
Updated information on the injection site 
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Section 7.1 
Text updated to match section 4.3 
Section 8 
Confirmed access to the behavioural support programme is a 
scheduled programme of delivery 
Table 8.1 
Assessment schedule updated 
Section 8.5.2 
Reference to DMC has been removed 
Section 9.1.1 
Reference to liver and renal safety has been removed 
Section 10.2 
Updated wording to reflect normal practice of AE reporting 
Removed reference to the safety management plan 
Section 10.3.4 
Updated wording on how pregnancies will be followed 
Section 10.4.1 
Removed reference to DMC 
Section 12.4.2 
Updated wording 
Section 12.6 
 
Section 12.7 
Confirmed there will be no interim analyses 
Section 16.1 
Updated that behavioural support programme will be delivered by 
health advisors 
Section 16.4 
 
 
 
 
 
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Protocol summary 
Protocol 
number 
CKJX839A1GB01 
Full Title 
A phase IIIb, multicentre, randomised controlled study to evaluate the 
implementation, preference and utility for administration of inclisiran sodium in 
participants with Atherosclerotic Cardiovascular Disease (ASCVD) or ASCVD-risk 
equivalents and elevated Low Density Lipoprotein Cholesterol (LDL-C) using a 
primary care models in the NHS. 
Brief title 
VICTORION-Spirit: Study in Primary care evaluating Inclisiran deliveRy 
Implementation + enhanced SupporT  
Sponsor and 
Clinical Phase 
Novartis, Phase IIIb 
Investigation 
type 
Drug 
Study type 
Interventional, open label 
Purpose and 
rationale 
The implementation research study described in this protocol is designed to 
provide and assess evidence for the implementation of inclisiran within a primary 
care setting in the NHS.  The protocol describes an established implementation 
science approach utilising a Type 1 hybrid design. The study will focus on testing 
a clinical intervention in the appropriate real-world situation (in this case primary 
care) while observing and gathering information on its ‘implementability’. 
The study can therefore be divided into three main elements: 
• 
A prospective phase IIIb intervention with inclisiran +/- behavioural 
support compared to standard of care + behavioural support in a type 1 
hybrid implementation design in a primary care population.  
 
• 
 
 
 
 
 
• 
A process evaluation that will ascertain the views of patients and 
healthcare providers about the service they have received or provided and 
its potential transactability across the NHS. 
Primary 
Objective(s)  
The primary objective of this study is to demonstrate superiority of inclisiran +/- 
behavioural support compared to standard of care + behavioural support in a 
primary care setting, in terms of the percentage change in LDL-C from baseline to 
Day 270 in adults with elevated LDL-C. 
Secondary 
Objectives 
The secondary objectives of this study are to evaluate the implementation of 
inclisiran +/- behavioural support compared to standard of care + behavioural 
support in a primary care setting using the following assessments: 
• 
Measures of patient satisfaction using the validated CSQ-8 (Client 
Satisfaction Questionnaire) administered after treatment at day 90.  
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• 
Measures of patient activation and empowerment using the validated 
Patient Activation Measure (PAM) questionnaire administered after 
treatment at day 90. 
• 
Measures of adherence to cardiovascular disease self-management using 
the 
validated 
Patient 
Activation 
Measure 
(PAM) 
questionnaire 
administered after treatment at day 90 and using assessment of 
medication adherence during the study period. 
• 
A process evaluation conducted using the Consolidated Framework for 
Implementation Research (CFIR) which will explore inclisiran delivery at 
three levels: 
o 
Feasibility and acceptability of delivery models for inclisiran to 
patients 
o 
Feasibility and acceptability of delivery models for inclisiran to 
providers (inner setting) 
o 
Wider ‘transactability’ of the proposed delivery models (outer 
setting) 
o 
The service costs of each delivery model 
o 
The acceptability and perceived sustainability of patient 
identification and referral routes 
• 
Serious adverse event profile 
Study design 
A phase IIIb, multicentre, randomised controlled study to evaluate the 
implementation, preference and utility for administration of inclisiran sodium in 
participants on established lipid lowering medication or, have been 
recommended lipid lowering therapy by their healthcare provider but are unable 
to tolerate treatment, with elevated low density lipoprotein cholesterol (LDL-C) in 
a primary care population. 
900 eligible participants will be randomised (300 per treatment group) at up to 30 
primary care centres across Greater Manchester. Eligibility and recruitment to the 
study will be optimised by using NWEH’s proven Feasibility Assessment and 
Recruitment System for Improving Trial Efficiency (FARSITE) for identification and 
recruitment at participating GP practices. 
At the baseline visit/screening on receipt of a signed consent form, eligible 
participants will be randomised to one of the three treatment groups:  
• 
Group 1: Participants will continue to receive their background lipid 
lowering therapy plus behavioural support  
• 
Group 2: Participants will continue to receive their background lipid 
lowering therapy, plus inclisiran for injection (delivered in an injection-only 
model). 
• 
Group 3: Participants will continue to receive their background lipid 
lowering therapy, plus inclisiran for injection, plus behavioural support. 
The study duration will be approximately 9 months. 
Study 
population 
The population of interest is adult participants with elevated cholesterol who are 
receiving treatment with established lipid lowering medication or, have been 


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recommended lipid lowering therapy by their healthcare provider but are unable 
to tolerate treatment. 
900 participants (300 per treatment group) at up to 30 primary care centres in the 
localised geographical region of Greater Manchester will be required for this 
study. 
Key Inclusion 
criteria 
• 
Male or female participants ≥18 years of age. 
• 
Patients on established lipid lowering medication or, have been recommended 
lipid lowering therapy by their health care provider but are unable to tolerate 
treatment. 
• 
A total cholesterol measurement at screening that is ≥4 mmol/L [approximately 
160 mg/dL].  
• 
Participants on lipid-lowering therapies should be on a stable dose for 
≥30 days before screening with no planned medication or dose change. 
Key Exclusion 
criteria 
1. 
A triglyceride measurement at screening that is ≥4.52 mmol/L 
2. 
Medical or surgical history that might limit the individual’s ability to take 
study treatments for the duration of the study and/or put the participant at 
significant risk (e.g. severe respiratory disease; cancer or evidence of 
spread within approximately the last 5 years, other than non-melanoma 
skin cancer; or history of alcohol or substance misuse). 
3. 
Current or planned renal dialysis or transplantation. 
4. 
Acute coronary syndrome or stroke less than 4 weeks before the 
screening visit. 
5. 
Coronary revascularization procedure planned within the next 6 months 
6. 
Women of child-bearing potential (unless using adequate contraception) 
7. 
Previous, current or planned treatment with a monoclonal antibody 
targeting PCSK9, or with a drug known to be contra-indicated with 
inclisiran. 
8. 
Previous exposure to inclisiran or participation in a randomised study of 
inclisiran. 
9. 
Current or previous participation in a clinical study with an unlicensed drug 
or device within 30 days or five half-lives of the screening visit, whichever 
is longer. 
Study 
treatment 
The study treatment, KJX839/Inclisiran for Injection (sub-cutaneous use), is a 
sterile formulation of inclisiran sodium in water for injection packaged in vial or 
glass pre-filled syringe (PFS) presentations 
Treatment of 
interest 
Participants will be assigned to one of three of the following treatment groups in a 
ratio of 1:1:1. 
Group 1: Participants will continue to receive their background lipid lowering 
therapy plus behavioural support 
Group 2: Participants will continue to receive their background lipid lowering 
therapy, plus inclisiran for injection (delivered in an injection-only model). 


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Group 3: Participants will continue to receive their background lipid lowering 
therapy, plus inclisiran for injection (delivered in an injection-only model), plus 
behavioural support. 
Efficacy 
assessments 
A capillary blood sample will be taken for immediate analysis of the participant’s 
lipid profile
 for assessment of efficacy. This will be performed at 
screening/baseline visit, day 90 and end of study (EOS) visit.  
Parameters to be assessed include: 
 
 
 
 
 
  
• 
Non-HDL (calculated) 
• 
LDL-C calculated using Friedewald 
Key safety 
assessments 
Adverse events will be collected throughout the study period using ConneXon data 
platform. 
The AEs to be recorded are:  
• 
All SAEs whatever the causal relationship to the to the Investigational 
Medicinal Product (IMP) or to a procedure required by the study protocol 
• 
AEs leading to treatment discontinuation 
Other 
assessments  
Comparisons between the Group 2 and 3 and the different delivery models will 
analyse whether the ‘supported inclisiran’ arm generates greater benefits than the 
injection only model in terms of outcomes other than LDL cholesterol: patient 
adherence, acceptability (both through PROMs) and wider cardiovascular risk. A 
process evaluation will build on and extend the study results, providing in-depth 
data on adherence and acceptability (through detailed interviews) with patients 
and professionals involved in the trial.  
Data analysis 
The primary effectiveness objective of this study is to demonstrate superiority of 
each inclisiran arm compared to standard of care + behavioural support in terms 
of the percentage change from baseline in LDL-C to Day 270 in adults with 
elevated LDL-C. The statistical hypotheses that will be tested for each inclisiran 
arm are as follows:  
• 
H0: The difference between participants treated with inclisiran (+/- 
behavioural support) and standard of care + behavioural support in the 
least squares mean percentage change from baseline to the Day 270 visit 
in LDL-C= 0 
• 
Ha: The difference between participants treated with inclisiran (+/- 
behavioural support) and standard of care + behavioural support in the 
least squares mean percentage change from baseline to the Day 270 visit 
in LDL-C < 0 
The primary endpoint will be analysed using an analysis of covariance model 
(ANCOVA) with imputation for missing data performed using the washout model 
as discussed in Section 12.4.2. The difference in least squares means between 
treatment groups and corresponding 2-sided 95% confidence intervals will be 
reported. The Full Analysis Set (FAS) will be used for this analysis. Full details on 
the model and imputation will be provided in the SAP. 
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The process evaluation will be conducted and analysed using the Consolidated 
Framework for Implementation Research (CFIR).  
Key words 
implementation, preference, utility, process evaluation, inclisiran,  Atherosclerotic 
Cardiovascular Disease, ASCVD, ASCVD-risk equivalents, Cholesterol, LDL-C, 
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1 
Introduction 
1.1 
Background 
1.1.1 
Cardiovascular benefits of lowering LDL cholesterol  
Elevated low-density lipoprotein associated cholesterol (LDL-C), is one of the major risk 
factors for coronary heart disease (CHD) (Grundy et al, 2004). Despite advances in treatment, 
atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death and disability 
worldwide and is expected to remain so beyond 2040 (Foreman et al, 2018). After 30 years of 
progress, death rates associated with ASCVD may be increasing in the United States once more 
(Benjamin et al, 2019).  
Multiple factors contribute to the development of ASCVD. However, strong and consistent 
evidence from genetics, epidemiology, and randomised trials, establishes that among these 
factors, LDL-C is not merely a biomarker of increased risk, but a causal and modifiable factor 
in ASCVD (Ference et al, 2017). 
Large outcome trials have consistently confirmed the benefit of cholesterol lowering therapy 
(statins).  In the largest study, the Heart Protection Study, 20,536 subjects were treated with 
simvastatin for five years. The study was large enough to allow multiple subgroup analyses. 
These showed that the reduction in relative risk was similar even when subjects had risk factors 
including diabetes, hypertension, and smoking (Goldstein, 2015). A recent meta-analysis of 22 
statin trials involving 134,000 participants concluded that for each reduction of LDL-C of 1 
mmol/l (40 mg/dl) cardiovascular events are reduced by 20%, even in people who were 
considered to be at low risk (Cholesterol Treatment Trialists, 2012). These findings have made 
statin the cornerstone of clinical practice.  
Despite the proven efficacy of statins, there is still a considerable variability in individuals to 
these drugs, even when being treated with a high intensity regime (Ridker, 2016). Furthermore, 
not all people tolerate statins or are able to take statins at sufficient intensive doses, and some 
observational studies have demonstrated as many as half of individuals who begin statin therapy 
discontinue it within 12 months (Zang, 2013).  
Therefore, there is a clear unmet medical need for additional options beyond current available 
treatments for the lowering of LDL-C.  
1.1.2 
Inhibition of PCSK9 as a therapeutic target  
LDL Receptors (LDLR) on the surface of liver cells are a key determinant of circulating levels 
of LDL-C (Goldstein and Brown, 2009). Proprotein convertase subtilisin/kexin type 9 (PCSK9) 
is an enzyme mainly of hepatic origin that circulates in the blood and binds to the LDLR 
(Seidah, 2014). The PCSK9-LDLR complex is then degraded by lysosomes in the liver cells 
and circulation of LDLR to the surface of the liver cells is reduced. As a consequence, the 
number of LDL receptors on liver cells is reduced and there is reduced uptake of LDL-C from 
the blood (Horton et al, 2007). Lower levels of circulating PCSK9 lead to higher hepatic LDLR 
expression and lower circulating LDL-C levels.  
Gain of function mutations in the PCSK9 gene result in familial hypercholesterolaemia and 
increased rates of coronary events. By contrast, loss of function mutations are associated with 


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reductions in LDL-C levels and lower risk of coronary events. From a safety perspective, 
individuals with no circulating PCSK9 due to compound heterozygous loss of function 
mutations in PCSK9 do not appear to have any obvious clinical disadvantages (Zhao, 2006). 
Mechanistic studies of PCSK9 have identified PCSK9 as playing a key role in controlling the 
levels of LDLR on the surface of hepatocytes. PCSK9 is responsible for degrading LDLR and 
prevents recycling to the cell surface where it removes LDL-C from the plasma. Therapeutic 
strategies designed to reduce circulating PCSK9 include binding it in the circulation with 
monoclonal antibodies or modified binding proteins and reducing production of it in the liver 
with small interfering RNAs (siRNAs).  
Clinical studies with PCSK9 blocking antibodies have demonstrated significant effects on 
lowering LDL-C in healthy volunteers and in subjects with hypercholesterolemia with and 
without statins (Banerjee, 2012, Dias et al, 2012, Milazzo, 2012, Raal et al 2012). In addition, 
recent clinical studies indicate that statin treatment increases PCSK9 levels and as a result, may 
limit statin effectiveness as the dose is increased (Careskey et al, 2008; Davignon and Dubuc, 
2009; Welder et al, 2010). Collectively these studies support the hypothesis that lowering of 
circulating plasma PCSK9 by inhibiting the synthesis of PCSK9 protein in hepatocytes should 
lower LDL-C, potentially resulting in reduced risk of CHD. 
1.1.3 
Inhibition of PCSK9 with siRNA has potential advantages over 
antibodies  
Ribonucleic acid interference (RNAi) is a naturally occurring cellular mechanism mediated by 
small interfering RNAs (siRNAs) for regulating gene expression. Inclisiran is a chemically 
synthesised siRNA, covalently linked to a ligand containing three N-acetylgalactosamine 
(GalNAc) 
residues. 
These 
GalNAc 
residues 
bind 
to 
abundant 
liver-expressed 
asialoglycoprotein receptor (ASGPR), leading to inclisiran uptake specifically into hepatocytes. 
When introduced into the hepatocyte, inclisiran engages the natural pathway of RNA 
interference (RNAi) by binding intracellularly to the RNA-induced silencing complex (RISC), 
enabling it to cleave mRNA molecules encoding PCSK9 specifically. The cleaved PCSK9 
mRNA is degraded and thus unavailable for protein translation, which results in decreased 
levels of the PCSK9 protein. A single siRNA-bound RISC is catalytic and cleaves many mRNA 
transcripts and the duration of action is anticipated to be longer than other mechanisms. A key 
potential advantage of inclisiran’s mechanism of action is that the duration of its effect is longer 
than that of monoclonal antibodies to PCSK9. 
1.1.4 
Clinical efficacy and safety  
The efficacy of inclisiran was evaluated in three phase III studies in patients with ASCVD or 
ASCVD risk equivalents (type 2 diabetes mellitus, familial hypercholesterolaemia, or 10-year 
risk of 20% or greater of having a cardiovascular event assessed by Framingham Risk Score or 
equivalent) and/or familial hypercholesterolaemia (FH). Patients were taking a maximally 
tolerated dose of statin with or without other lipid-modifying therapy and required additional 
LDL-C reduction (patients unable to reach their treatment goals). Approximately 17% of 
patients were statin intolerant. Patients were administered subcutaneous injections of 284 mg 
inclisiran or placebo on day 1, day 90, day 270 and day 450. Patients were followed until day 


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540. The effect of inclisiran on cardiovascular morbidity and mortality has not yet been 
determined. 
In the phase III pooled analysis, subcutaneously administered inclisiran lowered LDL-C 
between 50% and 55% as early as day 90 (Figure 1-1), which was maintained during long-term 
therapy. Maximal LDL-C reduction was achieved at day 150 following a second administration. 
Small but statistically significant increased LDL-C reductions up to 65% were associated with 
lower baseline LDL-C levels (approximately <2 mmol/l [77 mg/dl]), higher baseline PCSK9 
levels and higher statin doses and statin intensity. 
Figure 1-1 
Mean percentage change from baseline LDL-C in patients with primary 
hypercholesterolaemia and mixed dyslipidaemia treated with 
inclisiran compared to placebo (pooled analysis) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
To date, injection site reaction is the only adverse drug reaction that has been identified for 
inclisiran. None of the reported injection site reactions were considered to be serious.  
In Phase II study MDCO-PCS-15-01 (ORION-1), clinically relevant injection site reactions 
were reported in a total of 13 (3.5%) inclisiran-treated subjects and no subjects (0.0%) in the 
placebo group following a single dose (single and double dose groups combined) through Day 
90. Injection site reactions were reported in a total of 6 (3.4%) inclisiran-treated subjects and 
no subjects (0.0%) in the placebo group following a second dose. No observed difference or 
dose relationship was observed between inclisiran groups. The frequency of injection site 
reactions was similar after a second dose of inclisiran (3.4%) to that observed after the first dose 
(3.5%). All AEs at the injection site resolved without sequelae with the exception of one subject 
who received a single dose of inclisiran sodium 300 mg on Day 1 and continued to have a 2 
mm erythema spot at the injection site on Day 210.  
Mean percentage change from baseline 
No. of patients 
Placebo 
Inclisiran 
Inclisiran 
Placebo 


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In the Phase III studies MDCO-PCS-17-03 (ORION-9), MDCO-PCS-17-04 (ORION-10) and 
MDCO-PCS-17-08 (ORION-11), more inclisiran-treated subjects, 8.2% (150/1833), reported 
at least one Treatment Emerged Adverse Events (TEAE) at the injection site than placebo-
treated subjects 1.8% (33/1822). Of the 183 subjects with a TEAEs at the injection site, the 
majority had a mild event (4.2%; 154/3655 subjects) and none had a severe event. No inclisiran-
treated subject had a serious TEAE at the injection site. Four (4) inclisiran-treated subjects 
withdrew from study drug due to non-serious TEAEs at the injection site.  
From the reported TEAEs at the injection site, more inclisiran-treated subjects (5.0%; 91/1833) 
reported clinically relevant TEAEs at the injection site (preferred terms of injection site 
erythema, injection site hypersensitivity, injection site pruritus, injection site rash, and injection 
site reaction) than placebo-treated subjects (0.7%; 12/1822). Clinically relevant TEAEs at the 
injection site were reported for inclisiran-treated subjects as follows: injection site erythema (37 
events in 30 subjects), injection site hypersensitivity (3 event in 2 subjects), injection site 
pruritus (9 events in 8 subjects), injection site rash (20 events in 13 subjects), and injection site 
reaction (84 events in 56 subjects). The time to first clinically relevant TEAEs at the injection 
site was usually observed more than 12 hours after the time of injection and this was similar for 
those that were clinically relevant. The TEAE at the injection site were generally transient. 
1.1.4.1 
ASCVD and ASCVD risk equivalents 
Two studies were conducted in patients with ASCVD and ASCVD risk equivalents (ORION-10 
and ORION-11). Patients were taking a maximally tolerated dose of statins with or without 
other lipid-modifying therapy, such as ezetimibe, and required additional LDL-C reduction. As 
lowering LDL-C is expected to improve cardiovascular outcomes, the co-primary endpoints in 
each study were the percentage change in LDL-C from baseline to day 510 relative to placebo 
and the time-adjusted percentage change in LDL-C from baseline after day 90 and up to day 540 
to estimate the integrated effect on LDL-C over time. 
ORION-10 was a multicentre, double-blind, randomised, placebo-controlled 18-month study 
conducted in 1,561 patients with ASCVD. The mean age at baseline was 66 years (range: 35 to 
90 years), 60% were ≥65 years old, 31% were women, 86% were White, 13% were Black, 1% 
were Asian and 14% were Hispanic or Latino ethnicity. The mean baseline LDL C was 
2.7 mmol/l (105 mg/dl). Sixty-nine percent (69%) were taking high-intensity statins, 19% were 
taking medium-intensity statins, 1% were taking low-intensity statins and 11% were not on a 
statin. The most commonly administered statins were atorvastatin and rosuvastatin. 
Inclisiran significantly reduced the mean percentage change in LDL-C from baseline to day 510 
compared to placebo by 52% (95% CI: -56%, -49%; p <0.0001).Inclisiran also significantly 
reduced the time-adjusted percentage change in LDL-C from baseline after day 90 and up to 
day 540 by 54% compared to placebo (95% CI: -56%, -51%; p <0.0001). At day 510, the 
LDL-C target of <1.8 mmol/l (70 mg/dl) was achieved by 84% of inclisiran patients with 
ASCVD compared to 18% of placebo patients. 
Consistent and statistically significant (p<0.0001) reductions in percentage change in LDL-C 
from baseline to day 510 and time-adjusted percentage change in LDL-C from baseline after 
day 90 and up to day 540 were observed across all subgroups irrespective of baseline 


