Clinical trial NCT02546323
Conditions: Atherosclerosis
Keywords: Rosuvastatin 20 mg treatment, Carotid Intima-Media Thickness, Chinese subjects, Subclinical atherosclerosis
Sponsor: AstraZeneca
Start date: 2015-09-17; Completion date: 2019-01-29
Enrollment: 543 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the effects of of rosuvastatin 20 mg compared to placebo for treating Chinese patients with subclinical atherosclerosis.

Detailed description:
This study is a randomized, double-blind, placebo-controlled, multicenter parallel group study assessing the effects of rosuvastatin 20 mg treatment for 104 weeks on the change in intimamedia thickness (IMT) of the common carotid artery (CCA), carotid bulb, and internal carotid artery (ICA) in adult Chinese subjects with subclinical atherosclerosis.

Arms: arm 1: 20 mg tablets, Daily oral dose arm 2: Matching placebo tablets
Interventions: intervention 1: Rosuvastatin intervention 2: Placebo
Intervention descriptions: intervention 1: 20mg tablets, orally once daily for the duration of the 104-week treatment period intervention 2: Matching placebo tablets, orally once daily for the duration of the 104-week treatment period.

Protocol documents:
Prot_000.pdf: 
1 (113)
Clinical Study Protocol
Drug Substance
Rosuvastatin calcium
Study Code
D3565C00003
Edition Number
2.0
Date
28 Mar 2018
A Randomized, Double-blind, Placebo-controlled, Multicenter Parallel 
Group Phase 3 Study Measuring the Effect of Rosuvastatin 20 mg on 
Carotid Intima-Media Thickness in Chinese Subjects
Sponsor:
AstraZeneca UK Limited, 600 Capability Green, Luton, LU1 3LU, UK
The following Amendment(s) and Administrative Changes have been made to this protocol since the date of 
preparation:
Amendment No.
Date of Amendment
Local Amendment No:
Date of Local Amendment
Administrative 
Change No.
Date of Administrative 
Change
Local Administrative 
Change No.
Date of Local 
Administrative Change
1
22-Oct-2015
This submission document contains confidential commercial information, disclosure of which is prohibited 
without providing advance notice to AstraZeneca and opportunity to object.
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The clinical study protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
2 (113)
VERSION HISTORY
 
 
 
 
CCI


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
3(113)
 
 
 
 
Initial Version 1.0, 4 Mar 2015
CCI


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
4(113)
PROTOCOL SYNOPSIS
A Randomized, Double-blind, Placebo-controlled, Multicenter Parallel 
Group Phase 3 Study Measuring the Effect of Rosuvastatin 20 mg on 
Carotid Intima-Media Thickness in Chinese Subjects
National Coordinating Investigators
Prof. Yong Jun Wang, MD 
 
 
 
Prof. Yun Dai Chen, MD 
 
 
 
Study site(s) and number of subjects planned
Approximately 506 Chinese subjects will be randomized to study treatment.  The study will be 
conducted across approximately 30 sites in China.
543 Chinese subjects were randomized into study when the recruitment was completed, these 
randomized patients were from 25 sites in China.
Study period
Phase of development
Estimated date of first subject enrolled
3Q 2015
Phase 3
Estimated date of last subject completed
1Q 2019
Phase 3
PPD
PPD


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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Study design
This study is a randomized, double-blind, placebo-controlled, multicenter parallel group study 
assessing the effects of rosuvastatin 20 mg treatment for 104 weeks on the change in intima-
media thickness (IMT) of the common carotid artery (CCA), carotid bulb, and internal carotid 
artery (ICA) in adult Chinese subjects with subclinical atherosclerosis.
Objectives
Primary Objective:
Outcome Measure:
To assess the efficacy of rosuvastatin 20 mg 
compared to placebo on slowing progression 
of carotid intima-media thickness (CIMT) over
104 weeks in Chinese subjects with subclinical 
atherosclerosis
Annualized rate of change in mean of the maximum 
(MeanMax) CIMT measurements from each of the 
12 carotid artery sites based on all scans performed 
during the 104-week study period
Secondary Objective:
Outcome Measures:
To assess the efficacy of rosuvastatin 20 mg 
compared to placebo over 104 weeks on
slowing progression of intima-media 
thickness (IMT) in carotid artery segments and 
on blood lipids in Chinese subjects with 
subclinical atherosclerosis 

Annualized rate of change in the MeanMax IMT 
of the near and far walls of the right and left CCA

Annualized rate of change in the MeanMax IMT 
of the near and far walls of the right and left 
carotid bulb

Annualized rate of change in the MeanMax IMT 
of the near and far walls of the right and left ICA

Annualized rate of change in the mean of the 
mean (MeanMean) IMT of the near and far walls 
of the right and left CCA

Change in low density lipoprotein cholesterol 
(LDL-C), total cholesterol, high density 
lipoprotein cholesterol (HDL-C), triglycerides, 
non-HDL-C, apolipoprotein (Apo) B, ApoA-I, 
non-HDL-C/HDL-C, and ApoB/ApoA-I
Safety Objective:
Outcome Measure :
To assess the safety and tolerability of 
rosuvastatin 20 mg compared to placebo over 
104 weeks in Chinese subjects with subclinical 
atherosclerosis
Safety assessments will include adverse events (AEs), 
serious adverse events (SAEs), AEs leading to 
discontinuation, changes in clinical laboratory 
analyses (chemistry, hematology, and urinalysis), 
vital signs, 12-lead electrocardiograms (ECGs), and 
physical examination