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demographics, baseline disease characteristics (including gender, age, body mass index, race 
and baseline statin use), comorbidities and geographic regions. 
ORION-11 was an international, multicentre, double-blind, randomised, placebo-controlled 
18-month study which evaluated 1,617 patients with ASCVD or ASCVD risk equivalents. 
More than 75% of patients were receiving a high-intensity statin background treatment, 87% of 
patients had ASCVD and 13% were ASCVD risk equivalent. The mean age at baseline was 
65 years (range: 20 to 88 years), 55% were ≥65 years old, 28% were women, 98% were White, 
1% were Black ,1% were Asian and 1% were Hispanic or Latino ethnicity. The mean baseline 
LDL-C was 2.7 mmol/l (105 mg/dl). Seventy-eight percent (78%) were taking high-intensity 
statins, 16% were taking medium-intensity statins, 0.4% were taking low-intensity statins and 
5% were not on a statin. The most commonly administered statins were atorvastatin and 
rosuvastatin. 
Inclisiran significantly reduced the mean percentage change in LDL-C from baseline to day 510 
compared to placebo by 50% (95% CI: -53%, -47%; p<0.0001). Inclisiran also significantly 
reduced time-adjusted percentage change in LDL-C from baseline after day 90 and up to 
day 540 by 49% compared to placebo (95% CI: -52%, -48%; p<0.0001). 
At day 510, the LDL-C target of <1.8 mmol/l (70 mg/dl) was achieved by 82% of inclisiran 
patients with ASCVD compared to 16% of placebo patients. In patients with an ASCVD risk 
equivalent, the LDL-C target of <2.6 mmol/l (100 mg/dl) was achieved by 78% of inclisiran 
patients compared to 31% of placebo patients. 
Consistent and statistically significant (p<0.05) percentage change in LDL-C from baseline to 
day 510 and time-adjusted percentage change in LDL-C from baseline after day 90 and up to 
day 540 was observed across all subgroups irrespective of baseline demographics, baseline 
disease characteristics (including gender, age, body mass index, race and baseline statin use), 
comorbidities, and geographic regions. 
1.1.4.2 
Heterozygous familial hypercholesterolaemia 
ORION-9 was an international, multicentre, double-blind, randomised, placebo-controlled 
18-month trial in 482 patients with heterozygous familial hypercholesterolaemia (HeFH). All 
patients were taking maximally tolerated doses of statins with or without other lipid-modifying 
therapy, such as ezetimibe, and required additional LDL-C reduction. The diagnosis of HeFH 
was made either by genotyping or clinical criteria (“definite FH” using either the Simon Broome 
or WHO/Dutch Lipid Network criteria). 
The co-primary endpoints were the percentage change in LDL-C from baseline to day 510 
relative to placebo, and the time-adjusted percentage change in LDL-C from baseline after 
day 90 and up to day 540 to estimate the integrated effect on LDL-C over time. Key secondary 
endpoints were the absolute change in LDL-C from baseline to day 510, the time-adjusted 
absolute change in LDL-C from baseline after day 90 and up to day 540 and the percentage 
change from baseline to day 510 in PCSK9, total cholesterol, Apo-B, and non-HDL-C. 
Additional secondary endpoints included the, individual responsiveness to inclisiran and the 
proportion of patients attaining global lipid targets for their level of ASCVD risk.  The mean 
age at baseline was 55 years (range: 21 to 80 years), 22% were ≥65 years old, 53% were 
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ethnicity. The mean baseline LDL-C was 4.0 mmol/l (153 mg/dl). Seventy-four percent (74%) 
were taking high-intensity statins, 15% were taking medium-intensity statins and 10% were not 
on a statin. Fifty-two percent (52%) of patients were treated with ezetimibe. The most 
commonly administered statins were atorvastatin and rosuvastatin. 
Inclisiran significantly reduced the mean percentage change in LDL-C from baseline to day 510 
compared to placebo by 48% (95% CI: -54%, -42%; p<0.0001).Inclisiran also significantly 
reduced the time-adjusted percentage change in LDL-C from baseline after day 90 and up to 
day 540 by 44% compared to placebo (95% CI: -48%, -40%; p<0.0001). 
At day 510, 52.5% of inclisiran patients with ASCVD achieved their LDL-C target of 
<1.8 mmol/l (70 mg/dl) compared to 1.4% of placebo patients with ASCVD, while in the group 
with ASCVD risk equivalents 66.9% of inclisiran patients achieved their LDL-C target of 
<2.6 mmol/l (100 mg/dl) compared to 8.9% of placebo patients. Consistent and statistically 
significant (p<0.05) percentage change in LDL-C from baseline to day 510 and time-adjusted 
percentage change in LDL-C from baseline after day 90 and up to day 540 were observed across 
all subgroups irrespective of baseline demographics, baseline disease characteristics (including 
gender, age, body mass index, race and baseline statin use), comorbidities, and geographic 
regions. 
1.1.5 
Background to the research framework  
There is evidence to show that real-world adherence with lipid lowering therapies is suboptimal 
(Akyea et al., 2019). The phase III clinical development programme summarised in Section 
1.1.4 demonstrates the effective LDL-C reduction profile of inclisiran.  In addition, the dosing 
regimen of 6-monthly maintenance injections provides a delivery method which may help to 
improve adherence to lipid lowering therapies with minimal impact on 
 
 
The potential to address large population health burdens, such as cardiovascular disease, is 
greater in integrated healthcare systems that are able to support innovation.  This requires 
understanding how a new technology such as inclisiran could be deployed and delivered into a 
system of care in such a manner that it would be possible to treat the appropriate patients at a 
population-health level.   
The UK National Health Service (NHS) presents an ideal framework within which to consider 
population health approaches for the implementation of new health technologies.  This is due 
to the primary care focused management of patients with chronic conditions, the increasing 
robustness of electronic medical records (EMR), clear and aligned commissioning processes 
and goals within the NHS Long-Term plan regarding the optimisation of service delivery to 
patients within their locality.   
Within the NHS, the Greater Manchester Health and Social Care partnership - a geographical 
region covering in excess of 2 million patients – presents an ideal test-bed opportunity to 
research the implementation of inclisiran with a population health approach utilising a primary 
care model of delivery.  This is due to the cohesion of the primary and secondary care EMR in 
Greater Manchester, their established use of implementation science approaches to assess new 
interventions and their established primary care networks.    
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The implementation research study described in this protocol is designed to provide and assess 
evidence for the implementation of inclisiran within a primary care setting in the NHS.  The 
protocol describes an established implementation science approach utilising a Type 1 hybrid 
design described in subsequent sections.  
2 
Purpose and rationale 
The purpose of this study is to evaluate the implementation of inclisiran in a regional primary 
care setting in the UK.   
Using implementation science methodology, the study seeks to assess the effect of 9 months 
treatment with inclisiran +/- behavioural support, compared to standard of care + behavioural 
support, on LDL-C reduction, 
 assessments of patient and healthcare 
professional (HCP) satisfaction, 
 and healthcare service process 
evaluation. 
3 
Objectives 
3.1 
Primary Objective 
The primary objective of this study is to demonstrate superiority of inclisiran +/- behavioural 
support compared to standard of care + behavioural support in a primary care setting, in terms 
of the percentage change in LDL-C from baseline to Day 270 in adults with elevated LDL-C. 
3.2 
Secondary Objectives 
The secondary objectives of this study are to evaluate the implementation of inclisiran +/- 
behavioural support compared to standard of care + behavioural support in a primary care 
setting using the following assessments: 
• Measures of patient satisfaction using the validated CSQ-8 (Client Satisfaction 
Questionnaire) administered after treatment at day 90. 
• Measures of patient activation and empowerment using the validated Patient Activation 
Measure (PAM) questionnaire administered after treatment at day 90.  
• Measures of adherence to cardiovascular disease self-management using the validated 
Patient Activation Measure (PAM) questionnaire administered after treatment at day 90 
and using assessment of medication adherence during the study period. 
• A process evaluation conducted using the Consolidated Framework for Implementation 
Research (CFIR) which will explore inclisiran delivery at three levels: 
• Feasibility and acceptability of delivery models for inclisiran to patients 
• Feasibility and acceptability of delivery models for inclisiran to providers (inner 
setting) 
• Wider ‘transactability’ of the proposed delivery models (outer setting) 
• The service costs of each delivery model 
• The acceptability and perceived sustainability of patient identification and referral 
routes 
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• Serious adverse event profile and adverse events leading to treatment discontinuation 
3.3 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
4 
Study design  
This study is an implementation research study that utilises implementation science 
methodology and use of the electronic medical record (EMR).   
The study is based on the following principles: 
• It is run in the setting where inclisiran is intended to be implemented in clinical practice, 
with the intention of understanding the effects of innovations within the real world 
conditions of everyday clinical practice 
• Inclusion / exclusion criteria reflect the proposed license, with the intention of working 
with populations that will be affected by an intervention, rather than selecting patients 
who are suitable for a standard clinical trial. 
• Health delivery context: taking account institutional and health system contexts – 
including the viewpoints of various stakeholder including commissioners, system 
managers and clinicians. 
The primary focus of this study is implementation and ‘transactability’ – how to organise, 
deliver and maintain an innovative treatment for ASCVD in a primary care setting in a 
sustainable way.  
4.1 
Overview of Implementation Science 
Implementation Science is the scientific study of methods to promote the systematic uptake of 
proven clinical treatments, practices, organisational, and management interventions into routine 
practice, and hence to improve health (Eccles et al, 2006). This also encompasses the study of 
influences on patient, professional, and organisational behaviours in healthcare systems. 
The field is largely focused on interventions which have established effectiveness in the 
healthcare (non-trial) environment, after marketing-authorisation.  It is unusual to encounter 
implementation science in trials of interventions ahead of marketing authorisation.  However, 
increasingly, implementation science methods are employed in pragmatic effectiveness studies 
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in order to provide a route to appropriately accelerated deployment and more rapid patient 
benefit. This type of approach is key to understanding how and why innovations are 
successfully implemented in some settings but not others and is increasingly necessary to 
provide evidence for patient access to new technologies. This need to gather data to inform 
implementation efforts has become a mainstay of guidance for pragmatic evaluations (Moore, 
2015).  
This study is best conceptualised as a hybrid design (Pinnock et al, 2017). Hybrid designs have 
emerged from wider concerns relating to the need to speed up the transfer of clinical research 
findings into routine practice. In an effectiveness-implementation hybrid design there is a dual 
focus a priori in assessing clinical effectiveness in the appropriate setting and implementation 
(see Figure 4-1).  
Figure 4-1 
Types of research design (adapted from Lane-Fall et al, 2019) 
 
This study is a type 1 hybrid design where the focus is on testing a clinical intervention in the 
appropriate real-world situation (in this case primary care) while observing and gathering 
information on its ‘implementability’. The interventional aspect of the study will be categorised 
as a phase IIIb, multicentre, open-label, randomised controlled study in 900 participants  on 
established lipid lowering medication or, have been recommended lipid lowering therapy by 
their healthcare provider but are unable to tolerate treatment.  
Type 1 hybrid designs sit at the boundaries of implementation science and are used to identify 
what is needed to support implementation in the real world - exploring the resources, behaviours 
and practices that can act as ‘barriers’ or ‘enablers’ to the implementation of a given 
intervention.  Gathering this information on the active components and optimal model of service 
delivery is the crucial first step of planning to scale to spread the delivery of an intervention 
more widely in the appropriate patient population.  
The phase III ORION clinical development program demonstrated the safety and efficacy of 
inclisiran in the clinical trial setting (Section 1.1.4). However, it is acknowledged that 


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randomised clinical trials by definition are highly controlled and enroll a more selected patient 
population than is expected to be prescribed the medication post-approval.
 
 
 
 
 
A Type 1 hybrid design intends to minimise the burden of the trial on participants and healthcare 
providers whilst mimicking the real-world delivery of healthcare as closely as possible. The 
Salford Lung Study (Vestbo, 2016) was the first pre-registration pragmatic trial, achieved using 
bespoke technology developed by NWEH (New, 2014) designed to achieve these aims. This 
approach integrated primary and secondary care Electronic Medical Record (EMR) systems 
from hospitals and surrounding primary care practices in real time, allowing HCP to identify 
patients, assess outcomes, and collect real life setting data without direct contact with patients, 
in addition to providing safety surveillance by remote monitoring (Collier, 2016). 
4.2 
The structure of this study and use of the EMR 
This study will be conducted using NWEH’s ConneXon trials platform which integrates patient 
level electronic healthcare record data from primary care and secondary care via national data 
sources, to support the integration of ‘real-world evidence’ from individually consented 
participants.  The majority of data will be directly extracted from the patient EMR in order to 
minimise direct participant contact and maximise the outcomes of interest related to 
implementation. Some study specific data not routinely collected will also be reported by the 
investigator or delegate in an integrated Electronic Case report Form (eCRF) for accuracy and 
in compliance with regulatory standards. 
The study can therefore be divided into three main elements: 
• A prospective phase IIIb intervention with inclisiran +/- behavioural support compared to 
standard of care + behavioural support in a type 1 hybrid implementation design in a 
primary care population.  
 
 
 
• A process evaluation that will ascertain the views of patients and healthcare providers 
about the service they have received or provided and its potential transactability across the 
NHS. 
The population of interest is adult participants on established lipid lowering medication or, have 
been recommended lipid lowering therapy by their healthcare provider but are unable to tolerate 
treatment. Based on the statistical power calculation (see Section 12.8) 900 participants (300 
per treatment group) at up to 30 primary care centres will be recruited.  
4.3 
The Process Evaluation Sub-Study  
The primary focus of the VICTORION-Spirit study is implementation and ‘transactability’ – 
how to organise, deliver and maintain an innovative treatment for secondary prevention in a 
P
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primary care setting in a sustainable way. This information will be used to inform future 
implementation efforts in the NHS and beyond. 
Understanding how and why healthcare innovations are successfully implemented in some 
settings but not others is a key issue in supporting appropriate broader uptake and access to 
innovative medicines.  The role of process evaluation is to shed light on the structures, resources 
and processes through which successful delivery can be achieved. We will explore how 
inclisiran may be implemented into routine care pathways using approaches that are feasible 
and acceptable both to patients and to those providing the services.  
To identify what is needed to support the implementation of inclisiran in the real world, we will 
draw upon a framework known as the Consolidated Framework for Implementation Research 
(CFIR) (Damschroder 2009). Grounded in Diffusion of Innovations theory, CFIR is widely 
used in implementation research to guide systematic assessment factors that influence 
intervention implementation and effectiveness (Kirk 2016). The framework comprises a 
comprehensive taxonomy of 39 operationally defined constructs across five domains that are 
likely to influence the implementation of complex interventions.  These are: 
1. Intervention characteristics – are there features of the intervention might influence 
implementation (in this case inclisiran itself and/or the delivery mode) 
2. Inner setting – how do the ways that general practices organise care delivery influence 
implementation 
3. Outer setting – are there wider contextual or policy factors that might influence 
implementation and sustainability 
4. The characteristics of individuals involved in implementation 
5. How the process of implementation is actually enacted  
Each of these five domains is further divided into constructs that have been associated with 
effective 
implementation 
(for 
detailed 
descriptions 
of 
each 
construct 
see: 
http://www.cfirguide.org/). We selected the CFIR as our guiding framework because it provides 
a standardised structure for aggregating findings in a systematic manner. Using CFIR we will 
explore inclisiran delivery at three levels: 
1. Feasibility and acceptability of delivery models for inclisiran to patients 
2. Feasibility and acceptability of delivery models for inclisiran to providers (inner setting) 
3. Wider ‘transactability’ of the proposed delivery models (outer setting) 
4.3.1 
Level 1: Feasibility and acceptability of delivery models for inclisiran 
to patients 
4.3.1.1 
Design and setting 
We will conduct semi-structured telephone interviews with patients to understand the feasibility 
and acceptability of each delivery models for inclisiran.   
4.3.1.2 
Sampling and recruitment 
Purposive sampling techniques will be used to recruit respondents to assess how the different 
delivery modes are experienced.  We expect to conduct a minimum of 30 interviews in this 
phase. This sample should allow some scope to examine how adherence, acceptability and 


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experience varies across different demographic groups and ensure diversity in relation to 
individual variables such as age, gender, ethnicity and deprivation. The final sample size will 
be contingent on iterative analysis and saturation of themes.   
4.3.1.3 
Data collection 
Telephone interviews will be arranged at a day/time suitable for the respondent.  We will use 
topic guides informed by CSQ and PAM to understand patients’ interactions with and 
experience of each delivery model. Interviews will cover access and ask how acceptable patients 
found both the injection and the processes of care delivery. As data collection progresses, the 
topic guide will be iteratively reviewed to incorporate issues not previously included, but which 
are relevant to the study.  With the respondents’ permission, telephone interviews will be 
digitally audio-recorded on a university provided encrypted audio device.  The researcher will 
write field notes (immediately following a telephone interview) to provide context to the 
transcribed interview data.   
4.3.1.4 
Analysis 
Interviews will be audio-recorded with consent, transcribed and thematically analysed using a 
modified framework approach and using NVivo software to manage the data. This produces a 
matrix of summarised data providing a structure for analysis and interpretation (Gale 2013). 
This approach will allow us to: (a) answer the specific research questions we have set, whilst 
(b) allowing important insights to be produced inductively. The use of a modified framework 
approach will also utilise the strengths of Framework analysis in providing structure to the 
analysis of large datasets, especially allowing comparisons between different participant groups 
on key issues. As per (Gale 2013), we also intend to engage the wider research team in the 
analysis process. 
4.3.2 
Level 2: Feasibility and acceptability of delivery models for inclisiran 
to providers 
4.3.2.1 
Design and setting 
We will conduct telephone interviews with providers (Practice Managers, GPs, Pharmacists, 
Practice Nurses, etc.) to explore the implementation of each delivery model in primary care and 
understand the structures, resources and processes required to deliver inclisiran as part of 
routine practice.  
4.3.2.2 
Sampling and recruitment 
We will aim to conduct semi-structured telephone interviews with a purposive sample of 
practice nurses, pharmacists, GPs and practice managers drawn from across all the proposed 
delivery models.  We expect to conduct up to 50 interviews in this phase.  We will sample 
across participating sites to ensure maximum variance in practice type and geographical area. 
4.3.2.3 
Data collection 
Telephone interviews will be arranged for a time/day to suit the respondent. Interview topic 
guides will be informed by CFIR and will focus on the barriers and enablers to integrating 


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inclisiran delivery within existing practice routines. Specifically, we will focus on 
understanding: 
• Stakeholders’ perceptions about the relative advantage of the inclisiran and intervention 
complexity; 
• How each delivery model is understood and compares with existing practices; 
• How each delivery model is locally adapted and translated into practice; 
• The acceptability and perceived sustainability of patient identification and referral routes; 
• Assessing barriers and enablers (and any unintended consequences) to implementation. 
As with patient interviews, the topic guide will be iteratively reviewed to incorporate issues not 
previously included, but which are relevant to the study.  With the respondents’ permission, 
telephone interviews will be digitally audio-recorded on a university provided encrypted audio 
device.  The researcher will write field notes (immediately following a telephone interview) to 
provide context to the transcribed interview data.  
4.3.2.4 
Analysis 
Interviews will be audio-recorded with consent, transcribed and thematically analysed using a 
modified framework approach and using NVivo software to manage the data. By ‘modified’ we 
mean that we will initially use the Framework approach to take an inductive approach to theme 
generation. Subsequent theme refinement will be deductive and guided by CFIR. This will 
enable us to produce a matrix of summarised data providing a structure for analysis. The 
overarching implementation analysis will then explore professional perceptions and attitudes 
towards inclisiran and each model of delivery; consider initial and enduring challenges as well 
as any unintended consequences arising from implementation. The analysis will then consider 
their wider ‘transactability’ of each delivery model namely the active ingredients in the form of 
structures, resources and processes required to enable successful delivery elsewhere.  
4.3.3 
Level 3: Exploring wider system readiness for inclisiran 
4.3.3.1 
Design and setting 
We will conduct telephone interviews with NHS commissioners and regional and national 
policy makers to explore the wider ‘transactability’ of the proposed delivery models for 
inclisiran beyond the auspices of the trial setting.  
4.3.3.2 
Sampling and recruitment 
A mix of purposive and snowball sampling techniques will be used to recruit respondents. We 
expect to conduct a minimum of 10 interviews in this  phase. We anticipate that interviews will 
include NHS commissioners, and representatives from the Academic Health Science Network, 
NHS England and the NHS Accelerated Access Collaborative. We will work with Health 
Innovation Manchester to identify potential targets for interview. Once identified, we will send 
potential respondents an email inviting them to take part in an interview (with the participant 
information sheet attached). Reminder emails will be sent to non-responders. Snowball 
recruitment may be employed if additional names are provided by participants.   


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4.3.3.3 
Data collection 
Telephone interviews will be arranged for a time/day to suit the respondent. Interview topic 
guides will again be informed by CFIR and will explore the strategic vision for innovation 
uptake in the NHS generally and views on and preferences for the delivery models to be 
implemented specifically. In doing so, interviewees will be asked to consider issues relating the 
wider ‘transactability’ of the proposed delivery models for inclisiran beyond the auspices of the 
trial setting. This will include necessary structures, resources and processes as well as preferred 
forms of reimbursement. 
4.3.3.4 
Data analysis 
Initial analysis will follow a similar approach to the provider interviews above from which a 
blueprint of how to implement inclisiran more widely will be generated. This blueprint will 
combine data from all three levels of inquiry with implementation costs and outcomes to 
identify the ‘core enabling ingredients’ and preferred model of service delivery deemed 
necessary to support the uptake of inclisiran across the NHS. 
Implementation costs will be largely made up of the time and resources required to deliver each 
inclisiran model. The costs of health professional input will be based on national average rates 
using 
PSSRU 
(Personal 
Social 
Services 
Research 
Unit) 
estimates 
(https://www.pssru.ac.uk/project-pages/unit-costs/). The length of each clinical encounter will 
be collected and coded to each practice, and costed on the basis of the full economic costs of 
the staff involved. Estimates of the additional time required from the general practice staff will 
be obtained. These unit costs will then be multiplied by the time spent recorded in the call log 
or timesheet during the trial period to estimate the costs of delivering each model. The data will 
be used to construct models of the potential implementation costs from a Clinical 
Commissioning Group perspective and how these costs may vary with different levels of 
implementation. 
4.3.4 
Standards of reporting 
We will adhere to recommendations of the EQUATOR Network (Enhancing the QUAlity and 
Transparency Of health Research) for transparent and accurate reporting and wider use of health 
research. The standards for reporting qualitative research (SRQR) guidance will be used to 
ensure rigorous reporting of the process evaluation.  
Without sufficient detail, it can be difficult for other interested parties to determine what was 
actually implemented and/or for others to use or replicate the intervention in other studies or 
settings. We will ensure the quality of intervention description for each delivery model through 
use of the Template for Intervention Description and Replication (TIDieR) checklist. 
4.4 
Patient identification and recruitment process 
4.4.1 
Cohort finding solutions 
In addition to lipid profile and implementation outcomes, this trial also seeks to inform NHS 
England (NHS-E) on appropriate patient identification strategies that may be used to identify 
and treat the estimated 300,000 patients in England with established ASCVD and LDL-C 


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>2.6mmol/L  that could benefit from treatment with inclisiran. It is anticipated that this delivery 
will be in primary care via GPs but working in collaboration with other HCPs.  Therefore, 
patient identification and recruitment processes are an important component of the study design. 
The challenges to identifying this patient population are:  
• Consistency of query generation 
GP systems have the capability to create queries based on coded information within the system. 
There are four GP system suppliers in the UK. Queries can be generated at system wide level 
but are more commonly done at a local / federation level. There is no guarantee of consistency.  
• Incomplete coded data at GP level  
Work previously conducted between NWEH and The Medicines Company (MDCO) 
demonstrated that a significant number of events for patients with ASCVD which occurred in 
secondary care were not coded in primary care.  
• Identifying the intervention resistant population  
Understanding how to access and engage with those patients who resist intervention and are 
likely to be the most in need of a cholesterol lowering medication, and gain the greatest benefit.   
4.4.2 
Patient identification in this study 
The study will be conducted in primary care centres across Greater Manchester with a network 
of research ready GPs. Eligibility and recruitment to the study will be optimised by using 
NWEH’s proven Feasibility Assessment and Recruitment System for Improving Trial 
Efficiency (FARSITE) for identification and recruitment at participating GP practices (see 
Section 8.2).   
FARSITE uses coded GP data to create a single query run across participating practices over a 
de-identified data set. Using the primary care data set and outcomes from initial recruitment 
phases as ‘training data’, NWEH will apply its machine learning tools to understand how the 
recruitment can be refined by modelling for missing data around secondary care events.  This 
modelling will look at data beyond the clinically coded data directly related to ASCVD and will 
include other comorbidities and social determinants as recorded in GP data.  
FARSITE will be used to identify the most suitable GP practices within Greater Manchester by 
ascertaining the maximum number of patients from up to 30 GP practices that meet the inclusion 
criteria. Once the list of potential patients per practice has been identified, the GP will review 
the patient’s medical records manually to confirm eligibility for the study against the inclusion 
/ exclusion criteria (Section 5.1).   
There may be occasions for individual GP practices to use their local electronic health record 
(EHR) to run local searches to identify eligible participants.  Such use of EHR searches would 
only be in exceptional circumstances as part of business contingency planning to minimise 
impact of a slower than expected recruitment rate on study delivery. 
In the event of a global health disruption event, such as a pandemic/epidemic (e.g. COVID-19), 
that limits or restricts access to Greater Manchester primary care centres, there may be occasion 
that primary care centres are identified which are located in the surrounding geographical area 
of Greater Manchester, however this would only be in exceptional  circumstances. 


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Following their review of the list of potential patients, the GP will write to eligible patients 
inviting their participation in the study using the REC approved invitation letter and brief patient 
information sheet (PIS). This process of inviting potential participants will optimised using the 
FARSITE Recruitment tool. The invitation letter will give clear instructions as to the study 
requirements, as well as the details of the study team so that interested patients can easily 
contact the appropriate person directly if they wish to participate in the study. Once the 
invitation letter and brief PIS have been sent out to the patient, a follow-up telephone call from 
either the patient’s GP or delegate will be completed to confirm receipt and establish the 
patients’ interest in the study. Patients which express an interest will be sent the full PIS and 
invited to attend a screening visit.  
4.5 
Treatment groups and outcome assessments   
Participants will be required to attend at least three study visits, including a baseline/screening 
visit, a Day 90 visit and an end of study visit (EOS) during the study period. Participants 
randomised to Group 1 do not need to attend the Day 1 visit but can receive a phone call instead. 
Visits will be planned in accordance with the timings described in the Assessment Schedule 
(see Table 8-1) 
 At the baseline visit/screening on receipt of a signed consent form, eligible participants will be 
randomised to one of the three treatment groups:  
• Group 1: Participants will continue to receive their background lipid lowering therapy 
(see Section 6.1.2 plus behavioural support (see Appendix 1)). 
• Group 2: Participants will continue to receive their background lipid lowering therapy 
(see Section 6.1.2), plus inclisiran for injection (delivered in an injection-only model). 
• Group 3: Participants will continue to receive their background lipid lowering therapy 
(see Section 6.1.2), plus inclisiran for injection (delivered in an injection-only model), 
plus behavioural support (see Appendix 1). 
In order to confirm the efficacy findings from the phase III inclisiran studies in the primary care 
setting, Group 1 will form an enhanced control group. Participants in this group will continue 
to receive their background lipid lowering therapy optimised by monthly telephone based 
behavioural support programme delivered throughout the study period.  
Participants randomised to Group 2 and Group 3 will be administered a single SC 300mg 
inclisiran injection at predefined time points described in the visit schedule and assessments 
(Section 8).  The HCP who administers each dose of inclisiran for participants randomised to 
Group 2 and Group 3 will be decided by the GP PI at each site, in common with clinical practice 
within that primary care setting.  Therefore, inclisiran may be administered by a GP, practice 
nurse, practice pharmacist or delivered and administered by a homecare team (Figure 4-2).  
Participants receiving inclisiran administered by a GP, practice nurse or practice pharmacist 
will be required to attend their GP practice or local Hub for administration of the study drug. 
The homecare team will administer inclisiran to participants in their own home setting. These 
visits will be performed by experienced HCPs with anaphylaxis training and following local 
guidelines and SOPs. This approach to recruitment is to enable participants who ordinarily may 
be unable to attend the GP practice due to a debilitating condition or travel burden to be involved 


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in the study.  If a participant receives the study medication at home the lipid profile test at Day 
90 will also be performed at home. 
In the event of a global health disruption event, such as a pandemic/epidemic (e.g. COVID-19), 
that limits or prevents access to the GP practice, an alternative qualified research site already 
participating in the study may be used to conduct study activities per protocol. 
All participants will receive a point of care blood test (see visit schedule in Section 8) to assess 
changes in lipid profile during the study.    
All participants will be required to complete patient reported outcomes (PROMs) as part of the 
study. The CSQ-8 and PAM validated PROMs questionnaires and/or the 
 
(Appendix 2
) will be provided to the study participant following their clinic visit. The 
participant is able to complete the questionnaire away from the clinical setting, thus providing 
the participant with sufficient space and time. Participant’s refusal to complete all or any part 
of a PROM should be documented in the study data capture system and should not be captured 
as a protocol deviation.  
The questionnaires will be returned to NWEH’s research office in a stamped addressed 
envelope, for transcription into the eCRF.  The questionnaires will be reviewed for 
completeness by the study team and participants contacted to ascertain any missing responses, 
the data will then be transcribed on to the eCRF.  Unreturned questionnaires will be followed 
up twice at 2-weekly intervals. 
Quantitative and qualitative methods (see Section 4.3) will be used to explore patient experience 
and adherence to the different models of care. 
 
 
These will be based on existing validated PROMS 
questionnaires used for other conditions (see Appendix 4). 
Any adverse events reported on a returned questionnaire will be assessed against the SAE 
reporting criteria for this study (Section 10) by the investigator or delegate and reported 
accordingly. 
NWEH’s ConneXon trials platform will be utilised for remote safety monitoring with minimal 
intervention, thereby reducing patient visits and maintaining real-world conditions for 
participants. Using this technology all 
 and serious adverse events (SAEs) 
will be alerted to the study team and reported to the sponsor within 24 hours of awareness. 
4.5.1 
Rationale for choice of background therapy 
Participants taking part in this clinical study will continue to receive guideline recommended 
standard of care as background therapy (including statin therapy and/or other LDL-C lowering 
therapies). 
4.5.2 
Rationale for dose/regimen and duration of treatment 
Previous studies have shown that a 300 mg dose of inclisiran sodium is well tolerated and 
provides maximum efficacy (i.e. doses higher than 300 mg did not provide additional efficacy 
in LDL-C lowering) (See Section 1.1.4). The 300 mg dose of inclisiran will be administered on 
Day 1 and Day 90. Modelling and simulation has demonstrated that this regimen will allow for 
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the necessary robust and sustained reduction in PCSK9 (and LDL-C) and has the potential to 
tackle the lack of adherence generally seen in the chronic management of subjects with 
hypercholesterolemia. The 300 mg dose of inclisiran will be used for the entire duration of this 
study for participants receiving inclisiran.  
4.5.3 
Rationale for choice of comparator arm 
Inclisiran is expected to receive regulatory authority approval for use in addition to current 
standard of care for lipid management.  Data from the UK healthcare environment shows that 
around 98% of patients with an LDL-C of >2.6mmol/L receive treatment with a statin as their 
standard of care.  As lipid treatment should be accompanied by dietary and lifestyle advice, it 
was therefore appropriate for the comparator arm in this study to be standard of care for lipid 
management plus access to behavioural support.  
Figure 4-2 
Schematic of study design  
 
4.6 
Risks and benefits 
Participants taking part in this study will continue to receive guideline recommended standard 
of care as background therapy (including statin therapy and/or other LDL-C lowering therapies) 
when administered inclisiran. Patients in this study will receive access to behavioural supportive 
care and/or inclisiran, and some degree of improved lipid management is expected in each 
treatment group.  Reductions of LDL-C have been associated with reduced CV risk both by 
epidemiology and in controlled clinical trials (see Section 1.1.4).  


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To date, injection site reaction is the only adverse drug reaction that has been attributed to 
inclisiran treatment. None of the reported injection site reactions were considered to be serious. 
The risk to participants in this trial may be minimised by compliance with the eligibility criteria 
and study procedures, as well as close clinical monitoring.  
Where possible, endpoint data will be recorded and captured utilising the participant’s  
electronic medical record, and study interventions will be kept to a minimum, in keeping with 
the implementation research methodology.  
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. 
Overall, the risk-benefit of inclisiran is favorable for this clinical trial.  
An expanded risk-benefit summary is provided in the Investigational Brochure.  
4.6.1 
Blood sample volume 
A capillary blood sample will be taken for immediate analysis of the participants’ lipid 
profile
 at the initial screening/baseline visit, day 90 and again at the end of study 
(EOS) visit.  A point of care testing machine will be used.  
Additional blood samples may be required for safety monitoring. 
Timings of blood sample collection are outlined in the assessment schedule (Section 8, Table 
8-1). 
5 
Study Population 
A total of 900 participants (300 per treatment group) at up to 30 primary care centres in the 
localised geographical region of Greater Manchester will be required for this study. The total 
duration of participant participation will be approximately 9 months (270 days). 
This study will include male or female participants ≥18 years of age, who are on established 
lipid lowering medication, or have been recommended lipid lowering therapy by their health 
care provider but are unable to tolerate treatment. 
Generalisability of the study population to the UK is essential; therefore, the study will be 
performed in a primary care setting across Greater Manchester and patients will be recruited by 
their GP. The Quality and Outcomes in Primary Healthcare clinical indicators (QOPH) 
demonstrate that chronic disease prevalence in Greater Manchester is comparable to the UK 
population as a whole (QOPH, 2018). Key data supporting the generalisability to the UK 
population is presented in Appendix 5.  
 
 
 
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5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study. 
2. Male or female participants ≥18 years of age. 
3. Patients on established lipid lowering medication, or have been recommended lipid 
lowering therapy by their health care provider but are unable to tolerate treatment. 
4. A total cholesterol measurement at screening that is ≥4 mmol/L [approximately 160 
mg/dL].  
5. Participants on lipid-lowering therapies should be on a stable dose for ≥30 days before 
screening with no planned medication or dose change. 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. Medical or surgical history that might limit the individual’s ability to take study 
treatments for the duration of the study and/or put the participant at significant risk (e.g. 
severe respiratory disease; cancer or evidence of spread within approximately the last 5 
years, other than non-melanoma skin cancer; or history of alcohol or substance misuse). 
2. Current or planned renal dialysis or transplantation. 
3. Acute coronary syndrome or stroke less than 4 weeks before the screening visit. 
4. Coronary revascularization procedure planned within the next 6 months.  
5. Women of child-bearing potential, unless they agree to abstinence or, if sexually active, 
agree to the use of effective methods of contraception during the study.  The effective 
contraception methods are one of the following: 
• Barrier method of contraception (male or female condom or occlusive cap (diaphragm 
or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository 
• Other more effective forms such as oral (estrogen and progesterone), injected or 
implanted combined hormonal methods of contraception or placement of an 
intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception or total abstinence or male/female 
sterilisation 
6. Women who are pregnant or breast-feeding. 
7. Previous, current, or planned treatment with a monoclonal antibody targeting PCSK9, or 
with a drug known to be contra-indicated with inclisiran. 
8. Previous exposure to inclisiran or participation in a randomised study of inclisiran. 
9. Current or previous participation in a clinical study with an unlicensed drug or device 
within 30 days or five half-lives of the screening visit, whichever is longer. 
10. Participants who plan to move away from the geographical area where the study is being 
conducted during the study period. 
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6 
Treatment 
6.1 
Study treatment 
The study treatment, Inclisiran for Injection (SC use), is a sterile formulation of inclisiran 
sodium in water for injection packaged in vial or glass pre-filled syringe (PFS) presentations.  
The covid-19 vaccination should not be given within 7 days of receiving IMP.   
6.1.1 
Investigational drug 
Table 6-1 
Investigational drug 
Product Name: 
Inclisiran  
Active ingredient 
Inclisiran sodium 
Dosage Form: 
Solution for Injection 
Unit Dose 
Inclisiran sodium 300 mg/1.5 mL vial (equivalent to 284 mg inclisiran) 
Route of 
Administration 
Subcutaneous (SC) use 
Physical Description 
Clear, colorless to pale yellow solution essentially free of particulates 
Manufacturer 
Alcami Corporation, Charleston, South Carolina, United States of 
America. 
6.1.2 
Additional study treatments 
Participants should be receiving a lipid-lowering therapy (such as a statin and/or ezetimibe) as 
background therapy, and should be on a stable dose for ≥30 days before screening with no 
planned medication or dose change prior to randomisation.  This treatment will be provided as 
part of normal clinical practice. 
Patients who have been recommended lipid lowering therapy by their HCP but are not able to 
tolerate their treatment are also eligible for this study.  These patients may receive treatment 
with inclisiran alone and the proportion of these patients included in the study will be reported 
in patient demographics.  
6.1.3 
Treatment groups 
Participants will be assigned at the baseline/screening visit to one of the following three 
treatment groups in a ratio of 1:1:1. 
• Group 1: Participants will continue to receive their lipid-lowering background therapy 
plus behavioural support (see Appendix 1) 
• Group 2: Participants will continue to receive their lipid-lowering background therapy 
plus inclisiran for injection (delivered in an injection-only model) 
• Group 3: Participants will continue to receive their lipid-lowering background therapy, 
plus inclisiran for injection (delivered in an injection only model), plus behavioural 
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6.1.4 
Post-Trial Access 
It is anticipated that inclisiran will have received regulatory authority approval and will be 
available for HCPs to prescribe at the point at which this study ends.  The investigator at each 
site should therefore determine whether the patient has derived clinical benefit and should be 
prescribed inclisiran as part of normal clinical practice following the end of the study. If 
regulatory authority approval has not been gained patients will revert back to standard of care 
following medication review by their GP.  
6.1.5 
Concomitant therapy  
As this is a pragmatic trial, all medications, procedures, and significant non-drug therapies 
(including physical therapy and blood transfusions) administered after the participant was 
enrolled into the study will be collected from the EMR to inform the outcomes of the study.  
Only relevant concomitant medications related to an AE will be manually entered in the eCRF. 
Table 6-2 
Therapy derived data 
Concomitant therapy 
Data to be entered into 
eCRF 
Automated data collection 
(primary and secondary via 
available national datasets) 
Demography  
X 
 