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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Target subject population
The study population will consist of asymptomatic adult, male and female Chinese subjects 
with 10-year ischemic cardiovascular disease (ICVD) risk <10% based on the 2007 China 
Adult Dyslipidemia Management Guidelines.  To qualify for entry into the study, men must 
be age ≥45 and <70 years, and women must be age ≥55 and <70 years, with HDL-C 
≤60 mg/dL (1.6 mmol/L).  At screening subjects must be asymptomatic.
Subjects with only hypertension and age as cardiovascular disease (CVD) risk factors or 
subjects without hypertension who have 3 or more other risk factors (including age) must 
have:

Fasting LDL-C of ≥120 mg/dL (3.1 mmol/L) and <160 mg/dL (4.1 mmol/L).
Subjects without hypertension who have fewer than 3 other risk factors (including age) must 
have:

Fasting LDL-C of ≥120 mg/dL (3.1 mmol/L) and <190 mg/dL (4.9 mmol/L).
Additionally, all subjects must have triglycerides <500 mg/dL (5.65 mmol/L) and a maximum 
IMT of ≥1.2 mm and <3.5 mm.
Duration of treatment
Rosuvastatin or placebo will be administered once daily for a 104-week treatment period.
Investigational product, dosage and mode of administration
The investigational product will be rosuvastatin 20 mg and placebo in oral tablet form for 
once daily use.  Subjects will be encouraged to take the medication at the same time each day.
Statistical methods
Analysis sets
Three analysis sets will be used for data analysis:

The intent-to-treat (ITT) population consists of all randomized subjects.  Subjects 
will be analyzed according to the treatment randomized.

The per-protocol (PP) population is a subset of the ITT population that includes 
subjects without any important protocol deviations.  The criteria for important 
protocol deviations will be defined in the statistical analysis plan.  Subjects will be 
analyzed according to the treatment actually received.  

The safety analysis set will consist of all subjects who take at least 1 dose of 
investigational product or placebo.  Subjects will be analyzed according to 
treatment actually received.  For subjects who received both treatments during the 


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
7(113)
study, the algorithm to be used for assignment of treatment will be detailed in the 
statistical analysis plan.
The ITT population will be the primary efficacy analysis population.  The CIMT analysis will 
be performed based on both the ITT and PP populations, and lipid and apolipoprotein analyses 
will be performed on the ITT population only.  Safety parameters will be summarized on the 
safety analysis set.
Methods for statistical analysis
A linear mixed-effects model will be used for the CIMT primary analysis to assess the 
difference in the annualized rate of change in the MeanMax CIMT measurements across 
12 carotid artery sites between rosuvastatin 20 mg and placebo treatment over 104 weeks.  
For the primary efficacy analysis, the dependent variable is the maximum CIMT measurement 
from 3 interrogation angles at each of the 12 carotid artery sites at each timepoint of CIMT 
measurement during the 104-week study period.  The model includes fixed effects for 
treatment group, time, time by treatment interaction, ICVD risk (<5%/5% to 10%), age, sex, 
centre and scan reader, and random effects for the intercept and slope at the individual subject 
level and carotid artery site within subject.  Ultrasound machine will be included as a fixed 
effect as well if different types of machines are deployed across sites.  For time of CIMT 
measurement, the 2 pre-randomization visits and the final 2 visits at the end-of-study will be 
treated as separate time points.  Details will be defined in the Statistical Analysis Plan.  Time, 
as a continuous variable, is the interval from the date of randomization to the date of CIMT 
measurement.  Differences in annualized change between rosuvastatin and placebo will be 
evaluated by testing the time-by-treatment interaction term.
The same statistical method used for the primary efficacy analysis will be applied to model the 
segment-specific secondary CIMT efficacy outcome measurements.  The difference in the 
annualized rate of change between rosuvastatin and placebo for the secondary CIMT outcome 
measures will also be evaluated by testing the time-by-treatment interaction term in each 
model fitting.
Secondary lipid and lipoprotein outcome measures are the percentage change from baseline, 
which will be analyzed by analysis of covariance with terms for treatment in the model.  For 
lipid measurements (LDL-C, total cholesterol, HDL-C, triglycerides, non-HDL-C, non-HDL-
C/HDL-C), both the analysis of the percent change from baseline at the final visit and the 
analysis of the percent change from baseline to time-weighted average during treatment will 
be performed.  In the evaluation of change from baseline to final visit, missing observations 
will be imputed by last observation carried forward (LOCF).  The time-weighted average lipid 
value is defined as the lipid value multiplied by the number of days since the last lipid 
assessment, summed for all lipid observations, and divided by the sum of days between all 
visits.  No imputation will be made for lipid missing values for the time-weighted average 
analysis.  For apolipoprotein measurements (ApoB, ApoA-I, ApoB/ApoA-I), the analysis of 
the percent change from baseline to final visit (LOCF) will be performed.


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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No multiplicity adjustment will be applied to the secondary efficacy analysis.
Safety outcome measures including AEs, SAEs, AEs leading to discontinuation, changes in 
clinical laboratory analyses (chemistry, hematology, and urinalysis), vital signs, 12-lead 
ECGs, and physical examination will be summarized descriptively for the safety analysis set.  
No formal statistical tests will be performed.
The study does not include any interim analysis.


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
9(113)
TABLE OF CONTENTS
PAGE
TITLE PAGE............................................................................................1
VERSION HISTORY...............................................................................2
PROTOCOL SYNOPSIS..........................................................................4
TABLE OF CONTENTS..........................................................................9
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..............15
1.
INTRODUCTION ..................................................................................17
1.1
Background and rationale for conducting this study ................................17
1.2
Rationale for study design, doses and control groups...............................19
1.3
Benefit/risk and ethical assessment .........................................................21
1.4
Study Design...........................................................................................22
2.
STUDY OBJECTIVES...........................................................................23
2.1
Primary objective....................................................................................23
2.2
Secondary objectives...............................................................................23
2.3
Safety objectives.....................................................................................23
3.
SUBJECT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL..........24
3.1
Inclusion criteria .....................................................................................24
3.2
Exclusion criteria ....................................................................................24
3.3
Subject enrollment and randomization.....................................................26
3.4
Procedures for handling incorrectly enrolled or randomized subjects.......26
3.5
Methods for assigning treatment groups..................................................27
3.6
Methods for ensuring blinding ................................................................27
3.7
Methods for unblinding...........................................................................28
3.8
Restrictions.............................................................................................28
3.9
Discontinuation of investigational product ..............................................29
3.9.1
Procedures for discontinuation of a subject from investigational product.30
3.10
Criteria for withdrawal............................................................................30
3.10.1
Screen failures ........................................................................................30
3.10.2
Withdrawal of the informed consent........................................................30
3.11
Discontinuation of the study....................................................................31


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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4.
STUDY PLAN AND TIMING OF PROCEDURES................................31
4.1
Screening period .....................................................................................33
4.1.1
Visit 1 (Week -6) ....................................................................................33
4.1.2
Visit 2 (Week -4) and Visit 3 (Week -2)..................................................34
4.2
Treatment period.....................................................................................34
4.2.1
Visit 4 (Week 0; Baseline) ......................................................................34
4.2.2
Visit 5 (Week 6)......................................................................................35
4.2.3
Visit 6 (Week 13)....................................................................................35
4.2.4
Visit 7 (Week 26)....................................................................................36
4.2.5
Visit 8 (Week 39)....................................................................................36
4.2.6
Visit 9 (Week 52)....................................................................................36
4.2.7
Visit 10 (Week 65)..................................................................................37
4.2.8
Visit 11 (Week 78)..................................................................................37
4.2.9
Visit 12 (Week 91)..................................................................................38
4.2.10
Visit 13 (Week 104)................................................................................38
4.2.11
Early Termination Visit...........................................................................39
4.3
Follow-up period.....................................................................................39
5.
STUDY ASSESSMENTS.......................................................................39
5.1
Efficacy assessments...............................................................................40
5.1.1
IMT Assessment .....................................................................................40
5.1.2
Lipid parameters .....................................................................................40
5.2
Safety assessments..................................................................................41
5.2.1
Laboratory safety assessments.................................................................41
5.2.2
Medical history and physical examination (including height and weight) 42
5.2.3
ECG........................................................................................................43
5.2.4
Vital signs...............................................................................................43
5.3
Other assessments...................................................................................43
5.3.1
Risk assessment ......................................................................................43
5.4
Pharmacokinetics ....................................................................................43
5.5
Pharmacodynamics .................................................................................43
5.6
Pharmacogenetics ...................................................................................43
5.7
Biomarker analysis..................................................................................43
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT..................44
6.1
Definition of adverse events....................................................................44
6.2
Definitions of serious adverse event ........................................................44
6.3
Recording of adverse events....................................................................44
6.3.1
Time period for collection of adverse events ...........................................44
6.3.2
Follow-up of unresolved adverse events..................................................44
6.3.3
Variables.................................................................................................45