Relevant medical 
history/current medical history  
 
X 
Composite cardiovascular risk 
X 
 
HbA1c 
 
X 
Lipid profile
 
X 
 
Adverse Events  
X 
 
AE relevant concomitant 
medications and relevant 
medical history  
X 
 
Concomitant medications 
 
X 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
randomising a participant or allowing a new medication to be started. If the participant is already 
enrolled, contact Novartis/Sponsor to determine if the participant should continue participation 
in the study. 
The following medications/treatments are not permitted to be added to existing therapy during 
the study: 
• Medications prescribed to lower LDL-C (e.g. statins, ezetimibe, lomitapide, mipomersen, 
niacin, colesevelam, bile acid absorption inhibitors, monoclonal antibodies directed 
towards PCSK9).  
• Any medication taken for the purpose of lipid lowering, including over-the-counter or 
herbal therapies. 
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6.2 
Participant numbering, treatment assignment, randomisation  
6.2.1 
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 entire participation in the trial. The Participant No. consists of the Center 
Number (Centre No.), assigned by Novartis to the investigative site, with a sequential 
participant number suffixed to it, so that each participant is numbered uniquely across the entire 
database. Upon the participant signing the informed consent form, the participant is assigned to 
the next sequential Participant No. available. A new Participant No. will be assigned at every 
subsequent enrollment if the participant is re-screened.  
6.2.2 
Treatment assignment, randomisation  
At the baseline visit, all eligible participants will be randomised 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 fulfils all the inclusion/exclusion criteria. The IRT 
will assign a randomisation 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 randomisation numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased. A participant randomisation list will be produced by the IRT 
provider using a validated system that automates the random assignment of participant numbers 
to randomisation numbers. These randomisation 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 randomisation scheme for participants will be reviewed and 
approved by a member of the Randomisation Office. 
6.2.3 
Recruitment cap 
During recruitment the study team may consider it appropriate to cap the recruitment of patients 
who have an LDL-C <2.6mmol/L, in order to ensure the results remain generalisable for the 
purposes of NHS-E.    
6.3 
Dose escalation and dose modification 
Investigational or other study treatment dose adjustments and/or interruptions are not permitted. 
6.4 
Additional treatment guidance 
6.4.1 
Treatment compliance  
Participants assigned to Group 1 and Group 3 (See Section 6.1.3) will receive monthly 
telephone based behavioural support (see Appendix 1). As part of this programme, compliance 
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therapy. Participants in Group 2 and Group 3 (See Section 6.1.3) will be reminded to attend or 
be available for each administration of the study drug by the investigator or designated person. 
Participants will be encouraged to contact their GP practice if they miss their appointment.  In 
addition to this participants may receive SMS text reminders for their appointments from their 
GP practice, as is common with clinical practice.  
Adherence with study medication will be based on analysis of medications dispensed (for 
standard of care treatment) and administered (for inclisiran treatment) during the study. 
6.4.2 
Recommended treatment of adverse events 
At present there is insufficient information to provide specific recommendations regarding 
treatment of adverse events (AEs). 
Medication used to treat adverse events (AEs) must be recorded as appropriate within the eCRF 
(See Section 10). 
6.5 
Preparation and dispensation  
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section. 
A unique medication number is printed on the study medication label. 
As per the treatment assigned to the participant, investigator staff will select the study treatment 
to dispense to the participant. The study medication has a 2-part label (base plus tear-off label. 
Immediately before dispensing the package to the participant, site personnel will detach the 
outer part of the label from the package and affix it to the participant’s source document. 
6.5.1 
Handling of study treatment and additional treatment  
6.5.1.1 
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 Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number. 
The investigator 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 
monitors during site visits or remotely and at the completion of the trial.  
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
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accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site. 
6.5.2 
Instruction for prescribing and taking study treatment  
Study drug injections will be performed by qualified clinical staff delegated by the investigator. 
The site of injection is the abdomen; alternative injection sites include the upper arm or thigh. 
Injections should not be given into areas of active skin disease or injury such as sunburns, skin 
rashes, inflammation, tattoos or skin infections. 
Participants will be administered one s.c. injection of study drug at pre-defined visits as 
specified in the Assessment Schedule (Section 8) and summarised below. 
Participants randomised to group 2 or 3 will receive one injection of inclisiran on Day 1 and a 
second injection of inclisiran on Day 90.  
Injections will be administered after all other study assessments have been completed for the 
visit. 
Should a participant develop signs or symptoms of anaphylaxis when study drug is injected, the 
investigator or delegate will need to collect a blood sample for tryptase within 30 minutes of 
the onset of anaphylaxis (or as soon as possible). 
All kits of study treatment assigned by the IRT will be recorded in the IRT system. 
7 
Informed consent procedures 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation) IRB/IEC-approved informed consent. 
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. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug 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 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. 
7.1 
Participants who will be asked for consent 
The following patient informed consents are included in this study: 
• Main study consent, which also includes:  


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• Consent for patients to be contacted to participate in the Process Evaluation 
component of this study (as described in Section 4.3) 
• As applicable, Pregnancy Outcomes Reporting Consent for female participants  
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. 
Male participants must be informed that if a female partner becomes pregnant while he is 
enrolled in the study, contact with the female partner will be attempted to request her consent 
to collect pregnancy outcome information. 
The following Healthcare Professional and Commissioner consents are included in this study: 
• Up to 50 HCPs and a minimum of 10 Commissioners will be approached for to participate 
in the Process Evaluation component of this study (as described in Section 4.3) 
• HCPs and Commissioners will be asked to give consent for their participation in this 
element of the study prior to the Process Evaluation interviews (Section 7.2). 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
7.2 
Remote consent 
In the event of a global health disruption event, such as a pandemic/epidemic (e.g. COVID-19), 
that may challenge the ability to obtain a standard written informed consent due to limits that 
prevent an on-site visit, the Investigator may conduct the informed consent discussion remotely 
(e.g. telephone, video conference). 
7.3 
Informed consent procedures for the process evaluation 
All potential research respondents (patients, HCPs or Commissioners) who are recruited for 
telephone interviews as part of the process evaluation will receive verbal and written 
information (participant information sheet) regarding the study and will be encouraged to ask 
questions prior to taking part.  It will be made clear that participation in the interview is purely 
voluntary and respondents are able to withdraw from the interview at any time, without giving 
a reason.  Following the consent outlined above verbal consent will be confirmed before 
undertaking the telephone interview which we will audio-record separately to the interview 
audio-recording. 
7.3.1 
Confidentiality and anonymity 
Once a participant (patient, HCP or Commissioner) gives consent to participate in the process 
evaluation, they will be provided with a unique identifier.  This unique identifier is assigned for 
the purposes of the process evaluation.  Audio recordings and transcriptions will be identified 
only by their unique identifier and not the name of the respondent.  The key to the unique 
identifier and respondent’s details will only be accessible to members of the study team and 
stored electronically on the University of Manchester secure server, separate to the de-identified 
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Transcription of audio-recordings will be undertaken by a University of Manchester approved 
external transcription company.  Audio recordings will be uploaded to the transcription 
company via a secure server.  We will remove any personal identifying information (such as 
names, places) from transcriptions once they are returned. 
8 
Visit schedule and assessments 
The Assessment Schedule (Table 8-1) lists all of the assessments and when they will be 
performed. 
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1) or as close to the designated day/time as possible. Missed or rescheduled visits 
should not lead to automatic discontinuation. Participants who prematurely discontinue the 
study for any reason should be scheduled for a visit as soon as possible, at which time all of the 
assessments listed for the final visit will be performed. At this final visit, all dispensed 
investigational product should be reconciled. 
8.1 
Domiciliary visits 
In the event of a global health disruption event, such as a pandemic/epidemic (e.g. COVID-19), 
that limits or prevents the conduct of site study visits per protocol, special effort should be made 
to conduct on-site visits. If it is not feasible to conduct on-site visits, visits to the patient’s home 
can be attempted. These visits will be performed by experienced HCPs with anaphylaxis 
training and following local guidelines and SOPs. 
Table 8-1 
Assessment schedule  
Period 
Screening 
Treatment 
 
Visit Name 
Screening/ 
Baseline 
Treatment Period 
End of Study 
Day 
(-14 to -1) 
Day 1 
(± 14 days) 
Day 90 
(± 14 days) 
Day 270 
 (± 14 days)  
Obtain informed consent 
X 
 
 
 
Demography 
X 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
Relevant / current medical history1 
 
Height 
X 
 
 
X 
Smoking Status  
X 
 
 
X 
Dietary advice status 
X 
 
 
X 
Exercise status 
X 
 
 
X 
HbA1c2 
X 
  
  
X 
Lipid profile
 
X 
 
X 
X 
Urine pregnancy test for WOCBP 
X 
 
 
 
Adverse Events4 
X 
 
Prior/Concomitant Medications5 
 
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Period 
Screening 
Treatment 
 
Visit Name 
Screening/ 
Baseline 
Treatment Period 
End of Study 
Day 
(-14 to -1) 
Day 1 
(± 14 days) 
Day 90 
(± 14 days) 
Day 270 
 (± 14 days)  
Patient Reported Outcomes (PAM) 6 
X 
 
X 
 
Patient Reported Outcomes (CSQ-8)6  
 
 
X 
 
Behavioural Support Programme7 
 
Participants in the inclisiran + behavioural support 
and standard of care + behavioural support arms 
will have access to this service throughout the 
study 
Process Evaluation8 
 
 
 
Study drug administration 
 
X  
X 
 
IWRS/IRT Registration/Randomisation 
X 
X10 
X 
X 
X = assessment to be recorded in the clinical database or received electronically from a vendor 
1 ConneXon Data Platform to automate regular collection from EMR. 
2 ConneXon Data Platform to automate collection of closest recorded value prior to the screening/baseline visit and EOS visit. 
3 Capillary sample to be taken for immediate analysis using a CardioChek device for analysis of lipid profile (
 
LDL-C and non-HDL). 
4 After screening/baseline visit all SAE’s will be monitored and collected using ConneXon Data Platform (see Section 10). 
5 Use of ConneXon Data Platform to automate regular collection from EMR. 
 
 
7 The behavioural support programme consists of a telephone based support service providing advice on diet, lifestyle, medication adherence, and 
CV risk management. Patients will have access to a scheduled programme of delivery 
8 Process Evaluation interviews will be carried out in line with the study visits at Day 1 and Day 90. 
 
 
10 Patients randomised to Group 1 do not need to attend this visit but can have a phone call instead 
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8.2 
Screening 
Screening (Days -14 to -1) 
Eligibility and recruitment to the study will be optimised by using NWEH’s proven feasibility 
and recruitment system FARSITE.   
FARSITE, is a tool for searching, finding, and contacting patients with research opportunities, 
whilst still preserving their confidentiality. The principle behind FARSITE is to maintain 
patient confidentiality by anonymising the information given to researchers, and only allowing 
GPs to decide whether their patient should be contacted. Researchers do not have access to 
individual patient records, information about individuals who meet the criteria for a protocol is 
only available to the patient’s GP practice.  All identifiable records are seen only by the GP as 
the data controller, and a handful of NWEH and Salford Royal Foundation Trust (SRFT) 
technical staff by exception to maintain the FARSITE system. Researchers see only de-
identified records, as the datasets are held in two different databases stored securely on the N3 
NHS network (see Figure 8-1). 
Figure 8-1 
FARSITE System Overview  
 
NWEH researchers will use the FARSITE Feasibility view which contains anonymised data 
during the initial stages of recruitment to see how many patients match the study protocol; the 
numbers of patients matching each inclusion criterion; and the numbers belonging to each 
registered GP practice. FARSITE will identify and be used to contact the most suitable GP 
practices within Greater Manchester to ascertain the maximum number of patients from up to 
30 GP practices. Once the list of potential patients is identified, the GP will review the patient’s 
medical records manually and confirm eligibility.  There are no screening laboratory tests 


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required to be performed for this study, total cholesterol inclusion criteria will be determined 
by the pathology results available in the patients EMR.   
The following procedures will be performed within 14 days prior to study treatment: 
• Informed consent 
• Assessment of inclusion and exclusion criteria 
• Demographics  
• Vital signs (
 height, 
) 
• CV risk (smoking status, diet, exercise, HbA1c if available) 
• Lipid profile
 
• Randomisation  
It is permissible to re-screen a participant if s/he fails the initial screening; however, each case 
must be discussed and agreed with the Sponsor on a case-by-case basis and can be only once 
per patient during the study period. 
8.2.1 
Information to be collected on screening failures 
Participants who sign an informed consent form and are subsequently found to be ineligible 
prior to randomisation will be considered a screen failure. The reason for screen failure should 
be recorded on the eCRF. 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 phase (see SAE section for 
reporting details). If the participant fails to be randomised, the IRT must be notified within 2 
days of the screen fail that the participant was not randomised. 
Participants who are randomised and fail to start treatment, e.g. participants randomised in error, 
will be considered an early terminator. The reason for early termination should be recorded on 
the appropriate eCRF. 
8.3 
Participant demographics/other baseline characteristics 
Baseline demographic information will be collected during screening/baseline visit and will 
include age, sex and race/ethnicity. These data will be recorded in the eCRF.  
Relevant medical and surgical history recorded within the last 5 years will be extracted from 
the EMR from the date of consent. (see Section 6.1.5 Table 6-2) 
Concomitant medication taken within the last 5 years will be extracted from the participants’ 
primary care EMR from date of consent.  
Cardiovascular risk assessment  
Information required to assess composite cardiovascular risk will include;  
 
   
 
   
• Height - measured at screening/baseline visit and EOS visit   
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• Smoking status -collected at screening/baseline visit and EOS visit   
• Dietary advice status -collected at screening/baseline visit and EOS visit   
• Exercise status (calculated using Physical Activity Index (PAI) see Appendix 6) - 
collected at screening/baseline visit and EOS visit   
These data will be recorded in the eCRF. 
• HbA1c- if available the closest recoded value prior to the screening/baseline visit and EOS 
visit to be extracted from the EMR.  
8.4 
Efficacy Assessments  
Lipid Profile
 
A capillary blood sample will be taken for immediate analysis of the participant’s lipid 
profile
 for assessment of efficacy. This will be performed at screening/baseline 
visit, day 90 visit and EOS (day 270) visit (see Assessment Schedule Table 8-1).  
Parameters to be assessed include: 
 
 
 
 
 
  
• Non-HDL (calculated) 
• LDL-C calculated using Friedewald 
These data will be recorded in the eCRF 
Patient Reported Outcomes Questionnaires 
The Client Satisfaction Questionnaire and Patient Activation Measure (PAM) questionnaire 
will be administered after treatment at day 90.  Patients will take the questionnaires to complete 
after the study visit and return them via post. 
The Process Evaluation 
The process evaluation will be conducted by Manchester University using the Consolidated 
Framework for Implementation Research (CFIR). 
8.4.1 
Efficacy assessment - Primary 
• Percentage change in LDL-C from baseline to day 270 
8.4.2 
Efficacy assessment - Secondary 
• CSQ administered after treatment at day 90. 
• PAM questionnaire administered after treatment at day 90. 
• Process evaluation 
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8.5 
Safety 
8.5.1 
Pregnancy 
Females of child-bearing potential are defined as all females physiologically capable of 
becoming pregnant. 
Serum/urine pregnancy tests will be performed for all females of child-bearing potential 
according to the Assessment Schedule (Table 8-1). A positive urine pregnancy test should be 
confirmed with a serum pregnancy test. Additional pregnancy tests may be performed at the 
investigator’s discretion during the study and/or if requested by local requirements. 
Participants becoming pregnant must be discontinued from study drug. However, a participant 
may choose to remain in the study should she become pregnant, and be followed according to 
the protocol-defined study visits. 
8.5.2 
SAEs 
All SAEs whatever the causal relationship to the research, AEs leading to study treatment 
discontinuation and other situations relevant to the safety (pregnancy and treatment errors) (see 
Section 10.3.4. and 10.3.5) of the participants must be followed up and fully and precisely 
documented in order to ensure that the sponsor has the necessary information to continuously 
assess the benefit-risk balance of the clinical trial. 
8.6 
Laboratory assessments  
There are no regular laboratory tests required by this protocol. All blood tests will be performed 
locally by clinical pathology laboratories, in common with usual practice. Methods for 
sampling, handling and analysis will be the same as usually applied in routine care. 
Abnormal laboratory findings, that are detected during the study or are present at baseline and 
significantly worsen following study drug administration, and are deemed as clinically 
significant by the investigator will be recorded as AEs if they lead to treatment discontinuation 
(or SAEs if they meet the definition see Section 10). 
9 
Study discontinuation and completion 
9.1 
Discontinuation and completion 
9.1.1 
Study treatment discontinuation and study discontinuation 
Discontinuation of study treatment for a participant occurs when study treatment is stopped 
earlier than the protocol planned duration 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. 
Study treatment must be discontinued under the following circumstances: 
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• Pregnancy 
• Use of prohibited treatment as per recommendations in the prohibited treatment section 
• Any situation in which study participation might result in a safety risk to the participant 
 
Emergence of the following adverse events:  
• Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the participant’s overall status, prevents the participant from continuing 
participation in the study 
• Severe hypersensitivity reaction occurs, including the following: anaphylaxis 
associated with, fever, chills, urticaria, dyspnea, headache, myalgia, hypotension.  
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s premature discontinuation of study 
treatment and record this information. 
Participants who discontinue study treatment should NOT be considered withdrawn from the 
study UNLESS they explicitly withdraw their consent (see Section 9.1.2 Withdrawal of 
Informed Consent' section). Where possible, they should be encouraged to return for the 
assessments indicated in the Assessment Schedule. If they fail to return for these assessments 
for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be made to contact the 
participant/pre-designated contact as specified in the lost to follow-up section. This contact 
should preferably be done according to the study visit schedule. 
Participants who discontinue treatment without withdrawing consent are effectively allowing 
use of their data via the electronic system for the purposes of evaluating many of the study 
endpoints, e.g. for the equivalent of the protocol-defined 9 month study interval. 
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 
Participants who discontinue study treatment or withdraw consent from the study will not be 
replaced. 
9.1.2 
Withdrawal of informed consent 
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time.  
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 his/her consent and 
record this information. 
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. 


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All efforts should be made to complete the assessments prior to study discontinuation. A final 
evaluation at the time of the participant’s study discontinuation should be made as detailed in 
the assessment table. 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation. 
9.1.3 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw, 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. 
9.1.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time. 
Reasons for early termination: 
• 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 drug 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 prematurely withdrawn participant. 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 sponsor depending on local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial.  
9.2 
Study completion and post-study treatment 
Study completion is defined as when the last participant finishes their EOS visit and any repeat 
assessments associated with this visit have been documented and followed-up appropriately by 
the Investigator or, in the event of an early study termination decision, the date of that decision. 
All randomised and/or treated participants will be remotely monitored for safety events using 
ConneXon trials platform 30 days after their EOS visit. All SAEs reported during this time 
period must be reported as described in Section 10. 
Continuing care should be provided by the investigator and/or referring physician based on 
participant availability for follow-up. 
This care may include: 
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10 
Safety monitoring and reporting 
10.1 
Definition of adverse events  
10.1.1 
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. 
10.1.2 
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 ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalisation or prolongation of existing hospitalisation, unless 
hospitalisation is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition  
• 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 form 
• 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 jeopardises 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 hospitalisation but might jeopardise 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 hospitalisation or development of dependency or abuse (please refer to the ICH-
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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. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.  
10.2 
Reporting requirements for adverse events  
In this study, only SAEs will be detected, documented and reported. AEs leading to treatment 
discontinuation will be documented. 
• The investigator or delegate has the responsibility for managing the safety of individual 
participants and identifying and reporting events that meet the definition of AE leading to 
treatment discontinaution, and SAEs.  
• Novartis qualified medical personnel will be readily available to advise on trial related 
medical questions or problems. 
• NWEH’s ConneXon trials platform will be utilised for remote safety monitoring. Using 
this technology all 
 SAEs will be alerted to the study team.  SAEs will 
be reported to the sponsor within 24 hours of awareness. 
• AEs also may be detected when they are volunteered by participants during or between 
visits or other assessments such as when the patient reported outcomes questionnaires 
(CSQ-8, PAM 
) are returned to the study team (see 16.2 Appendix 2: The 
CSQ-8 PROMs Questionnaire, 16.3 Appendix 3: The PAM PROMs Questionnaire and 
16.4 Appendix 4:
). 
10.3 
Collection and assessment of adverse events  
10.3.1 
Adverse event severity  
The severity of AE will be assessed by the investigator or delegate.  
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
10.3.2 
Relationship to study treatment 
The relationship between the AE and the investigational product will be assessed using a binary 
assessment. The investigator should determine whether there is a reasonable suspected causal 
relationship to the medicinal product based on the definitions below: 
• Suspected relationship - There is a reasonable possibility that the administration of the 
investigational product caused the AE. There is evidence to suggest a causal relationship 
between the investigational product and the AE  
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• Not suspected relationship- There is no reasonable possibility that the administration of 
the investigational product caused the AE. There is no temporal relationship between the 
investigational product and event onset, or an alternative etiology has been established 
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 
• Its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported 
• Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
• Action taken regarding study treatment. 
The Investigator will have the ultimate responsibility for determining causality and seriousness.  
In the interim period, until the Investigator review, the opinion of the appropriately delegated 
research nurse will be used for collecting and reporting. If the research nurse suspects a causal 
relationship to an AE, this will be escalated to the Investigator for immediate review.  
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 
• Dose not changed 
• Drug interrupted/withdrawn 
• Its outcome (i.e. recovery status or whether it was fatal) 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at regular 
intervals 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). 
Adverse event monitoring should be continued for at least 30 days following the EOS visit. 
10.3.3 
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 EOS visit must be reported to Novartis 
safety within 24 hours of learning of its occurrence.  
Detailed instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site. 


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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 
within 24 hours of the investigator or delegate receiving the follow-up information. 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, 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 EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
Any SAEs experienced after the 30 day period should only be reported to Novartis Safety if the 
investigator suspects a causal relationship to study treatment. 
10.3.4 
Pregnancy reporting 
Pregnancies 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
trial participant must be asked to read and sign a pregnancy consent form to allow the 
investigator to ask about her 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 until one year after birth 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 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 and pregnancy outcome. Any SAE experienced 
during pregnancy must be reported. 
10.3.5 
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 HCP, participant or consumer (European 
Medicines Agency (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. 