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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6.3.4
Causality collection.................................................................................46
6.3.5
Adverse events based on signs and symptoms.........................................46
6.3.6
Adverse events based on examinations and tests .....................................46
6.3.7
Hy’s Law ................................................................................................47
6.4
Reporting of serious adverse events ........................................................47
6.5
Overdose.................................................................................................47
6.6
Pregnancy ...............................................................................................48
6.6.1
Maternal exposure...................................................................................48
6.6.2
Paternal exposure....................................................................................49
6.7
Management of investigational product-related toxicities: Dose 
reductions ...............................................................................................49
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ........49
7.1
Identity of investigational product(s).......................................................49
7.2
Dose and treatment regimens ..................................................................49
7.3
Labelling.................................................................................................49
7.4
Storage....................................................................................................49
7.5
Compliance.............................................................................................50
7.6
Accountability.........................................................................................50
7.7
Concomitant and other treatments ...........................................................51
7.7.1
Prohibited medications............................................................................51
7.7.2
Warfarin (including warfarin derivatives and Coumadin) ........................52
7.7.3
Other concomitant treatment ...................................................................52
8.
STATISTICAL ANALYSES..................................................................52
8.1
Statistical considerations .........................................................................52
8.2
Sample size estimate ...............................................................................52
8.3
Definitions of analysis sets......................................................................53
8.3.1
Efficacy analysis sets ..............................................................................53
8.3.2
Safety analysis set...................................................................................53
8.4
Outcome measures for analyses...............................................................53
8.4.1
Primary variable......................................................................................53
8.4.2
Secondary variables ................................................................................53
8.4.3
Safety variables.......................................................................................54
8.5
Methods for statistical analyses...............................................................54
8.5.1
Analysis of the primary efficacy variable ................................................54
8.5.2
Analysis of the secondary efficacy variables ...........................................55
8.5.3
Safety Analysis .......................................................................................55
8.5.4
Demographics and baseline data..............................................................56
8.5.5
Subgroup analysis...................................................................................56


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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8.5.6
Interim analysis.......................................................................................56
8.5.7
Sensitivity analysis..................................................................................56
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA..............56
9.1
Training of study site personnel ..............................................................56
9.2
Monitoring of the study...........................................................................56
9.2.1
Source data .............................................................................................57
9.2.2
Study agreements....................................................................................57
9.2.3
Archiving of study documents.................................................................57
9.3
Study timetable and end of study.............................................................57
9.4
Data management by AstraZeneca ..........................................................58
10.
ETHICAL AND REGULATORY REQUIREMENTS............................58
10.1
Ethical conduct of the study ....................................................................58
10.2
Subject data protection............................................................................58
10.3
Ethics and regulatory review ...................................................................59
10.4
Informed consent ....................................................................................59
10.5
Changes to the protocol and informed consent form................................60
10.6
Audits and inspections ............................................................................60
11.
LIST OF REFERENCES ........................................................................61
12.
APPENDIX ............................................................................................65
12.1
Appendix A Additional Safety Information.............................................66
12.2
Appendix B International Airline Transportation Association (IATA) 6.2 
Guidance Document................................................................................69
12.3
Appendix C Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law....................................................................71
12.3.1
Introduction ............................................................................................72
12.3.2
Definitions ..............................................................................................72
12.3.3
Identification of potential hy’s law cases.................................................72
12.3.4
Follow-up ...............................................................................................73
12.3.4.1
Potential Hy’s Law Criteria not met ........................................................73
12.3.4.2
Potential Hy’s Law Criteria met..............................................................73
12.3.5
Review and Assessment of potential hy’s law cases ................................74
12.3.6
References ..............................................................................................75
12.4
Appendix D Guidance for Management of Muscle Symptoms and 
Increased Creatine Kinase (CK) ..............................................................76
12.5
Appendix E Therapeutic Lifestyle Changes (TLC) Diet ..........................79
12.6
Appendix F Definition of China Adult Dyslipidemia Management 
Guidelines Risk Factors ..........................................................................81


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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12.7
Appendix G Carotid Ultrasound Process .................................................83
12.7.1
Ultrasound Training and Certification .....................................................86
12.7.1.1
Introduction ............................................................................................86
12.7.1.2
Training ..................................................................................................86
12.7.1.3
Sonographer Certification .......................................................................86
12.7.1.4
Reader Certification................................................................................87
12.7.1.5
Performance and Maintenance of Equipment ..........................................87
12.7.1.6
Image Data Recording.............................................................................87
12.7.1.7
Contact Addresses...................................................................................87
12.7.2
Ultrasound Exam Summary ....................................................................89
12.7.2.1
Extensive Carotid Disease.......................................................................89
12.7.2.2
Carotid Segments....................................................................................89
12.7.2.3
Standardized Interrogation Angles ..........................................................90
12.7.2.4
Instrumentation.......................................................................................91
12.7.2.5
Personnel ................................................................................................92
12.7.2.6
Administration of Image Data .................................................................92
12.7.2.7
Exclusion Guidelines Based On Carotid Ultrasound................................92
12.7.3
Ultrasound Protocol ................................................................................93
12.7.3.1
Exploratory Scout Scan...........................................................................95
12.7.3.2
Transverse Exploratory Scan...................................................................95
12.7.3.3
OAI (Optimal Anatomical Interrogation) Angle ......................................96
12.7.3.4
Longitudinal Exploratory Scan................................................................97
12.7.3.5
Preliminary Scan.....................................................................................98
12.7.3.6
Longitudinal Scan for 12 Selections at Defined Angles ...........................98
12.7.3.7
Confirmation of Tip of Flow Divider, Boundary Optimization and Focus 
Setting ..................................................................................................100
12.7.4
Comprehensive Protocol Overview/Summary.......................................101
12.7.4.1
Sonographer Work Protocol..................................................................101
12.7.4.2
Start of the 12 Selections.......................................................................101
12.7.5
Ultrasound Image Reading....................................................................103
12.7.5.1
Reading Protocol...................................................................................103
12.7.5.2
Reading Station Instrumentation ...........................................................103
12.7.5.3
Personnel ..............................................................................................103
12.7.5.4
Acquisition of B-mode Image Measurement Data .................................103
12.7.5.5
Image Frame Selection from Digital Files .............................................103
12.7.5.6
Marking of Arterial Boundaries.............................................................104
12.7.5.7
Doppler Data Analysis ..........................................................................104
12.7.5.8
Primary CIMT Outcome .......................................................................104
12.7.5.9
Secondary CIMT Outcomes..................................................................104
12.7.5.10 Transmission of Data ............................................................................104
12.7.6
Timing of the Reading Process..............................................................105
12.7.6.1
Screening Scans....................................................................................105
12.7.6.2
Initial Follow-up Scans .........................................................................105
12.7.6.3
Batch Readings at Close-out .................................................................105
12.7.7
Quality Control/Quality Assurance Procedures......................................106
12.7.7.1
Purpose of QC/QA Programs ................................................................106