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Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate eCRF irrespective of whether or not associated with an AE/SAE and reported 
to Safety only if associated with an SAE. 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. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
eCRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE leading to 
treatment 
discontinuation 
Only if associated with 
an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
11 
Data Collection and Database management 
11.1 
Data collection 
Data not requiring a separate written record will be defined in the protocol and the Assessment 
Schedule (Section 8, Table 8-1) and can be recorded directly on the eCRFs. All other data 
captured for this study will have an external originating source (either written or electronic) 
with the eCRF not being considered as source. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
Designated investigator staff will enter the data required by the protocol into the participant 
casebooks within the Electronic Case Report Form (eCRF). The eCRF has been built using fully 
validated secure web-enabled software that conforms to 21 CFR Part 11 requirements, research 
staff will not be given access to the eCRF until they have been trained. Automatic validation 
programs check for data discrepancies in the eCRF, allow modification and/or verification of 
the entered data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (entered into the 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 of the eCRF, the investigator will receive copies of the participant data 
for archiving at the investigational site. 
This study will also use electronic technology to collect source data automatically, using an 
electronic system (the “Data Platform”) to capture source data files. Information to be originally 
captured and controlled via automated means includes medical histories, concomitant 
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study. Data collected automatically in this way will be used for both remote monitoring of 
subject safety, and for study data analyses. Research staff have no access to the Data Platform 
system. 
Both the eCRF and the Data Platform systems meet the fundamental elements of data quality 
(e.g. attributable, legible, contemporaneous, original, and accurate) that are expected of paper 
records in FDA guidance, are fully validated and conform to 21 CFR Part 11 requirements.  
11.2 
Database management and quality control 
Data will be entered into a fully validated study database by the NWEH study team. Central 
Data Management will be completed in line with NWEH Central Data Management and 
Monitoring procedures. 
Data Quality will be accomplished by a combination of automated data validation queries and 
manual Central Data Management completed by the NWEH Clinical Data Management 
(CDM). 
All eCRF forms will require monitoring by the CDM and marking as Data Quality Review 
Complete. 
Queries are raised within the eCRF and their response and resolution will be managed by the 
CDM within defined timelines. Designated research staff are required to respond promptly to 
queries and to make any necessary changes to the data. 
PROM questionnaires will be completed by participants in a paper format, and reviewed for 
completeness by the study team and then transcribed in to the eCRF.  
Events, interventions and findings derived from the electronic data will be collected and 
converted into Structured Data Tabular Model (SDTM) by NWEH before sending to Novartis 
for analysis. Medical history/current medical conditions and adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA) terminology by Novartis and 
NWEH.  
Dates of screenings, randomisations, screen failures and study completion, as well as 
randomisation codes and data about all study treatment (s) dispensed to the participant will be 
tracked using an Interactive Response Technology (IRT). The system will be supplied by a 
vendor, who will also manage the database. The data will be sent electronically to Novartis and 
NWEH at specific timelines. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked. Any changes to the database after that time can only 
be made after written agreement by Novartis development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis/ 
representative will review the protocol and data capture requirements (i.e. eCRFs) with the 
investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and GCP compliance and the quality/integrity of the sites’ data. The field monitor will 
visit the site to check the completeness of participant records, the accuracy of data capture / 


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data entry, the adherence to the protocol and to Good Clinical Practice, the progress of 
enrollment, and to ensure that study treatment is being stored, dispensed, and accounted for 
according to specifications. 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 a 
centralised Novartis CRA organisation. Additionally, a central analytics organisation may 
analyse data & identify risks & trends for site operational parameters, and provide reports to 
Novartis clinical teams to assist with trial oversight. 
The investigator or delegate must maintain source documentation for each participant in the 
study, consisting of hospital or clinic electronic medical records containing demographic and 
medical information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to source documents in the EMR and 
participant's site file. The investigator must also keep the original informed consent form signed 
by the participant (a signed copy is given to the participant). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 
11.3.1 
Remote study initiation and monitoring visits  
In the event of a global health disruption event, such as a pandemic/epidemic (e.g. COVID-19), 
requiring social distancing or limited travel/attendance to site, remote site initiation and 
monitoring could be considered. 
12 
Data analysis and statistical methods 
Details of the statistical analysis and data reporting will be summarised in the Statistical 
Analysis Plan (SAP) document finalised before data lock. Any data analysis carried out 
independently by the investigator should be submitted to Novartis before publication or 
presentation. Efficacy and safety analyses will be performed after all participants have 
completed the Day 270 visit or discontinued prior to the Day 270 visit. All available data from 
the clinical database will be included in the analysis. 
12.1 
Analysis sets   
The Full Analysis Set (FAS) comprises of all randomised participants with the exception of 
those mis-randomised participants who did not receive study drug. Mis-randomised participants 
are defined as not qualified for randomisation and are inadvertently randomised into the study. 
According to the intent to treat principle, participants will be analysed according to the 
treatment they have been assigned to during the randomisation procedure. The FAS will be used 
in analyses for the primary, secondary, 
 efficacy objectives. 
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The Safety Set includes all participants who received at least one dose of study treatment. 
Participants will be analysed according to the study treatment received. This will be the primary 
population for the safety analyses. 
12.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including medical history will be summarised 
descriptively by treatment group for the FAS. 
Categorical data will be presented as frequencies and percentages by treatment group. For 
continuous data, non-missing observations, mean, standard deviation, median, minimum, and 
maximum will be presented. For continuous data, the 1st and 3rd quartile will also be presented 
by treatment group. 
Relevant medical histories and current medical conditions at baseline will be summarised 
separately by system organ class and preferred term, by treatment group. Histories of statin 
intolerance will be summarised by treatment group. 
12.3 
Treatments 
The Safety set will be used for the analyses below. 
The number of participants dosed at each dosing visit, number of study doses administered, 
duration of exposure in days, and dose administered will be summarised by treatment group.  
Lipid-modifying therapy use at screening and the baseline/Randomisation visit (Day 1) will be 
summarised by treatment group. New or changed lipid-modifying therapy after baseline will be 
summarised by treatment group. 
Other concomitant medications and significant non-drug therapies prior to and after the start of 
the study treatment will be summarised according to the Anatomical Therapeutic Chemical 
(ATC) classification system, by treatment group. 
12.4 
Analysis of the primary endpoint(s)/estimand(s) 
12.4.1 
Definition of primary endpoint(s)/estimand(s) 
The primary effectiveness question of interest is: What is the effect of the test treatment 
inclisiran (+/-  behavioural support) and standard of care + behavioural support on change in 
LDL-C after 270 days of treatment in adults on established lipid lowering medication or who 
have been recommended lipid lowering therapy by their health care provider but are unable to 
tolerate treatment, regardless of treatment discontinuation for any reason and regardless of 
unforeseen change in the concomitant lipid lowering therapy. 
The justification for the primary estimand is that it will capture both the effect of the study drug 
and the effect of changes in additional medication(s) used for lipid lowering, if they occur, in a 
primary care setting. 
The primary estimand is described by the following attributes: 


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1. Population: Adults with elevated LDL-C on established lipid lowering medication or, have 
been recommended lipid lowering therapy by their health care provider but are unable to tolerate 
treatment. Further details about the population are provided in Section 5. 
2. Endpoint: Percentage change in LDL-C from baseline to Day 270. 
3. Treatment of interest: The randomised treatment (inclisiran alone or inclisiran with 
behavioural support) as add-on to the control treatment of lipid-lowering background therapy 
plus behavioural support. The type and dose of the concomitant lipid-lowering therapy should 
remain stable during the study. Further details about the investigational treatment and control 
treatment are provided in Section 6. 
The summary measure: difference between treatments in least squares mean percentage change 
at Day 270. 
The strategy for handling intercurrent events (treatment discontinuation, use of prohibited 
medications, deviation in background treatment or death) will be described in the SAP. 
 
12.4.2 
Statistical model, hypothesis, and method of analysis 
The primary effectiveness objective of this study is to demonstrate superiority of each inclisiran 
(+/- behavioural support) arm compared to standard of care + behavioural support  in terms of 
the percentage change from baseline in LDL-C to Day 270 in adults with elevated LDL-C. The 
statistical hypotheses that will be tested for each inclisiran arm are as follows:  
• H0: The difference between participants treated with inclisiran (+/- behavioural support) 
and standard of care + behavioural support in the least squares mean percentage change 
from baseline to the Day 270 visit in LDL-C= 0 
• Ha: The difference between participants treated with inclisiran (+/- behavioural support) 
and standard of care + behavioural support  in the least squares mean percentage change 
from baseline to the Day 270 visit in LDL-C < 0 
The primary analysis will use an analysis of covariance model (ANCOVA) on the percent 
change in LDL-C from baseline to Day 270 to test the superiority of inclisiran (+/-  behavioural 
support) over standard of care + behavioural support after missing data imputation. The model 
will include a fixed effect for treatment and the baseline LDL-C value. Multiple imputation will 
be used to impute missing data using a washout model. A total of 100 imputed datasets will be 
created. The model will be fitted to each imputed dataset, and results will be combined using 
Rubin's combination rules. The difference in least squares means between treatment groups and 
corresponding 2-sided 95% confidence intervals will be calculated. The FAS will be used for 
this analysis. Full details on the model and imputation will be provided in the SAP. 
The washout model will be used to explore the assumption that missing Day 270 visit data are 
missing not at random in participants in the inclisiran groups who discontinue the study 
treatment early before the Day 270 visit and cannot be followed for scheduled LDL-C 
assessments. Early terminating participants in the standard of care + behavioural support group 
will have missing data imputed based on the missing at random assumption. Full details will be 
provided in the SAP. 


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The family-wise error rate for comparisons of the two inclisiran arms with the lipid-lowering 
background therapy plus behavioural support arm will be controlled using the Holm procedure. 
12.4.3 
Handling of remaining intercurrent events of primary estimand 
No remaining intercurrent events beyond those described above (treatment discontinuation, use 
of prohibited medications, deviation in background treatment or death) are expected. 
12.4.4 
Handling of missing values not related to intercurrent event 
Other missing data are expected to be intermittent missing data and will be assumed to be 
missing at random. Imputation details for data missing at random in the washout model will be 
provided in the SAP. 
12.4.5 
Sensitivity analyses for primary endpoint/estimand 
Sensitivity analyses to assess the robustness of the estimation in the presence of deviations from 
the assumptions specified in the primary analysis will be specified in the SAP. 
12.4.6 
Supplementary analysis 
Details of supplementary analyses will be specified in the SAP (if required). 
12.4.7 
Supportive analyses 
No supportive analyses are planned. 
12.5 
Analysis of secondary endpoints/estimands 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) 
The following are key secondary efficacy endpoints: 
• Mean difference in total score using the validated CSQ-8 (Client Satisfaction 
Questionnaire) administered after treatment at day 90.  
• Mean difference in total score using the validated Patient Activation Measure (PAM) 
questionnaire administered after treatment at day 90. 
• Measures of adherence to cardiovascular disease self-management using the validated 
Patient Activation Measure (PAM) questionnaire administered after treatment at day 90 
and using assessment of medication adherence during the study period. 
• A process evaluation conducted using the Consolidated Framework for Implementation 
Research (CFIR)  
The analysis methodology used for the process evaluation is described separately in Section 
4.3. 
The key secondary endpoints will be analysed using an ANCOVA model that includes 
treatment and baseline value (as appropriate). Full details, including possible sensitivity 
analyses, will be provided in the SAP. 
Descriptive summaries by treatment group will be presented. 


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12.5.2 
Safety endpoints 
For all safety analyses, the safety set will be used. All tables will be presented by treatment 
group. 
Safety summaries (tables, figures) include only treatment emergent 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) with the exception of baseline data which will 
also be summarised where appropriate (e.g. change from baseline summaries). In addition, a 
separate summary for deaths including on treatment and post treatment deaths will be provided. 
In particular, summary tables for adverse events (AEs) will summarise only treatment emergent 
AEs. 
Adverse events 
The number (and percentage) of participants with serious adverse events and treatment 
emergent adverse events leading to discontinuation (started after the first dose of study 
medication) will be summarised in the following ways: 
• by treatment, primary system organ class and preferred term. 
• by treatment, primary system organ class, preferred term and maximum severity. 
• by treatment, Standardised MedDRA Query (SMQ) and preferred term. 
Separate summaries 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 is only counted 
once towards the total of the primary system organ class. 
Adverse events which will be counted for a specific treatment period are those which are 
treatment-emergent. These events are those with an onset after the start of the treatment period, 
or which were present prior to the start of the treatment period but increased in severity, changed 
from being not suspected to being suspected of study drug relationship, or developed into SAEs 
after the start of the treatment period. 
 
 
 
 
12.6 
  
 
 
 
 
 
 
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12.7 
Interim analyses 
There are no interim analyses planned for this study. 
12.8 
Sample size calculation 
The primary effectiveness endpoint of the study is percent change of LDL-C from baseline. 
However, the sample size is driven by patient experience (CSQ-8) and patient activation 
(PAM); two key secondary outcomes in this trial. Although these outcomes are increasingly 
used in pragmatic and implementation trials, there is less consensus over ‘clinically meaningful’ 
differences for such outcomes. The trial has been powered to detect differences equivalent to a 
Cohen’s effect size of 0.3, approximating a ‘small-to-medium’ effect in conventional terms 
(Cohen 1988). This would be consistent with effect sizes in pragmatic, primary care trials using 
self-reported health outcomes, and with similar outcomes in a recent systematic review on 
coaching among patients with cardiovascular risk factors (An 2020). A sample size of 300 
patients per arm would be able to detect this effect size with 90% power using a one-sided 
significance level of 0.025 (this includes a 20% allowance for drop-out in this primary care 
setting).  
This sample size could also detect a reduction of at least 10% change of LDL-C from baseline 
in the inclisiran group  (+/-  behavioural support) compared to the standard of care + behavioural 
support group (assuming a standard deviation of 30% in the control group and 20% in the 
inclisiran group  (+/- behavioural support) based on observed results from previous inclisiran 
studies). 
The total sample size for the study will be 900 participants. 
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonised Tripartite Guidelines for Good Clinical Practice, with applicable local 
P
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regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. Prior to study 
start, the investigator is required to sign 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. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
13.3 
Publication of study protocol and results  
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalisation 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 
etc.). 
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. 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
14 
Protocol adherence 
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 


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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. 
14.1 
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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15 
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Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic 
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Larsen, D. L., Attkisson, C. C., Hargreaves, W. A., & Nguyen, T. D. (1979). Assessment of 
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16 
Appendices 
 
Appendix 1 
Behavioural support programme 
Appendix 2 
The CSQ-8 PROMs Questionnaire 
Appendix 3 
The PAM PROMs Questionnaire 
Appendix 4 
 
Appendix 5 
Generalisability of the Greater Manchester Population to the UK 
Appendix 6 
Calculating the 4-level Physical Activity Index (PAI) 
16.1 
Appendix 1: Behavioural Support Programme 
To determine whether additional supported care can improve health behaviour, self-efficacy 
and health status, consented participants randomised to Group 1 and Group 3 will receive 
monthly telephone-based support call.  
Behavioural Support will consist of a telephone-based lifestyle intervention to motivate and 
support participants to make effective choices for improving self-management including 
behaviour change, goal setting and empowerment.  
This model of behavioral support is based on a well-established service involving non-clinical 
health advisors trained in motivational interviewing techniques. This was first developed from 
the Pro-active Call Centre Treatment Support randomised controlled trial (Young et al 2005) 
which demonstrated that pro-active healthcare adviser support improves glucose control in 
people with type 2 diabetes. 
The telephone-based, lifestyle intervention will provide monthly support to enable participants 
to make positive behaviour changes. An initial call will be delivered by a health advisor and is 
focused on action planning to ensure each participant understands their diagnosis, the 
importance of reducing CV risk and taking medications correctly and how they can reduce their 
own risk. A lifestyle goal is then set together to help begin to achieve this, and participants will 
receive a pack of information, on CV disease and advice on healthy eating to help participants 
with goal setting and facilitate their understanding of risk.  
The remainder of the programme is delivered by dedicated health advisors and consists of 
monthly telephone calls sequentially covering diet, exercise, medication and where necessary 
additional advice about glucose management and smoking cessation. 
The behavioural support programme will be provided by a qualified medical support team.  
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16.2 
Appendix 2: The CSQ-8 PROMs Questionnaire 
The Client Satisfaction Questionnaire© (CSQ) is a portfolio of measurement instruments 
(CSQScales®) designed to assess consumer satisfaction with health and human services, 
including governmental and public benefit programs and services.  It is derived from the work 
of Larsen et al. 1979.   
The CSQ scales are well-validated and have been used extensively in the healthcare 
environment for comparison of interventions, clinical trials, clinical epidemiology, community 
epidemiology studies and field studies (https://csqscales.com/faqs/). Each scale measures the 
recipients’ direct satisfaction with specific services offered and received within a particular time 
frame from a specific provider or service setting. 
The CSQ-8 is the standard self-administered CSQ scale containing 8 items that comprise the 
measurement of satisfaction with services and measurement of improvement of capacity to cope 
and change adaptively.  Items include questions enquiring about respondents’ opinions and 
conclusions about services they have received or are currently receiving. Response options 
differ from item to item, but all are based on a four-point scale. Examples include: “How 
satisfied are you with the amount of help you have received?” (which response options: 1 
= ”Quite dissatisfied”, 2 = ”Indifferent or mildly dissatisfied”, 3 = ”Mostly satisfied”, 4 = ”Very 
satisfied”; and, “Have the services you received helped you to deal more effectively with your 
problems?” (Which has the response options: 4 = Yes, they helped a great deal”, 3 = ”Yes, they 
helped somewhat”, 2 = ”No, they didn't help”, 1 = “No, they seemed to make things worse”.  
All items are positively worded; however, the directionality of response options span the 
spectrum from very negative to very positive; and the numerical anchors for items are reversed 
randomly (from high to low or low to high) from item to item to minimise stereotypic response 
sets. While addressing several elements that contribute to service satisfaction, the CSQ-8 has 
no subscales and reports a single score measuring a single dimension of overall satisfaction.  
Scoring the CSQ-8 
A total score is produced by summing all item responses, with a higher scores indicating higher 
satisfaction.  The outcome is the mean difference in total score between treatment groups 
(Attkisson and Zwick, 1982). For the CSQ-8 version, scores range from 8 to 32, with higher 
values indicating higher satisfaction. Scoring for other versions is similar after extrapolating for 
number of items. 


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16.3 
Appendix 3: The PAM PROMs Questionnaire 
The Patient Activation Measure (PAM®) questionnaire is a 10- or 13-item survey that assesses 
a person’s underlying knowledge, skills and confidence integral to managing his or her own 
health and healthcare (https://www.insigniahealth.com/products/pam-survey).  It is validated 
and has been supported by NHS-E to use across the NHS.  
The PAM segments individuals into one of four activation levels along an empirically derived 
100-point scale. Each level provides insight into an extensive array of health-related 
characteristics, including attitudes, motivators, and behaviors. Individuals in the lowest 
activation level do not yet understand the importance of their role in managing their own health, 
and have significant knowledge gaps and limited self-management skills. Individuals in the 
highest activation level are proactive with their health, have developed strong self-management 
skills, and are resilient in times of stress or change. 
 
The PAM can be used to assess patient support strategies and programmes, and is reliable and 
validated for use with all patients, including those managing chronic conditions and engaged in 
disease prevention efforts. PAM is widely used today in population health management 
programs, disease and case management systems, wellness programs, medical home projects, 
care transitions, value-based programs, and much more. 
This study will use the 13-point PAM questionnaire, which will be complemented by data on 
medication adherence to inclisiran or standard of care recorded during the trial.  The 13 item 
PAM consists of 13 statements relating to patients beliefs about health care, confidence in their 
management of health related tasks, and self-assessed knowledge of their condition (Hibbard 
and Gilburt, 2014). For each statement patients are required to say how much they either agree 
or disagree on a response scale of 1–5, where 1 represents “strongly disagree”, 4 represents 
“strongly agree” and 5 indicates that the statement is “not applicable” to them.  
A standardised spreadsheet in excel is used to score the PAM. Responses are used to generate 
a continuous score from 0 to 100 where higher scores indicate that the patient is more activated 
(Hibbard and Gilburt, 2014). Where participants have answered that a statement is not 


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applicable to them the data is treated as missing. A total score is generated where participants 
have answered at least 10 out of the 13 questions. 
The continuous PAM scores are then categorised into four levels for descriptive purposes using  
a calibration table. Those who fall into Level 1 are defined as passive recipients of care who do 
not understand that they can play an active role in their own healthcare. Level 2 includes patients 
who lack the basic knowledge and confidence to effectively self-manage (for example they may 
not understand the treatment options available to them or what their medications do). Level 3 
includes those who have a basic knowledge about their health but they lack the confidence and 
skills to engage in positive self-management behaviours. Level 4 is for patients who have the 
knowledge and confidence to self-manage but who may need support during times of personal 
stress or health crisis (Hibbard et al, 2005). 
The PAM has been found to be a valid and reliable measure in people with long-term conditions, 
such as those attending cardiac rehabilitation, (Hibbard et al, 2004) and in those patients with 
multi-morbidity (Skolasky et al, 2011).  