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Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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12.7.7.2
Monitoring Ultrasound Equipment Performance ...................................106
12.7.7.3
Monitoring Sonographer Performance...................................................107
12.7.7.4
Monitoring Reader Performance ...........................................................108
12.7.7.5
Use of Study Data.................................................................................109
12.7.7.6
Safety Monitoring .................................................................................109
12.7.8
Archival of Ultrasound Material............................................................109
12.8
Appendix H Assumptions for Sample Size Calculation .........................111
LIST OF TABLES
Table 1
Study plan................................................................................................ 32
Table 2
Laboratory Safety Assessments................................................................ 42
Table 3
Disallowed concomitant medications ....................................................... 51
LIST OF FIGURES
Figure 1 Study flow chart....................................................................................... 22
Figure 2 Three 10 mm segments (CCA/BIF/ICA), the tip of the flow divider (TFD) 
and the 6 boundaries. Gridlines were used to indicate the segments and to 
position the TFD in a standard way.......................................................... 90
Figure 3 The Meijer’s Carotid Arc is used to position the transducer at the 6 
predefined angles..................................................................................... 91
Figure 4 Example of ECG placement ..................................................................... 93
Figure 5 Example of the scan position and arc placement....................................... 94
Figure 6 Position the head of the participant 45 degrees to the contra-lateral side 
using the Meijer’s Carotid Arc; position the transducer 45 degrees to the 
posterior. ................................................................................................. 96
Figure 7 The different transverse orientations of the artery with the degrees of 
movement to obtain the OAI. In the lighter shade orientations the 
movement is towards the anterior. ........................................................... 97
Figure 8 The scan approach to obtain the OAI from the transverse plane and the 
longitudinal image of that particular scan plane ....................................... 97
Figure 9 Example of 3 selections: Text and/or on-screen indicators are placed to 
confirm the segment of interest and the scan angle................................... 99
Figure 10 Schematic overview of the carotid artery with the sequence of image 
selections illustrated .............................................................................. 100


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
15(113)
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this Clinical Study Protocol.
Abbreviation or 
special term
Explanation
AE
Adverse event
ALT
Alanine aminotransferase
Apo
Apolipoprotein
AST
Aspartate aminotransferase 
ATP
Adult Treatment Panel
CAD
coronary artery disease
CAI
Cholesterol-absorption inhibitor
CCA
Common carotid artery
CHD
Coronary heart disease
CIMT
Carotid intima-media thickness
CK
Creatine kinase
CVD  
Cardiovascular disease 
ECG
Electrocardiogram
eCRF
Electronic case report form
GCP
Good Clinical Practice
HDL-C
high-density lipoprotein cholesterol
HMG-CoA
Hydroxy-3-methylglutaryl coenzyme A
ICA
Internal carotid artery
ICH
International Conference on Harmonisation
ICVD
Ischemic cardiovascular disease
IMT
Intima-media thickness
INR
International normalized ratio
ITT
Intent-to-treat
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LDL-C
Low-density lipoprotein cholesterol
LOCF
Last observation carried forward
MeanMax
Mean of the maximum
MeanMean
Mean of the mean


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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Abbreviation or 
special term
Explanation
MI
Myocardial infarction
National Coordinating 
Investigator
The National Coordinating Investigator is the investigator coordinating the 
investigators and/or activities.  
NCEP
National Cholesterol Education Panel
PP
Per-protocol
SAE
Serious adverse event 
Statin
HMG-CoA reductase inhibitor
TLC
Therapeutic Lifestyle Changes
TSH
Thyroid stimulating hormone 
ULN
Upper limit of normal
WBDC
Web Based Data Capture