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16.4 
Appendix 4: 
 
 
 
 
 
 
 
 
 
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16.5 
Appendix 5: Generalisability of the Greater Manchester 
Population to the UK 
16.5.1 
Key indicators of generalisability of the Greater Manchester 
population to the UK 
 
The Quality and Outcomes in Primary Healthcare (QOPH) demonstrate that chronic disease 
prevalence in Greater Manchester is comparable across the UK population as a whole (Quality 
and Outcomes in Primary Healthcare data, 2018). 
16.5.2 
Greater Manchester population by ethnicity, compared with England 
and Wales 
 
 
The breakdown of the Greater Manchester population by ethnicity is very similar to that of 
England and Wales as a whole. Greater Manchester has a slightly higher Asian (Pakistani) 
population, a slightly lower White population and a slightly lower Black (Caribbean) population 
(Office of National Statistics Ethnic Group, 2011). 
0
20
40
60
80
100
White
Asian
Black
Mixed
Other
Ethnicity (coarse grained)
Greater Manchester (%)
England and Wales (%)


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16.5.3 
Greater Manchester population by Age, compared with England and 
Wales 
 
The age distribution of the Greater Manchester population is almost identical to that of the 
England and Wales population. Contrast for example, Inner London where the proportion of 
30-44-year olds can be as high as 30%, or local authorities on the South coast, where it can be 
as low as 14% (Office of National Statistics Age Group, 2011). 
16.5.4 
Greater Manchester male population, compared with England and 
Wales 
 
The proportion of males in the Greater Manchester population, stratified by age, is very similar 
to that for the UK as a whole. The biggest difference, 1.1%, occurs in the 80-84 age group 
(Office of National Statistics Male Group, 2011). 
0
5
10
15
20
25
Under
18
18-19 20-24 25-29 30-44 45-59 60-64 65-74 75-84 85-89 90 and
over
Age
Greater Manchester (%)
England and Wales (%)
0
10
20
30
40
50
60
20-24 25-29 30-34 35-39 40-44 45-49 50-55 55-59 60-64 65-69 70-74 75-79 80-84 85-89
Sex
Greater Manchester % Male
UK % Male


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16.6 
Appendix 6: Calculating the 4-level Physical Activity Index (PAI) 
The General Practice Physical Activity Questionnaire is intended for use in adults (16 – 74) 
years in routine general practice to provide a simple, 4-level Physical Activity Index (PAI) 
reflecting an individual’s current physical activity. The index can be cross-referred to Read 
codes for physical activity and can be used to help inform the decision as to when interventions 
to increase physical activity might be appropriate. 
Patients can be classified into four categories:  
Inactive        
• Sedentary job and no physical exercise or cycling 
Moderately 
inactive       
• Sedentary job and some but < 1 hour physical exercise and / or 
• cycling per week OR 
• Standing job and no physical exercise or cycling 
Moderately 
active         
• Sedentary job and 1-2.9 hours physical exercise and / or cycling 
per week OR 
• Standing job and some but < 1 hour physical exercise and / or 
cycling per week OR 
• Physical job and no physical exercise or cycling 
Active           
                   
• Sedentary job and ≥ 3 hours physical exercise and / or cycling 
• per week OR 
• Standing job and 1-2.9 hours physical exercise and / or cycling 
per week OR 
• Physical job and some but < 1 hour physical exercise and / or 
cycling per week OR 
• Heavy manual job 
Note: Questions concerning Walking, Housework/Childcare and Gardening/DIY have been 
included to allow patients to record their physical activity in these categories, however these 
questions have not been shown to yield data of a sufficient reliability to contribute to an 
understanding of overall physical activity levels. As noted above further questioning is required. 
Summary of the PAI 
Occupation 
Physical exercise and / or  
cycling (hr/wk) 
Sedentary 
Standing 
Physical 
Heavy Manual 
0 
Inactive 
Moderately  
Inactive 
Moderately  
Active 
Active 
Some but < 1 
Moderately  
Inactive 
Moderately  
Active 
Active 
Active 
1-2.9 
Moderately  
Active 
Active 
Active 
Active 
≥ 3 
Active 
Active 
Active 
Active 
 

SAP_001.pdf: 
Clinical Development 
KJX839/Inclisiran 
CKJX839A1GB01 / NCT04807400 
A phase IIIb, multicentre, randomised controlled study to evaluate 
the implementation, preference and utility for administration of 
inclisiran sodium in participants with Atherosclerotic 
Cardiovascular Disease (ASCVD) or ASCVD-risk equivalents and 
elevated Low Density Lipoprotein Cholesterol (LDL-C) using a 
primary care models in the NHS 
Statistical Analysis Plan (SAP) 
Property of Novartis 
 Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Template Version 4.0, Effective from 23-Apr-2021 
Author: 
Document type: 
SAP Documentation 
Document status: 
Amendment v1.1 
Release date: 
15-May-2023
Number of pages: 
37 


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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) 
31-Mar-
2023 
Prior to DB 
lock 
Creation of 
final version 1.0 
N/A – First version 
NA 
15-May-
2023 
Prior to DB 
lock 
Creation of 
amendment 1 
version 1.1 
• Updated number of 
imputations from 100 to 
500 
Section 2.5.2 
Section 5.5.1 & 
5.5.2 
• Removed text related to 
line plot 
• Added clarification text 
about baseline 
imputation values in 
sensitivity analysis 
Section 2.5.5 
• Added clarification text 
Section 2.10.1 
Section 5.4 
 
 
 
• Other minor format 
changes 
Section 2.5.2 & 
2.6.2 
 
 
 
 
 
 


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Table of contents 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 7 
1.1 
Study design............................................................................................................. 7 
1.2 
Study objectives, endpoints and estimands ............................................................. 9 
2 
Statistical methods ............................................................................................................. 11 
2.1 
Data analysis general information ......................................................................... 11 
2.1.1 
General definitions ................................................................................ 11 
2.2 
Analysis sets .......................................................................................................... 12 
2.2.1 
Subgroup of interest .............................................................................. 13 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 13 
2.3.1 
Patient disposition ................................................................................. 13 
2.3.2 
Demographics and other baseline characteristics ................................. 13 
2.3.3 
Medical History ..................................................................................... 14 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 14 
2.4.1 
Study treatment / compliance ................................................................ 14 
2.4.2 
Prior, concomitant and post therapies ................................................... 14 
2.5 
Analysis supporting primary objective(s) .............................................................. 15 
2.5.1 
Primary endpoint(s) ............................................................................... 15 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 16 
2.5.3 
Handling of intercurrent events ............................................................. 16 
2.5.4 
Handling of missing values not related to intercurrent event ............... 17 
2.5.5 
Sensitivity analyses ............................................................................... 17 
2.5.6 
Supplementary analyses ........................................................................ 18 
2.6 
Analysis supporting secondary objectives ............................................................. 19 
2.6.1 
Secondary endpoint(s) ........................................................................... 19 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 21 
2.6.3 
Handling of missing values ................................................................... 22 
2.7 
Safety analyses ....................................................................................................... 22 
2.7.1 
Adverse events (AEs) ............................................................................ 22 
2.7.2 
Deaths .................................................................................................... 24 
2.7.3 
Laboratory data ..................................................................................... 24 
2.7.4 
Other safety data ................................................................................... 24 
2.8 
Patient-reported outcomes ..................................................................................... 24 


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2.8.1 
The CSQ-8 PROMs Questionnaire ....................................................... 24 
2.8.2 
The PAM PROMs Questionnaire.......................................................... 24 
2.8.3 
 
2.9 
 
2.10 
 
 
 
 
 
 
 
2.11 
Interim analysis ...................................................................................................... 26 
3 
Sample size calculation ..................................................................................................... 26 
4 
Change to protocol specified analyses .............................................................................. 26 
5 
Appendix ........................................................................................................................... 26 
5.1 
Imputation rules ..................................................................................................... 26 
5.1.1 
Study drug ............................................................................................. 26 
5.1.2 
AE date imputation ............................................................................... 27 
5.1.3 
Concomitant medication date imputation ............................................. 28 
5.2 
AEs coding/grading ............................................................................................... 29 
5.3 
Search criteria for AE of special interest ............................................................... 29 
5.4 
Laboratory parameters derivations ........................................................................ 30 
5.5 
Statistical models ................................................................................................... 31 
5.5.1 
Multiple Imputation Wash-out model ................................................... 31 
5.5.2 
Imputation of undetectable data ............................................................ 33 
5.6 
Rule of exclusion criteria of analysis sets.............................................................. 34 
6 
Reference ........................................................................................................................... 36 
 
List of tables 
Table 2-1 
Analysis windows for each scheduled visit .......................................... 12 
Table 5-1 
Clinical notable criteria for selected laboratory tests ............................ 30 
Table 5-2 
Notable Liver function test values ........................................................ 30 
Table 5-3 
Range determination ............................................................................. 33 
Table 5-4 
Protocol deviation criteria leading to exclusion from analysis sets ...... 34 
 
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List of abbreviations 
AE(s) 
Adverse event(s) 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ASCVD 
Atherosclerotic Cardiovascular Disease 
ATC 
Anatomical Therapeutic Chemical 
 
 
CFIR 
Consolidated Framework for Implementation Research 
CRO  
Contract Research Organization 
CSQ-8 
Client Satisfaction Questionnaire 
CSR 
Clinical Study Report 
CTC 
Common Terminology Criteria 
DBL 
Direct Bilirubin 
 
 
 
 
ECG 
Electrocardiogram 
EMR 
Electonic Medical Record 
EOS 
End of Study 
EudraCT  
European Union Drug Regulating Authorities Clinical Trials 
Database  
eGFR 
Estimated glomerular filtration rate 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FAS 
Full Analysis Set 
HbA1C 
Hemoglobin A1c 
HDL-C 
High density lipoprotein cholesterol 
LDL 
Low density lipoprotein 
LDL-C 
Low density lipoprotein cholesterol 
MAR 
Missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities  
MMRM 
Mixed-effect model for repeated measures 
MNAR 
Missing not at random 
NICE 
National Institute for Health and Care Excellence 
PAM 
Patient Activation Measure  
PT 
Preferred term 
PROM 
Patient Reported Outcome Measure 
RAN 
Randomized set 
REML 
Restricted Maximum Likelihood 
 
  
s.c. 
Subcutaneous 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical Analysis Plan 
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SCR 
Screened set 
SD 
Standard deviation 
SMC 
Scottish Medicines Consortium 
SMQ 
Standardized MeDRA Query 
SOC 
System Organ Class 
SPIRIT 
Study 
in 
Primary 
care 
evaluating 
Inclisiran 
deliveRy 
Implementation + enhanced SupporT  
TBL 
Total Bilirubin 
 
 
 
 
TEAE 
Treatment emergent adverse event 
ULN 
Upper limit of normal 
 
 
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1 
Introduction 
This document includes the analysis details of study CKJX839A1GB01. Data will be analyzed 
according to section 12 (data analysis and statistical methods) of CKJX839A1GB01 amended 
protocol v02 dated 12-Sep-2022. 
The  efficacy and safety  analyses  will  be  conducted  after  all  participants  have  completed  
the Day 270 visit or discontinued prior to the Day 270 visit. There is no interim analysis planned 
for this study. The final analyses will be conducted when the trial has ended, and the results will 
be summarized in the final CSR.  
The analysis of Process Evaluation Sub-study data is out of scope of this SAP. 
1.1 
Study design 
A phase IIIb, multicentre, randomised controlled study to evaluate the implementation, 
preference and utility for administration of inclisiran sodium in participants on established lipid 
lowering medication or, have been recommended lipid lowering therapy by their healthcare 
provider but are unable to tolerate treatment, with elevated low density lipoprotein cholesterol 
(LDL-C) in a primary care population.  
This study is an implementation research study that utilises implementation science 
methodology with the primary focus being implementation and ‘transactability’ – how to 
organise, deliver and maintain an innovative treatment for ASCVD in a primary care setting in 
a sustainable way. 
900 eligible participants will be randomised (300 per treatment group) at up to 30 primary care 
centres across Greater Manchester.  
At the baseline visit/screening on receipt of a signed consent form, eligible participants will be 
randomised to one of the three treatment groups:  
• Group 1: Participants will continue to receive their background lipid lowering therapy 
plus behavioural support  
• Group 2: Participants will continue to receive their background lipid lowering therapy, 
plus inclisiran for injection (delivered in an injection-only model).  
• Group 3: Participants will continue to receive their background lipid lowering therapy, 
plus inclisiran for injection, plus behavioural support. 
Subjects in treatment group 1 will be referred to as the control group in this study. 
The study duration will be approximately 9 months. There are no interim analyses planned for 
this study. 
 
 
 
 
 


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Schematic of study design 
 
 
 
For elaborated details on study design please refer to the study design section of the protocol . 
 
 


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1.2 
Study objectives, endpoints and estimands  
 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• The primary objective of this study is 
to demonstrate superiority of inclisiran 
+/- behavioural support compared to 
standard of care + behavioural support 
in a primary care setting, in terms of the 
percentage change in LDL-C from 
baseline to Day 270 in adults with 
elevated LDL-C.  
• Percentage change in LDL-C from 
baseline to Day 270. 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
The secondary objectives of this study are to 
evaluate the implementation of inclisiran +/- 
behavioural support compared to standard of 
care + behavioural support in a primary care 
setting using the following assessments:  
 
• Measures of patient satisfaction using the 
validated CSQ-8 
(Client 
Satisfaction 
Questionnaire) 
administered 
after 
treatment at day 90. 
• Mean difference in total score using the 
validated CSQ-8 (Client Satisfaction 
Questionnaire) 
administered 
after 
treatment at day 90.  
• Measures 
of 
patient 
activation 
and 
empowerment using the validated Patient 
Activation Measure (PAM) questionnaire 
administered after treatment at day 90.  
• Mean difference in total score using the 
validated Patient Activation Measure 
(PAM) questionnaire administered after 
treatment at day 90.  
• Measures of adherence to cardiovascular 
disease 
self-management 
using 
the 
validated Patient Activation Measure 
(PAM) questionnaire administered after 
treatment at day 90 and using assessment 
of medication adherence during the study 
period. 
• The frequency and percentages of 
subjects in the four levels of the PAM 
scores (below) will be summarized. 
Highly activated patients (level 3 and 
level 4) are more likely to adhere to 
cardiovascular self-management and 
thus medication adherence. 
Level 1: Disengaged and overwhelmed 
Level 2: Become aware but still struggling 
Level 3: Taking action 


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Level 4: Maintaining behaviors and 
pushinng further. 
• A process evaluation conducted using the 
Consolidated 
Framework 
for 
Implementation Research (CFIR) which 
will explore inclisiran delivery at three 
levels:  
1. Level 1: Feasibility and acceptability of 
delivery models for inclisiran to patients  
2. Level 2: Feasibility and acceptability of 
delivery models for inclisiran to providers 
(inner setting)  
3. Level 3: Wider ‘transactability’ of the 
proposed delivery models (outer setting)  
4. The service costs of each delivery model  
5. The 
acceptability 
and 
perceived 
sustainability of patient identification and 
referral routes  
Data from the process evaluation will initially 
analysed blind to trial outcomes (this analysis 
will then be used to compare and explain any 
differences in outcomes between intervention 
arms). 
This SAP does not intend to describe 
methodology adopted for the Process 
Evaluation Sub-study data analysis. This 
study objective is listed for completeness 
only. For further detail on the process 
evaluation and planned analyses, please 
refer to section 4.3 of the Protocol. The 
analysis results will be reported in final 
CSR. 
• Serious adverse event profile  
• Incidence, severity and relationship to 
the study drug of treatment emergent 
adverse events, serious adverse events 
and adverse events leading to treatment 
discontinuation. 
• Incidence of on-treatment and post- 
treatment deaths. 
 
 
 
 
 
 
 
 
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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 analysis. 
Final analysis will be conducted after all participants either complete the study or discontinued 
early. Final analyses will be reported in Final CSR.  
Additional analysis may be conducted to evaluate the impact of COVID-19 pandemic, if 
required. 
2.1.1 
General definitions  
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: 
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For dates on or after the first date of study treatment, 
Study day = Assessment date – Date of first dose of study treatment + 1; 
For dates prior to the first date of study treatment, 
Study day = Assessment date – Date of first dose of study treatment. 
In case, participant has been randomized but has not received study treatment then 
randomization visit day will be considered as Day 1. 
Baseline definition: 
The baseline assessment is defined as the last non-missing assessment (scheduled or 
unscheduled) collected before the first dose of study treatment (Day 1) or randomization visit 
day, if no study treatment has been received. 
Post-baseline measurement: 
Post-baseline values are defined as those measurements that were collected after the first dose 
of study treatment or randomization visit if no study treatment has been received. 
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: 
Change from baseline = post-baseline value – baseline value. 
Percent change from baseline = (change from baseline / baseline value)*100. 
Visit windows: 
If there is more than one observation in a specific window, then the one closest to the target day 
will be used for analysis. If there are two or more observations that are equally distant to the 
target day and within the analysis window, the first of these observations will be selected for 
analysis. Observations that are out of the analysis window below will be classified as 
unscheduled visits and will not be included in the primary and key secondary efficacy analysis. 
However, all data will be included in the subject data listings.  
As shown in the table below, all visit will apply a window of ± 14 days. 
Table 2-1 
Analysis windows for each scheduled visit 
Visit Name 
Target day 
Analysis window 
Screening/Baseline 
-1 
Day -14 to -1 
Visit 1 
1 
Day 1 to 14 
Visit 2 
90 
Day 76 to 104 
End of Study 
270 
Day 256 to 284 
*Day 1 is defined as day of initiation of study drug administration or randomization visit day if no study 
treatment has been received. 
2.2 
Analysis sets  
Screened Set (SCR) will include all participants who provided study informed consent.  
Randomized set (RAN) will consist of all participants who received a randomization number, 
regardless of whether study treatment received or not. 