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
17(113)
1. INTRODUCTION
1.1
Background and rationale for conducting this study
Cardiovascular and cerebrovascular diseases caused by atherosclerosis are a serious problem
in China.  During the last 2 decades, the mortality and morbidity of coronary heart 
disease (CHD) has increased significantly in both cities and rural areas (Zhu et al 2007).  
Furthermore, the World Health Organization report in 1998 forecasted that the prevalence of 
CHD in China would increase 3.7-fold by the year 2030 compared with the year 2000 (WHO 
1998).
Atherosclerosis has a silent course for several decades before symptoms and atherothrombotic 
complications occur (Ross 1999), by which time the disease already has major 
histopathological consequences that are poorly reversible.  A 10-year follow-up study 
(CAFES-CAVES) showed the degree of atherosclerosis (assessed by carotid intima-media 
thickness [CIMT]) in low-risk, asymptomatic patients was strongly correlated with the 
10-year incidence of cardiovascular events (Belcaro et al 2001).  Three-hydroxy-3-
methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), which are the most 
widely used prescription medications for the treatment of hypercholesterolemia, have emerged 
as among the most effective means of reducing the risk of cardiovascular diseases (CVDs) in 
both primary and secondary prevention settings.  Statins have also been shown to slow the 
progression of, and even regress, atherosclerosis (Crouse et al 2007, Smilde et al 2001).  The
antiatherosclerotic effect of statins has been demonstrated previously for carotid 
atherosclerosis as assessed via B-mode ultrasound measurement of CIMT and for coronary 
atherosclerosis as assessed by quantitative coronary angiography and intravascular ultrasound.
Increases in CIMT can be used to evaluate early stages of atherosclerosis in a noninvasive 
manner, as CIMT increases serve as an important hazard and predictive factor of CVD (Onut 
et al 2012).  The ASAP trial demonstrated plaque regression from baseline in 
hypercholesterolemic patients treated with atorvastatin 80 mg compared to simvastatin 40 mg 
(–0.031 mm vs 0.036 mm, p < 0.0005 and p < 0.0017, respectively) (Smilde et al 2001). The 
ARBITER study similarly showed a reduction in CIMT by 0.034 mm with atorvastatin 80 mg 
vs 0.025 mm with pravastatin 40 mg after 12 months (p = 0.03) (Taylor et al 2002). Extensive 
research has confirmed that the incidence of cardiovascular events increases when CIMT is 
elevated in type 2 diabetic patients (Irie et al 2012).  Keo et al found that CIMT closely 
correlates with ischemic events in patients with atherosclerotic vascular disease (Keo et al 
2011).  In a meta-analysis, CIMT has been shown to be a reliable surrogate marker for 
cardiovascular events (Espeland et al 2005).  For these reasons as well as the fact that there is 
regulatory precedence, CIMT has been increasingly used as an endpoint in clinical trials.  
Using CIMT measurement as a biomarker for atherosclerosis progression may accelerate drug 
development by facilitating efficacy assessments before the occurrence of endpoints, such as 
myocardial infarction (MI), stroke, and death (Doneen and Bale 2013).  The 2010 China 
expert consensus on primary prevention of CVD indicated that CIMT can be used to assess 
overall cardiovascular risk (Consensus on primary prevention of CVD 2010).  The major 
advantage of CIMT is that it is completely non-invasive and can be repeated as often as 
required. It provides a continuous measure, since all subjects have a measurable carotid wall. 


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
18(113)
It is also relatively inexpensive to perform, and the technology is widely available (Onut et al 
2012).
CRESTOR™(rosuvastatin) is effective at lowering low-density lipoprotein 
cholesterol (LDL-C) concentrations.  In addition, rosuvastatin, like other statins, has favorable
effects on other components of the lipid and lipoprotein profile, such as raising high-density 
lipoprotein cholesterol (HDL-C) and reducing levels of total cholesterol and triglycerides.  
The principal evidence supporting the anti-atherosclerotic effects of rosuvastatin is based on 
the findings of METEOR, the pivotal Phase 3 registration study that evaluated the effects of 2-
year treatment with rosuvastatin 40 mg on the natural history of atherosclerosis of the carotid 
arteries (Crouse et al 2007).  The study enrolled 984 patients with hypercholesterolemia who 
were randomized in a 5:2 ratio to active treatment or placebo (702 rosuvastatin, 282 placebo).  
Patients were at low risk (defined as 10-year Framingham Risk Index <10%) for CHD
according to National Cholesterol Education Panel (NCEP) Adult Treatment Panel (ATP) III 
guidelines published in 2001 (NCEP 2001), and they were required to have evidence of 
subclinical atherosclerosis as assessed by CIMT.  Over the 2-year course of the study, 
rosuvastatin significantly slowed the progression of atherosclerotic disease as compared to 
placebo.  For the primary endpoint, there was a highly significant difference in the change in 
maximum CIMT across the 12 carotid sites relative to placebo (-0.0145 mm/year; 95% 
confidence interval for difference -0.0196, -0.0093; p<0.0001).  Rosuvastatin also delayed the 
progression of atherosclerotic disease as evidenced by a negative rate of change across the 
12 carotid sites over the 2-year study period (-0.0014 mm/year).  This delay in disease 
progression among the rosuvastatin-treated patients over the 2-year course of the study is 
particularly noteworthy when viewed in the context of the observed placebo rate of 
progression of +0.0131 mm/year (95% confidence interval 0.0087, 0.0174; p<0.0001).
Several clinical trials have shown the ability of rosuvastatin therapy to slow the progression of 
atherosclerosis in Chinese and other Asian subjects.  The REACH (Rosuvastatin Evaluation of 
Atherosclerotic Chinese Subjects) study showed that rosuvastatin therapy may induce a rapid 
and lasting decrease in carotid plaque lipid content as assessed by MRI in an average dose of 
11 mg/day after a 104-week treatment period (Du et al 2014).  A recent meta-analysis was 
conducted to determine the effect of rosuvastatin on regressing or slowing of the progression 
of carotid atherosclerosis in Chinese populations (1392 Chinese subjects treated with 
rosuvastatin from 28 studies) (Feng et al 2014).  Rosuvastatin doses ranged from 5 mg/day to 
20 mg/day, and with follow-up ranging from 6 to 12 months.  Compared with control/active
comparator groups, rosuvastatin treatment reduced intima-media thickness (IMT), plaque 
score, and plaque area, and was well tolerated in these studies.  In addition, the COSMOS 
study showed significant regression of coronary artery atheroma volume (assessed by
intravascular ultrasound) in a Japanese patient population after a 76-week rosuvastatin 
treatment period.  In that study, rosuvastatin doses were titrated based on LDL-C reduction 
using the 2.5 to 20 mg dose range, resulting in an average of dose of 16.9 mg/day (Takayama
et al 2009).