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Full Analysis Set (FAS) will consist of all randomised participants with the exception of those 
mis-randomised participants who did not receive study drug. Mis-randomised participants are 
defined as not qualified for randomisation and are inadvertently randomised into the study. 
According to the intent to treat principle, participants will be analysed according to the 
treatment they have been assigned to during the randomisation procedure. The FAS will be used 
in analyses for the primary, secondary, 
 efficacy objectives. 
Safety Set (SAF) will consist of all participants who received at least one dose of study 
treatment. Participants will be analysed according to the study treatment received. This will be 
the primary population for the safety analyses. 
2.2.1 
Subgroup of interest 
No subgroup analysis is planned. 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
2.3.1 
Patient disposition 
The overall number of participants who entered, completed, and discontinued the study will be 
summarized and listed, including the reasons for discontinuation. Duration on study is defined 
as: date of last known visit on study – date of first dose of treatment/ randomization visit, if no 
study treatment has been received.  
The duration on study will be summarized by treatment group. The screening disposition will 
be based on SCR. The FAS will be used for the summary and listing of patient disposition. The 
number of participants in the FAS will be summarized by treatment group. 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 concomitant 
medication, other), deviation using FAS. Listing of participants with protocol deviation will be 
provided.  
The number of participants included in each analysis set will be tabulated using RAN. 
Participants exclusion from analysis sets will be summarized for all patients 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 
Demographic and other baseline data including age, race, gender, baseline characteristics such 
as body height, 
 smoking history, Dietary advice status, Exercise status; baseline 
disease characteristics like LDL-C, baseline use of other lipid-lowering therapies (yes, no), 
statin intolerance history(yes, no), baseline diabetes status determined by the fasting glucose (≥ 
7.0 mmol/L) or random glucose (≥ 11.1 mmol/L) or HbA1C (≥ 6.5% or 48 mmol/mol) or 
medical history, baseline measurements 
 will be summarized descriptively by 
treatment group for FAS. Listings will also be provided. 
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Categorical data will be presented as frequencies and percentages by treatment group. For 
continuous data, non-missing observations, mean, standard deviation, median, 1st and 3rd 
quartile, minimum, and maximum will be presented. 
No inferential statistics will be provided for baseline comparability among the treatment groups. 
In addition, the following categorizations of continuous variables will be done: 
• 
Age groups < 65, ≥ 65 and < 75, ≥ 75  
• 
  
• 
LDL-C subcategories Category 1: ≤ 2.6 mmol/L, > 2.6 mmol/L; Category 2: ≤ 2.1 
mmol/L, > 2.1 - ≤ 2.6 mmol/L, > 2.6 - ≤ 3.3 mmol/L and > 3.3 mmol/L 
• 
  
2.3.3 
Medical History 
Relevant medical histories and current medical conditions at baseline will be summarised 
separately by system organ class and preferred term, by treatment group. Histories of statin 
intolerance will be summarised by treatment group. FAS will be used for the analysis. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
All summaries of treatments will be performed on the Safety Set, unless otherwise specified. 
2.4.1 
Study treatment / compliance 
The number of study doses administered, duration of exposure, patient year of exposure will be 
summarized by treatment group. Listings will be provided.  
The number of participants dosed will also be summarized by study visit and treatment group.  
Duration of exposure for inclisiran arms will be calculated as: minimum of (Date of last dose 
of treatment – Date of first dose of treatment + 180, Date of last known visit – Date of first dose 
of treatment).  
Duration of exposure for lipid lowering therapies will be calculated as: minimum of (Date of 
last dose of lipid lowering therapy – Date of first dose of lipid lowering therapy, Date of last 
known visit – Date of first dose of lipid lowering therapy).  
Patient-year of exposure will be calculated as duration of exposure/365.25. 
2.4.2 
Prior, concomitant and post therapies 
Medications are collected through EMR and in this system medication end date is not available.   
Lipid-lowering therapy use at screening and baseline/randomization visit (Day 1) will be 
summarized by treatment group. Lipid-lowering therapy newly added or changed after 
randomization will be summarized by treatment group. 
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Other medications will be listed and summarized according to the anatomical therapeutic 
chemical (ATC) classification system and preferred term, by treatment group. 
2.5 
Analysis supporting primary objective(s) 
The primary objective of this study is to demonstrate superiority of inclisiran +/- behavioural 
support compared to standard of care + behavioural support in a primary care setting, in adults 
with elevated LDL-C. Standard of care + behavioural support will be considered as control 
group as mentioned in section 1.1. 
2.5.1 
Primary endpoint(s) 
The primary endpoint is the percentage change in LDL-C from baseline to Day 270. 
The primary estimand is defined as follows. The primary effectiveness question of interest is: 
What is the effect of the test treatment inclisiran versus control on change in LDL-C after 270 
days of treatment in adults on established lipid lowering medication or who have been 
recommended lipid lowering therapy by their health care provider but are unable to tolerate 
treatment, regardless of treatment discontinuation for any reason and regardless of unforeseen 
change in the concomitant lipid lowering therapy. 
The justification for the primary estimand is that it will capture both the effect of the study drug 
and the effect of changes in additional medication(s) used for lipid lowering, if they occur, in a 
primary care setting.  
The primary estimand is described by the following attributes:  
Population 
Adults with elevated LDL-C on established lipid lowering 
medication or, have been recommended lipid lowering therapy by 
their health care provider but are unable to tolerate treatment. 
Variable 
Percentage change in LDL-C from baseline to Day 270 
Treatment 
The randomised treatment (inclisiran alone or inclisiran with 
behavioural support) as add-on to the control treatment of lipid-
lowering background therapy plus behavioural support, regardless of 
treatment discontinuation for any reason and regardless of unforeseen 
change in the concomitant lipid lowering therapy and regardless of 
use of prohibited medications. 
Summary measure 
Difference between treatments in mean percentage change in LDL-C 
from baseline to Day 270. 
Intercurrent events 
1. Study treatment discontinuation 
2. Deviation in background treatment 
3. Use of prohibited medications 
Patients who took extra dose of inclisiran (who are identified through EMR) during the study 
period will be excluded and additional analysis will  be provided. 


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2.5.2 
Statistical hypothesis, model, and method of analysis  
The primary effectiveness objective of this study is to demonstrate superiority of each inclisiran 
arm compared to control in terms of the percentage change from baseline in LDL-C to Day 270 
in adults with elevated LDL-C. The statistical hypotheses that will be tested for each inclisiran 
arm are as follows:  
• 
H0: The difference between participants treated with inclisiran and control in the least 
squares mean percentage change from baseline to the Day 270 visit in LDL-C= 0 
• 
Ha: The difference between participants treated with inclisiran and control in the least 
squares mean percentage change from baseline to the Day 270 visit in LDL-C < 0 
The primary objective will be achieved if null hypothesis (H0) rejected at the one-sided 
significance level of 0.025. 
The primary analysis will use an analysis of covariance (ANCOVA) model on the percent 
change in LDL-C from baseline to Day 270 to test the superiority of inclisiran over control after 
missing data imputation.  
Due to probable heterogeneity of variances between treatment groups, ANCOVA model which 
assumes unequal variances for treatment group will be used. The model will include the fixed 
effects of treatment group with baseline LDL-C as a covariate.  
Multiple imputation will be used to impute missing data using a washout model specified in  
Appendix 5.5.1. A total of 500 imputed datasets will be created. The ANCOVA model will be 
fitted to each imputed dataset, and results will be combined using Rubin's combination rules. 
The estimate and corresponding 2-sided 95% confidence intervals of mean difference between 
treatment groups will be calculated. p-value for hypothesis test for mean difference will also be 
provided. The FAS will be used for this analysis. The family-wise error rate for comparisons of 
the two inclisiran arms with the lipid-lowering background therapy plus behavioural support 
arm will be controlled using the Holm procedure. 
2.5.3 
Handling of intercurrent events  
The approach of accounting for intercurrent events is as follows: 
Primary estimand: 
Intercurrent 
events (ICEs) 
Strategy and justification of 
handling ICEs 
Missing value imputation 
Study 
treatment 
discontinuation 
Here interest is in effect of 
treatment regardless of treatment 
discontinuations due to any 
reasons other than intercurrent 
event. This event will be handled 
using a treatment policy 
strategy. 
The LDL-C data collected post 
discontinuation of study treatment 
will be included in the analysis. If 
there is no off-treatment data 
available, then missing data on Day 
270 or after treatment 
discontinuation will be imputed 
using missing not at random 
(MNAR) for inclisiran arms and 
using missing at random (MAR) 


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Intercurrent 
events (ICEs) 
Strategy and justification of 
handling ICEs 
Missing value imputation 
approach for placebo arm 
participants.  
Deviation in 
background 
treatment 
Interest is in effect of treatment 
regardless of substantial changes 
to background therapy during 
study treatment. This will be 
handled with a treatment policy 
strategy. 
The LDL-C data collected after 
deviation in background treatment 
will be included in the analysis. 
Missing values will be imputed in 
same way as mentioned in Appendix 
5.5.1 
Use of 
prohibited 
medications  
Interest is in effect of treatment 
regardless of changes in 
concomitant lipid lowering 
medication during study treatment. 
This will be handled with a 
treatment policy strategy. 
The LDL-C data collected after 
deviation in background treatment 
will be included in the analysis. 
Missing values will be imputed in 
same way as mentioned in Appendix 
5.5.1 
2.5.4 
Handling of missing values not related to intercurrent event 
The point of care device is used to measure lipid profile data at each visit. Any undetectable 
calculated LDL-C data due to device sensitivity for a lipid parameter will be considered as 
missing for the primary analysis.  
Undetectable data will be imputed separately as per Appendix 5.5.1 and used in a sensitivity 
analysis. 
LDL-C data will be calculated using Friedwald’s formula as mentioned below: 
LDL-C = Total cholesterol – HDL – Triglycerides/2.2 
Friedewald’s formula valid only when Triglycerides < 4.52 mmol/L 
 
 
 
 
 
 
Other missing data are expected to be intermittent missing data and will be assumed to be 
missing at random. The post-death missing values will be treated in same way as other missing 
data. Imputation details for data missing at random in the washout model has been provided in 
Appendix 5.5.1. 
2.5.5 
Sensitivity analyses  
The following sensitivity analyses will be performed for the primary estimand, to assess the 
robustness of the estimation in the presence of deviations from the assumptions specified in the 
primary analysis on the FAS only: 
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• 
Linear mixed-effect model for repeated measures (MMRM) analysis without multiple 
imputation  
Analyses using the MMRM will include fixed effects for treatment, visits, interaction between 
treatment and visits, baseline LDL-C and interaction between baseline LDL-C and visit. Day 
90 and 270 will be included as visit. The Restricted Maximum Likelihood (REML) estimation 
approach will be used with covariance structure set as "Unstructured". If the model does not 
converge with unstructured covariance matrix, the compound symmetry covariance matrix will 
be used in the mixed model.  
As a sensitivity analysis, the imputation algorithm will be changed from a regression approach 
to a multivariate normal model to include in the imputation information that is provided by 
undetectable LDL-C values. An LDL-C value is undetectable when either 
 
 are outside of the limit of detection. Based on the limit of detection and 
through Friedewald’s formula, a range for an LDL-C value can be calculated. In this sensitivity 
analysis, the LDL-C range is considered in the imputation model. As for the primary analysis, 
undetectable LDL-C values for either study arm are imputed under a MAR assumption, missing 
values in the placebo arm are imputed under a MAR assumption, and missing data on Day 270 
or after treatment discontinuation in the inclisiran arm are imputed using a wash-out model (i.e., 
using a jump-to-reference approach).  
In the sensitivity analysis, imputed baseline values will be restricted to ≥ 0.1 to avoid imputed 
values close to zero which can lead to numerical instabilities in the analysis of percentage LDL-
C change from baseline. 
The imputation will be carriedout using in SAS/R as mentioned in Appendix 5.5.2.  
The analysis will be carried out using ANCOVA procedure as mentioned in section 2.5.2. 
2.5.6 
Supplementary analyses 
Supplementary analysis of LDL-C change from baseline to Day 270 will be performed using 
linear mixed-effect model for repeated measures (MMRM) analysis with multiple imputation 
as specified in section 2.5.5. This supplementary analysis will be performed by assessing 
supplementary estimand as mentioned  below. 
 
Intercurrent events (Study treatment discontinuation and Deviation in background treatment) 
will be handled similarly as mentioned in primary endpoint (Refer section 2.5.3) and 
additionally below mentioned strategy will be used for “Use of prohibited medications”.  
 
ICE 
Strategy and justification of 
handling ICEs 
Missing value imputation 
Use of 
prohibited 
medications  
Interest is in effect of treatment 
regardless of changes in 
concomitant lipid lowering 
medication during study treatment. 
Use of prohibited medications 
(includes treatments which are 
LDL-C data after this event will be 
set to missing. Missing data after 
this event will be imputed in same 
way as mentioned in Appendix 
5.5.1. 
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ICE 
Strategy and justification of 
handling ICEs 
Missing value imputation 
added to existing background 
therapy during the study) will not 
be allowed in the study and  will 
lead to study treatment 
discontinuation. 
The LDL-C data collected after the 
use of any prohibited medication 
will not be included in the 
analysis. 
Hypothetical strategy with the 
hypothetical scenario ‘as if 
patients would have not received 
any prohibited medication. 
2.6 
Analysis supporting secondary objectives  
The secondary objectives of this study are to evaluate the implementation of inclisiran +/- 
behavioural support compared to standard of care + behavioural support in a primary care 
setting using the following assessments that will be reported based on this SAP are:  
• 
Measures of patient satisfaction using the validated CSQ-8 (Client Satisfaction 
Questionnaire) administered after treatment at day 90.  
• 
Measures of patient activation and empowerment using the validated Patient Activation 
Measure (PAM) questionnaire administered after treatment at day 90.  
• 
Measures of adherence to cardiovascular disease self-management using the validated 
Patient Activation Measure (PAM) questionnaire administered after treatment at day 90 
and using assessment of medication adherence during the study period.  
• 
Serious adverse event profile and adverse events leading to treatment discontinuation.  
The following secondary endpoint will be analysed by Manchester University and are not 
covered by this SAP: 
• 
A process evaluation conducted using the Consolidated Framework for Implementation 
Research (CFIR) which will explore inclisiran delivery at three levels:  
 Feasibility and acceptability of delivery models for inclisiran to patients  
 Feasibility and acceptability of delivery models for inclisiran to providers (inner 
setting)  
 Wider ‘transactability’ of the proposed delivery models (outer setting)  
 The service costs of each delivery model  
 The acceptability and perceived sustainability of patient identification and referral 
routes  
2.6.1 
Secondary endpoint(s) 
The following are key secondary efficacy endpoints:  


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• 
Mean difference in total score using the validated CSQ-8 (Client Satisfaction 
Questionnaire) administered after treatment at day 90.  
• 
Mean difference in total score using the validated Patient Activation Measure (PAM) 
questionnaire administered after treatment at day 90.  
• 
Measures of adherence to cardiovascular disease self-management using the validated 
Patient Activation Measure (PAM) questionnaire administered after treatment at day 90 
and using assessment of medication adherence during the study period.  
All the analyses on above endpoints will be based on observed data only. 
2.6.1.1 
The CSQ-8 PROMs Questionnaire 
The Client Satisfaction Questionnaire© (CSQ) is a portfolio of measurement instruments 
(CSQScales®) designed to assess consumer satisfaction with health and human services, 
including governmental and public benefit programs and services. 
Each scale measures the recipients’ direct satisfaction with specific services offered and 
received within a particular time frame from a specific provider or service setting.  
The CSQ-8 has 8 items and no subscales. and It reports a single score measuring a single 
dimension of overall satisfaction. 
A total score is produced by summing all item responses, with a higher scores indicating higher 
satisfaction. The outcome is the mean difference in total score between treatment groups. For 
the CSQ-8 version, scores range from 8 to 32, with higher values indicating higher satisfaction. 
Scoring for other versions is similar after extrapolating for number of items. 
The following endpoint will be analyzed with CSQ-8 PROMs Questionnaire data. 
Endpoint: Mean difference in total score using the validated CSQ-8 (Client Satisfaction 
Questionnaire) administered after treatment at day 90. Summary measure: Mean difference in 
total scores between treatment groups. 
2.6.1.2 
The PAM PROMs Questionnaire 
This study will use the 13-point PAM questionnaire, which will be complimented by data on 
medication adherence to Inclisiran or standard of care recorded during the trial. The 13 item 
PAM consists of 13 statements relating to patients beliefs about health care, confidence in their 
management of health related tasks, and self-assessed knowledge of their condition.  
For each statement patients are required to say how much they either agree or disagree on a 
response scale of 1–4, where 1 represents “strongly disagree” and 4 represents “strongly agree”. 
Patients may also answer “non-applicable” which is scored as 0. A total score is created by 
summing the scores for the 13 statements and multiplying by 13/(13-n) where n is the number 
of statements answered as “non-applicable” or missing. The total is rounded to the nearest 
integer. The total score in the range [13,52] is then converted to a score in the range [0,100] 
using a calibration table. Note that if n>3, the calibrated score defaults to 51.  
The continuous PAM scores are then categorized into four levels for descriptive purposes: 
according to the materials supplied by Insignia, scores less than 47.1 are level 1, scores between 


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47.1 and 53.2 are level 2, scores between 53.3 and 70.2 are level 3, and scores above 70.2 are 
level 4. 
The following endpoints will be analyzed with PAM PROMs Questionnaire data. 
• 
Endpoint: Mean difference in total score using the validated Patient Activation Measure 
(PAM) questionnaire administered after treatment at day 90. Summary measure: 
Difference between treatment groups in mean change in total scores from baseline to Day 
90. 
• 
Endpoint: Measures of adherence to cardiovascular disease self-management using the 
validated Patient Activation Measure (PAM) questionnaire administered after treatment at 
day 90 and using assessment of medication adherence during the study period. Summary 
measure: The frequency and percentages of subjects in the four levels of the PAM scores 
(below) will be summarized. Note that highly activated patients (level 3 and level 4) are 
more likely to adhere to cardiovascular self-management and thus medication adherence. 
Level 1: Disengaged and overwhelmed 
Level 2: Become aware but still struggling 
Level 3: Taking action 
Level 4: Maintaining behaviors and pushinng further 
2.6.2 
Statistical hypothesis, model, and method of analysis 
The key secondary variables will be analyzed as follows: 
• 
Mean difference in total score using the validated CSQ-8 (Client Satisfaction 
Questionnaire) administered after treatment at day 90 between the groups will be 
analyzed using ANOVA. The test statistics, mean difference,  95% confidence interval 
and the p-value obtained using the ANOVA will be presented. 
• 
The comparison between inclisiran and inclisiran + behavioural support also will be 
done and presented as mentioned above. Inclisiran arm will be considered as control for 
this analysis. 
• 
The descriptive statistics for the total CSQ score will be provided for each treatment 
group. 
 
• 
Mean difference in total score using the validated Patient Activation Measure (PAM) 
questionnaire administered after treatment from baseline today 90 will be analyzed 
using ANCOVA model. ANCOVA model which assumes unequal variances for 
treatment group will be used. The model will include the fixed effects of treatment group 
with baseline total scores as a covariate. The estimate and corresponding 2-sided 95% 
confidence intervals of mean difference between treatment groups will be calculated. p-
value for hypothesis test for mean difference will also be provided. The FAS will be 
used for this analysis. 
• 
The comparison between inclisiran and inclisiran + behavioural support also will be 
done and presented as mentioned above. Inclisiran arm will be considered as control for 
this analysis. 


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• 
Measures of adherence to cardiovascular disease self-management using the validated 
Patient Activation Measure (PAM) questionnaire administered after treatment at day 90 
and using assessment of medication adherence during the study period will be 
summarized by providing the frequency and percentages of subjects in the four levels 
of the PAM scores (below) by visit and treatment. Note, highly activated patients (level 
3 and level 4) are more likely to adhere to cardiovascular self-management and thus 
medication adherence. 
Level 1: Disengaged and overwhelmed 
Level 2: Become aware but still struggling 
Level 3: Taking action 
Level 4: Maintaining behaviors and pushinng further 
• 
Also frequecncy and percentage of subjects completed each item of PAM questionnaire 
will be summarized by visit and treatement. 
2.6.3 
Handling of missing values 
No imputation will be applied if the scores are missing at a visit in any the questionnaire. The 
proportion of missing data will be included in summaries to aid interpretation. 
2.7 
Safety analyses 
For all safety analyses, the safety set will be used. 
Safety summaries (tables, figures) will include only treatment emergent adverse events (i.e. 
adverse events started after the first dose of study treatment or adverse events that were present 
prior to start of study treatment but increased in severity during the course of the study). Listings 
will include all data.  
Vital signs values that have complete data and time values will be allocated to pre- or post-dose 
assessment (as per protocol) based on the actual date/time. For values with missing date/time, 
scheduled visit date and time will be used. This rule will be applied to data from scheduled 
visits only. If a measurement scheduled as pre-dose is actually performed post-dose, or vice 
versa, the data will not be used for by visit/time point summary. 
2.7.1 
Adverse events (AEs) 
The number (and percentage) of participants with TEAEs will be summarized by treatment 
groups and overall in the following ways:  
• 
By treatment, primary system organ class (SOC) and preferred term (PT).  
• 
By treatment, primary system organ class (SOC), PT and maximum severity.  
• 
By treatment, Standardized MeDRA query (SMQ) and PT.  
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to treatment discontinuation.  
Unless otherwise specified, SOCs will be sorted alphabetically and, within each SOC, the PTs 
will be sorted in descending order of frequency in the total column. A participant with multiple 


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adverse events within the same PT, the AE will be counted only once. A participant with 
multiple adverse events within a primary system organ class is only counted once towards the 
total of the primary system organ class. 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. 
AE reporting for CT.gov and EudraCT: For the legal requirements of clinicaltrials.gov and 
EudraCT, two required tables on treatment emergent adverse events which are not serious 
adverse events, on treatment emergent serious adverse events and SAE suspected to be related 
to study treatment will be provided by system organ class and preferred term 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.  
2.7.1.1 
Adverse events of special interest / grouping of AEs 
Adverse event of special interest (AESI): The number and percentage of participants who 
reported TEAEs of special interest will be summarized by PT, treatment group. 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. 
Listing of participants with adverse event of special interest will be provided. 
The Compound Case Retrieval Strategy (CRS) will be used to determine the MedDRA search 
criteria to be used to identify events of special interest.  
Adverse event of special interest will include the following:  
• 
Hepatotoxicity (Hepatic events) 
• 
New onset or worsening of diabetis mellitus 
For search criteria of AE of special interest, refer to Appendix 5.3. 


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The most recent list of adverse events of special interest at the time of database lock will be 
used. CRS listing will be provided. 
2.7.2 
Deaths 
Please refer section 2.7.1. 
2.7.3 
Laboratory data 
There are no regular laboratory tests required by this protocol. All blood tests will be performed 
locally by clinical pathology laboratories, in common with usual practice. Methods for 
sampling, handling and analysis will be the same as usually applied in routine care.  
Abnormal laboratory findings, that are detected during the study or are present at baseline and 
significantly worsen following study drug administration, and are deemed as clinically 
significant by the investigator will be recorded as AEs if they lead to treatment discontinuation. 
2.7.4 
Other safety data 
2.7.4.1 
Vital signs 
Absolute values, change from baseline and percentage change from baseline will be 
summarized for vital sign parameters by visit, time point and treatment group using overall data. 
Baseline and change from baseline in height, 
 will be summarized 
by visit, treatment group using overall data.  
All vital signs data will be listed by treatment group, participant, and visit/time and if ranges 
are available, abnormalities will be flagged. 
2.8 
Patient-reported outcomes 
2.8.1 
The CSQ-8 PROMs Questionnaire 
The details about Client Satisfaction Questionnaire (CSQ) and the endpoints were mentioned 
in section 2.6.1.1. For more details on the questionnaire, please refer to the study protocol. 
2.8.2 
The PAM PROMs Questionnaire 
The details about Patient Activation Measure (PAM) Questionnaire and the endpoints were 
mentioned in section 2.6.1.2. For more details on the questionnaire, please refer to the study 
protocol.  
2.8.3 
 
 
  
2.9 
 
 
 
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2.10 
 
  
 
 
 
 
 
 
 
 
 
  
2.10.1 
Other efficacy data 
A capillary blood sample will be taken for immediate analysis of the participants lipid 
profile
 for assessment of efficacy. This will be performed at screening/baseline visit, 
day 90 visit and EOS (day 270) visit  in the following:  
 
 
 
 
 
 
• 
Non-HDL (calculated)  
• 
LDL-C calculated using Friedwald  
Descriptive summaries by treatment group will be presented. 
 