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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1.2
Rationale for study design, doses and control groups
The proposed study is designed to evaluate the effect of rosuvastatin versus placebo on 
progression of CIMT in asymptomatic Chinese subjects who have a 10-year ischemic 
cardiovascular disease (ICVD) risk <10%.  The design is based on that of the pivotal 
METEOR study but includes only Chinese subjects.
The basic principle that guides cholesterol-lowering intervention is that the intensity of 
treatment is directly related to the degree of integrated risk for CVD (NCEP 2001).  
Cardiovascular disease risk results from the integration of multiple risk factors, and the 
concept of “integrated risk” evaluation is well recognized.  Population-based risk algorithms, 
such as the Framingham Risk Score, which was also used in the pivotal study METEOR, are 
widely used to identify individuals at various risk levels of developing cardiovascular events 
and to determine the aggressiveness of preventive therapy.  However, while the Framingham 
Risk Score is established to assess CHD risk, in China the risk factor patterns and the profile 
of CVD are different (Wu et al 2006).  Stroke is twice as prevalent as CHD in China (Chinese 
Society of Cardiology 2011), so it is inappropriate to estimate the total cardiovascular risk on 
the basis of the risk of CHD alone without considering stroke.
Although CHD and stroke have some differences in origin, atherosclerosis is a common 
pathophysiological basis for both.  Hypertension, hyperlipidemia, smoking, diabetes mellitus, 
obesity, age, and sex are widely accepted as major risk factors for atherosclerosis, CHD, and 
ischemic stroke (NCEP 2001).  To properly consider the potential hazards of dyslipidemia on
the Chinese population, Chinese scholars advocate using ICVD risk to represent integrated 
cardiovascular risk and Chinese prevalence characteristics (Wu et al 2004).  The concept of 
integrating the risk of CHD and ischemic stroke into a single model and then using the 
resulting model in clinical practice is particularly valuable in countries where stroke risk is 
high, as it is in China.  The 2007 China Adult Dyslipidemia Management Guidelines 
introduced a system of risk assessment that can be employed in subjects with/without existing 
CHD (or a CHD risk equivalent) and with/without hypertension by counting categorical risk 
factors (see Appendix F).  Combining this risk assessment system with blood lipid levels 
allows CVD risk to be comprehensively estimated, allowing stratification of risk and guiding 
treatment.  The risk stratification scheme singles out hypertension to reflect the characteristics 
of Chinese clinical practice.  
In the present study, classification of patient risk and definition of therapeutic goals for 
LDL-C will be based on the 2007 China Adult Dyslipidemia Management Guidelines.  The 
10-year ICVD risk is equivalent to approximately 5% to 10% when fasting LDL-C is 
≥120 mg/dL (3.1 mmol/L) and <160 mg/dL (4.1 mmol/L) for subjects with only hypertension 
(defined as blood pressure ≥140/90 mmHg or being on antihypertensive treatment) and age as 
CVD risk factors, and subjects without hypertension who have 3 or more other risk factors 
(including age).  The 10-year ICVD risk is equivalent to <5% when LDL-C is ≥120 mg/dL 
(3.1 mmol/L) and <190 mg/dL (4.9 mmol/L) for subjects without hypertension who have
fewer than 3 other risk factors (including age). The above-mentioned subjects will be the 
target patient population for current study.


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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This subject population largely overlaps with the subject population in the METEOR study, 
and the treatment recommendation/goals are similar, following the local guideline in Chinese 
and NCEP ATP III in METEOR.
The dose of 20 mg rosuvastatin has been selected for use in the present study as it is the 
maximum approved dose in China.  In this Chinese study, the intent is to arrest the 
progression of atherosclerosis to the same degree as was demonstrated in the METEOR trial, 
which used a dose of 40 mg rosuvastatin.
This study is expected to evaluate whether similar CIMT findings will be found with 
rosuvastatin therapy in a Chinese population as were found in the METEOR study.  
Additionally, the study has been designed to comply with Chinese regulatory requirements by 
generating data from Chinese subjects.