 
Line-Plot displaying mean and SE of change from baseline will be provided for all parameters 
using all available visits.  
 
Descriptive summaries by treatment group will be presented. 
Listing of all above endpoints for all available visits will be provided. 
The threshold analysis on LDL-C data will be performed. Frequency and percentage of patients 
with secondary prevention who achieved following threshold targets at day 270 will be 
provided. 
• 
<1.8 mmol/L (<70 mg/dL) 
• 
<1.4 mmol/L (<55 mg/dL) 
2.10.2 
 
 
 
 
  
PPD
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P
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2.10.3 
 
 
 
 
2.11 
Interim analysis 
There are no interim analyses planned for this study. 
3 
Sample size calculation 
The primary effectiveness endpoint of the study is percent change of LDL-C from baseline. 
However, the sample size is driven by patient experience (CSQ-8) and patient activation 
(PAM); two key secondary outcomes in this trial.  
The trial has been powered to detect differences equivalent to a Cohen’s effect size of 0.3, 
approximating a ‘small-to-medium’ effect in conventional terms  
A sample size of 300 patients per arm would be able to detect this effect size with 90% power 
using a one-sided significance level of 0.025 (this includes a 20% allowance for drop-out in this 
primary care setting).  
This sample size could also detect a reduction of at least 10% change of LDL-C from baseline 
in the inclisiran group compared to the control group (assuming a standard deviation of 30% in 
the control group and 20% in the inclisiran group based on observed results from previous 
inclisiran studies).  
The total sample size for the study will be 900 participants. 
4 
Change to protocol specified analyses 
• 
 
 
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
Missing/partial start date or end date of treatment will not be imputed. 
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5.1.2 
AE date imputation 
5.1.2.1 
AE start date imputation 
The following table explains the notation used in the logic matrix. Please note that completely 
missing start dates will not be imputed. 
 
Day 
Month 
Year 
Partial Adverse Event Start Date 
Not used 
MON 
YYYY 
Treatment Start Date 
Not used 
TRTM 
TRTY 
The following matrix explains the logic behind the imputation. 
 
MON MISSING 
MON < TRTM 
MON = TRTM 
MON > TRTM 
YYYY MISSING 
( 1 ) 
No convention 
( 1 ) 
No convention 
( 1 ) 
No convention 
( 1 ) 
No convention 
YYYY < TRTY 
( 2.a ) 
Before Treatment 
Start 
( 2.b ) 
Before Treatment 
Start 
( 2.b ) 
Before Treatment 
Start 
( 2.b ) 
Before Treatment 
Start 
YYYY = TRTY 
( 4.a ) 
Uncertain 
( 4.b ) 
Before Treatment 
Start 
( 4.c ) 
Uncertain 
( 4.c ) 
After Treatment 
Start 
YYYY > TRTY 
( 3.a ) 
After Treatment 
Start 
( 3.b ) 
After Treatment 
Start 
( 3.b ) 
After Treatment 
Start 
( 3.b ) 
After Treatment 
Start 
Before imputing AE start date, find the AE start reference date. 
• If the (imputed) AE end date is complete and the (imputed) AE end date < study drug 
start date then AE start reference date = min(informed consent date, earliest visit date). 
• Else AE start reference date = study drug start date 
Impute AE start date: 
1. If the AE start date year value is missing, the date uncertainty is too high to impute a 
rational date. Therefore, if the AE year value is missing, the imputed AE start date is set 
to NULL. 
2. If the AE start date year value is less than the treatment start date year value, the AE 
started before treatment. Therefore: 
a. If AE month is missing, the imputed AE start date is set to the mid-year point 
(01JULYYYY). 
b. Else if AE month is not missing, the imputed AE start date is set to the mid-month 
point (15MONYYYY). 
3. If the AE start date year value is greater than the study drug start date year value, the 
AE started after treatment. Therefore: 
a. If the AE month is missing, the imputed AE start date is set to the year start point 
(01JANYYYY). 
b. Else if the AE month is not missing, the imputed AE start date is set to the later of 
(month start point (01MONYYYY), AE start reference date + 1 day). 


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4. If the AE start date year value is equal to the study drug start date year value: 
a. And the AE month is missing the imputed AE start date is set to the AE reference 
start date + 1 day. 
b. Else if the AE month is less than the study drug start month, the imputed AE start 
date is set to the mid-month point (15MONYYYY). 
c. Else if the AE month is equal to the study drug start date month or greater than the 
treatment start date month, the imputed AE start date is set to the later of (month 
start point (01MONYYYY), AE start reference date + 1 day). 
If complete (imputed) AE end date is available and the imputed AE start date is greater than the 
(imputed) AE end date, then imputed AE start date should be set to the (imputed) AE end date. 
5.1.2.2 
AE end date imputaion 
For the purpose of date imputation the treatment follow-up period date is defined as the last 
available visit date. 
1. If the AE end date month is missing, the imputed end date should be set to the earliest 
of the (treatment follow up period date, 31DECYYYY, date of death). 
2. If the AE end date day is missing, the imputed end date should be set to the earliest of 
the (treatment follow up period date, last day of the month, date of death). 
3. If AE year is missing or AE is ongoing, the end date will not be imputed. 
4. If the imputed AE end date is less than the existing AE start date then use AE start date 
as AE end date. 
5.1.3 
Concomitant medication date imputation 
5.1.3.1 
CM start date imputation 
The following table explains the notation used in the logic matrix. 
 
Day 
Month 
Year 
Partial CM Start Date 
Not used 
MON 
YYYY 
Treatment Start Date 
Not used 
TRTM 
TRTY 
The following matrix explains the logic behind the imputation. 
 
MON MISSING 
MON < TRTM 
MON = TRTM 
MON > TRTM 
YYYY MISSING 
( 1 ) 
Uncertain  
( 1 ) 
Uncertain 
( 1 ) 
Uncertain 
( 1 ) 
Uncertain 
YYYY < TRTY 
( 2.a ) 
Before Treatment 
Start 
( 2.b ) 
Before Treatment 
Start 
( 2.b ) 
Before Treatment 
Start 
( 2.b ) 
Before Treatment 
Start 
YYYY = TRTY 
( 4.a ) 
Uncertain 
( 4.b ) 
Before Treatment 
Start 
( 4.a ) 
Uncertain 
( 4.c ) 
After Treatment 
Start 
YYYY > TRTY 
( 3.a ) 
( 3.b ) 
( 3.b ) 
( 3.b ) 


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MON MISSING 
MON < TRTM 
MON = TRTM 
MON > TRTM 
After Treatment 
Start 
After Treatment 
Start 
After Treatment 
Start 
After Treatment 
Start 
1. If the CM start date year value is missing, the imputed CM start date is set to one day prior 
to treatment start date.  
2. If the CM start date year value is less than the investigational study treatment start date year 
value, the CM started before treatment. Therefore:  
a. If the CM month is missing, the imputed CM start date is set to the mid –year point 
(01JULYYYY).  
b. Else if the CM month is not missing, the imputed CM start date is set to the mid-month 
point (15MONYYYY).  
3. If the CM start date year value is greater than the investigational study treatment start date 
year value, the CM started after treatment. Therefore:  
a. If the CM month is missing, the imputed CM start date is set to the year start point 
(01JANYYYY).  
b. Else if the CM month is not missing, the imputed CM start date is set to the month start 
point (01MONYYYY).  
4. If the CM start date year value is equal to the investigational study treatment start date year 
value:  
a. And the CM month is missing or the CM month is equal to the treatment start date month, 
then the imputed CM start date is set to one day prior to treatment start date.  
b. Else if the CM month is less than the treatment start date month, the imputed CM start 
date is set to the mid-month point (15MONYYYY).  
c. Else if the CM month is greater than the treatment start date month, the imputed CM 
start date is set to the month start point (01MONYYYY).  
If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the (imputed) CM end date, then imputed CM start date should be set to the (imputed) CM end 
date. 
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 
Search criteria for AE of special interest 
The Adverse events of special interest (AESIs) based on MedDRA terms are defined in the 
Case Retrieval Strategy (eCRS). To select the corresponding records from SAS dataset ECRS 
in Novartis computing environment, use  
• Compound name (DRGNAM)=” KJX839”,  
• Compound indication (DRGINDC)=” Hypercholesterolemia”,  
• Records with MDRAVER = 25.0 


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Safety topics flagged in the eCRS using the safety flag (PSURFL =YES) will be filtered and 
further safety topics mentioned in section 2.7.1.1 will be considered for analyses. 
5.4 
Laboratory parameters derivations 
The following table shows the criteria for clinically notable laboratory values. Not all 
parameters have notable criteria defined: 
Table 5-1 
Clinical notable criteria for selected laboratory tests 
Test 
Notable post-baseline criteria 
Glucose, fasting 
≥ 5.5 to < 7.0 mmol/L 
≥ 7.0 mmol/L 
HbA1c 
≥ 5.7 % to < 6.5 % (≥ 39 mmol/mol to < 48 
mmol/mol) 
≥ 6.5 % (≥ 48 mmol/mol) 
Table 5-2 
Notable Liver function test values 
 
The liver function tests are not required as per the assessment schedule of the protocol. This 
data collected from EMR based on the availability. Whatever data collected will be presented. 


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Normal ranges provided by medical team will be considered for this analysis since reference 
ranges are not collected in source data. 
5.5 
Statistical models 
5.5.1 
Multiple Imputation Wash-out model 
A multiple imputation washout model will be utilized for the primary efficacy analysis of the 
percentage change in LDL-C from baseline to Day 270 endpoint. The washout model can be 
thought of as a control-based PMM that will be used to explore the possibility of missing data 
being MNAR for subjects who discontinued the study early. For subjects who discontinued the 
study early, their missing values will be imputed under the assumption that their outcome would 
be similar to those in the control group with similar background characteristics. For subjects in 
the inclisiran groups only missing Day 270 values will be imputed. 
For subjects whose LDL-C values are undetectable i.e., both baseline and post-baseline due to 
device sensitivity for a lipid parameter in inclisiran groups will be considered as missing and 
imputed under MAR assumption. 
For subjects in the control group, their missing values over all visits after early termination as 
well as undetectable values including both baseline and post-baseline due to device sensitivity 
for a lipid parameter will be imputed based on the missing at random (MAR) assumption.  
Multiple imputation will be used to account for uncertainty in the imputation process and results 
from the imputed datasets will be combined using Rubin’s method. Further details are provided 
below.  
For the control group the following variables will be included in a multiple imputation 
procedure (SAS PROC MI), this assumes missing data are MAR: 
• 
Baseline value of efficacy measurement (continuous)  
• 
Observed value of efficacy measurement at Day 90 (continuous) 
• 
Observed value of efficacy measurement at Day 270 (continuous) 
For the subjects in the inclisiran group who completed the doses and with intermittent missing 
as well as undetectable data, the following variables will be included in a multiple imputation 
procedure (SAS PROC MI), this assumes missing data are MAR: 
• 
Baseline value of efficacy measurement (continuous) 
• 
Observed value of efficacy measurement at Day 90 (continuous) 
• 
Observed value of efficacy measurement at Day 270 from the inclisiran group 
(continuous)  
For the subjects in the inclisiran groups and with missing data at Day 270 which does not 
includes undetectable data, the following variables will be included in a multiple imputation 
procedure (SAS PROC MI), this assumes missing data are MNAR: 
• 
Baseline value of efficacy measurement (continuous)  


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• 
Observed value of efficacy measurement at Day 270 from the control group (continuous) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.5.2 
Imputation of undetectable data 
For each undetectable LDL-C value, a range is determined based on Friedewald’s formula. 
Below table will provide example range calculation when 
 
 are distributed in different categories. 
Table 5-3 
Range determination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
] 
As a next step, the undetectable LDL-C values are baseline are imputed to create 500 complete 
sets of baseline LDL-C values. The imputation is performed by fitting a normal distribution to 
all available baseline LDL-C values including the LDL-C ranges. The imputed values are 
obtained by sampling from the posterior predictive distribution. As prior distribution for mean 
and the standard deviation a normal distribution (mean=0, sd=10) and a half-t-distribution (df=3, 
scale=2.5) are chosen. 
To create 500 complete data sets of baseline and post-baseline LDL-C data sets, the following 
approach is performed for each of the 500 data sets with complete baseline LDL-C data. 
1. Fit a Bayesian linear mixed model to all available post-baseline LDL-C data including 
the LDL-C ranges from Day 90 and Day 270.  
a. The model includes study arm, visit, and baseline LDL-C as well as all 
interactions as fixed effects. 
b. The model includes a normally distributed patient-specific random effect and a 
normally distributed residual error. The variance of the residual error differs by 
study arm and visit. 
 
  
PPD
PPD


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2. For the missing values or undetectable LDL-C values of patient 𝑖𝑖 at visit 𝑗𝑗 in study arm 
𝑘𝑘 that are imputed under the MAR assumption, the imputed value is drawn from the 
posterior predictive distribution of the outcome (i.e., LDL-C) of patient 𝑖𝑖 at visit 𝑗𝑗 in 
study arm 𝑘𝑘. 
3. For the missing values of patient 𝑖𝑖 at visit 𝑗𝑗 in the inclisiran arm that are imputed under 
the jump-to-reference assumption, the imputed value is drawn from the posterior 
predictive distribution of the outcome (i.e., LDL-C) of patient 𝑖𝑖 at visit 𝑗𝑗 whereas the 
components (e.g., fixed effects and random effects) of the posterior predictive 
distribution that are associated with the inclisiran arm are replaced by the corresponding 
value from the placebo arm. 
The above imputation will be carried out using R software. 
Each of the 500 complete data sets is analyzed with an ANCOVA as specified for the primary 
analysis. The resulting point estimates will be combined using Rubin’s method.  
5.6 
Rule of exclusion criteria of analysis sets  
The protocol deviations (PD) and other criteria leading to complete exclusion from analyses 
sets are provided in below table, which may be updated prospectively and will be finalized 
before study DBL. 
Table 5-4 
Protocol deviation criteria leading to exclusion from analysis sets 
Protocol Deviation 
Excluding from 
Analysis set 
ID 
Desctiption 
RAN 
FAS 
SAF 
INCL01A 
No study informed consent prior to performing study 
assessments 
X 
X 
X 
INCL01B 
No signed informed consent exists at site 
X 
X 
X 
INCL02 
Participant's age < 18 years at screening visit 
 
 
 
INCL03A 
Participant not on statin therapy and intolerance not 
documented 
 
 
 
INCL03B 
Participant is indicated to have partial statin intolerance but 
not documented 
 
 
 
INCL04 
Participant's total cholesterol not available at screening visit 
or is <4mmol/L (160mg/dL) 
 
 
 
INCL05 
Participant's lipid-lowering therapy at study entry not stable 
for ≥ 30 days before screening visit 
 
 
 
EXCL01 
Participant has medical or surgical history that might limit the 
individual’s ability to take study treatments for the duration of 
the study and/or put the participant at significant risk  
 
 
 
EXCL02 
Current or planned renal dialysis or transplantation  
 
 
 


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Protocol Deviation 
Excluding from 
Analysis set 
ID 
Desctiption 
RAN 
FAS 
SAF 
EXCL03 
Participant had acute coronary syndrome or stroke less than 
4 weeks before the screening visit 
 
 
 
EXCL05 
Participant is a female of child-bearing potential and NOT 
agreeing to either abstinence or, if sexually active, to using 
effective methods of contraception  
 
 
 
EXCL06A 
Participant confirmed to be pregnant or nursing and 
randomized 
 
 
 
EXCL06B 
Pregnancy 
test(s) 
not 
performed 
at 
screening 
or 
randomization visit 
 
 
 
EXCL07 
Treatment with monoclonal antibodies directed towards 
PCSK9 initiated at any time during the course of the study 
 
 
 
EXCL08 
Participant 
has 
previous 
exposure 
to 
inclisiran 
or 
participation in a randomised study of inclisiran 
 
 
 
EXCL09 
Participants treated with other investigational medicinal 
products or devices within 30 days or five half lives 
(whichever is longer) of the screening visit 
 
 
 
EXCL10 
Participant who plans to move away from the geographical 
area where the study is being conducted during the study 
period 
 
 
 
EXCL11 
The participant has a triglyceride value of greater than or 
equal to 4.52 
 
 
 
COMD01 
Introduction of new lipid lowering therapy (either different 
statin or new additional therapy) during the study 
 
 
 
COMD02 
Treatment with monoclonal antibodies directed towards 
PCSK9 initiated at any time during the course of the study 
 
 
 
COMD03 
Another investigational treatment initiated at any time during 
the course of the study 
 
 
 
OTH01 
Study treatment given and/or assessment(s) performed after 
withdrawal of ICF  
 
 
 
OTH02 
Subject resumes study treatment after pregnancy but 
continues breast feeding 
 
 
 
OTH03 
Site closed due to GCP reason 
 
X 
 
OTH04 
Scheduled visit missed due to COVID-19 
 
 
 
OTH05 
Participant discontinues from study due to COVID-19 
situation 
 
 
 
OTH06 
Assessment / procedure at visits changed due to COVID-19 
 
 
 
OTH07 
Drug supply method changed due to COVID-19 
 
 
 


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Protocol Deviation 
Excluding from 
Analysis set 
ID 
Desctiption 
RAN 
FAS 
SAF 
OTH08 
The participant has withdrawn from the Behavioural Support 
calls so these calls are no longer being made 
 
 
 
OTH09 
Patient received behavioural support calls when they had not 
been randomised to receive these 
 
 
 
OTH10 
Patient did not receive behavioural support calls when they 
had been randomised to receive these 
 
 
 
OTH11 
Patient visits have occurred out of visit window and/or the 
visit is very late 
 
 
 
OTH12 
Other protocol deviation 
 
 
 
WITH01 
Participant became pregnant during the course of the study 
but study treatment was not discontinued 
 
 
 
WITH02 
Participant has been treated with monoclonal antibodies 
directed  towards PCSK9 but study treatment was not 
discontinued or re-started  
 
 
 
WITH03 
Participant has received other investigational treatments but 
study treatment was not discontinued or re-started 
 
 
 
WITH04 
Participant had a severe and persistent (>14 days despite 
appropriate treatment) injection site reaction but study 
treatment was not discontinued 
 
 
 
WITH05 
Participant had a confirmed anaphylactic reaction but study 
treatment was not discontinued 
 
 
 
TRT01 
Participant was given wrong medication number/pack or 
administered with study drug that was not stored 
appropriately or dosed with expired medication 
 
 
 
TRT02 
Participant was not randomized but took study drug 
X 
X 
 
TRT03 
Participant received study drug between screening visit and 
randomization (Day 1) visit by mistake 
 
 
 
TRT04 
Missed dosing for any reason other than participant safety or 
withdrawal (and non-COVID-19 related) 
 
 
 
TRT05 
Participant did not receive study treatment due to COVID-19 
 
 
 
TRT06 
Participant discontinues from treatment due to COVID-19 
situation 
 
 
 
6 
Reference 
CKJX839A1GB01 amended protocol v02 dated 12-Sep-2022. 
Attkisson, C. C. & Zwick, R. The client satisfaction questionnaire. Psychometric properties 
and correlations with service utilization and psychotherapy outcome. Eval. Program Plan. 5, 
233–237 (1982) 


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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.  
Hibbard J, Gilburt H. Supporting people to manage their health: An introduction to patient 
activation. 2014. The King’s Fund. 25-12-0016. http:// 
www.kingsfund.org.uk/publications/supporting-people-manage-their-health  
Hibbard J, Mahoney E, Stockard J, Tusler M. Development and testing of a short form of the 
patient activation measure (PAM). Health Serv Res. 2005; 40(6):1918–30.  
Hibbard J, Stockard J, Mahoney E, Tusler M. Development of the Patient Activation Measure 
(PAM): Conceptualizing and measuring activation in patients and consumers. Health Serv 
Res. 2004;39(4):1005–26.