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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1.3
Benefit/risk and ethical assessment
Clinical trials demonstrated that statin therapy is associated with a significant reduction in 
cardiovascular morbidity and mortality when used for either primary or secondary prevention 
of cardiovascular events (Collins et al 2003, Sever et al 2003, Baigent et al 2005).  A meta-
analysis by the Cholesterol Treatment Trialists shows that reduction of LDL-C with statin 
therapy significantly reduced the risk of major vascular events in individuals with a 5-year 
risk lower than 10%.  Each 1 mmol/L reduction in LDL-C produced an absolute reduction in 
major vascular events of about 11 per 1000 over 5 years (CTT Collaborators 2012).  
Additional evidence from imaging trials and epidemiologic studies suggests that initiation of 
statin therapy earlier in the course of atherosclerotic cardiovascular disease could more 
effectively prevent age-related progression of atherosclerosis. Strategies to improve primary 
prevention should be aimed at  managing the overall burden of a disease.  According to the 
American College of Cardiology/American Heart Association guidelines, statin treatment in 
the primary prevention setting is expected to benefit 40- to 75-year-old individuals who have 
LDL-C levels of 70 to 189 mg/dL, diabetes, or an estimated vascular risk ≥7.5 % (Stone et al 
2014).
Rosuvastatin has been available in China for approximately 10 years.  In various populations, 
it has been shown to be the most effective statin in improving the serum lipid profile and 
achieving LDL-C goals (Davidson 2002, Jones et al 2003, Strandberg et al 2004, Lloret et al 
2006).  Prospective, randomized studies demonstrate the ability of rosuvastatin to reduce the 
risk of cardiovascular events and stabilize atherosclerosis in Western countries in a low risk 
population.  The JUPITER (Justification for the Use of Statins in Prevention: an Intervention 
Trial Evaluating Rosuvastatin) study included 17,802 apparently healthy individuals with 
normal LDL-C (<130 mg/dL), but increased high-sensitivity C-reactive protein (≥2 mg/L) 
levels.  In this population, rosuvastatin 20 mg resulted in a significant reduction of 
cardiovascular events (by 44 %) (Ridker et al 2008).
Regarding the safety of rosuvastatin, analysis in the JUPITER trial showed that myopathy, 
hepatic injury, and cancer did not occur more frequently with rosuvastatin 20 mg than with 
placebo during its median follow up of approximately 2 years of treatment.  In our pivotal
placebo-controlled METEOR study, rosuvastatin 40 mg was well-tolerated during the 2 years 
of treatment.  No cases of hepatitis, rhabdomyolysis, or renal failure occurred.  In addition, 
Chinese patients taking 20 mg or more of rosuvastatin reported adverse events (AEs) that 
were consistent with its known safety profile or with medical conditions expected in the target 
population.  All the events are listed in the Chinese Package Insert and are consistent with the 
worldwide experience.
Overall, the benefit of rosuvastatin treatment in the prevention and management of 
atherosclerotic vascular disease appears to be greater than the risk of adverse effects.  The 
design of this study in Chinese subjects is very similar to the global METEOR study, and the 
use of placebo in such low-risk subjects is considered as ethical according to the 2007 China 
Adult Dyslipidemia Management Guidelines.  Also Therapeutic Lifestyle Changes (TLC) diet 
consultation will be provided in conjunction with study visits.  Lipid values will be monitored 
throughout the study.  Subjects will be monitored to ensure that they are within the entry 


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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criteria limits for LDL-C throughout the study. Subjects with only hypertension (defined as 
blood pressure ≥140/90 mmHg or on antihypertensive treatment) and age and no other risk 
factors and subjects without hypertension who have 3 or more other risk factors (including 
age) will be discontinued from the treatment if their LDL-C levels are ≥160 mg/dL (4.1 
mmol/L) on 2 consecutive visits during the study.  Subjects without hypertension who have
fewer than 3 other risk factors (including age) will be discontinued from the treatment if their 
LDL-C levels are ≥190 mg/dL (4.9 mmol/L) on 2 consecutive visits during the study and 
subsequent treatment will be advised by investigator based on local guideline.
More detailed information about the known benefit and risks of rosuvastatin can be found in 
the Investigator’s Brochure.
1.4
Study Design 
This study is a randomized, double-blind, placebo-controlled, multicenter parallel group study 
assessing the effects of rosuvastatin 20 mg treatment for 104 weeks on the change in IMT of 
the common carotid artery (CCA), carotid bulb, and internal carotid artery (ICA) in adult 
Chinese subjects with subclinical atherosclerosis. The study will be conducted across 
approximately 30 sites in China.  The study design is illustrated in Figure 1.
The study consists of 13 study visits:  3 for screening (Weeks -6 [Visit 1], -4
[Visit 2], -2 [Visit 3]), 1 baseline visit (Week 0, [Visit 4]), and 9 treatment visits (Weeks 6 
[Visit 5], 13 [Visit 6], 26 [Visit 7], 39 [Visit 8], 52 [Visit 9], 65 [Visit 10], 78 [Visit 11], 
91 [Visit 12], and 104 [Visit 13]).  Visits5-13 are to be conducted within ±7 days of the 
scheduled time.
Figure 1
Study flow chart


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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2. STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
To assess the efficacy of rosuvastatin 20 mg 
compared to placebo on slowing progression 
of carotid intima-media thickness (CIMT) over 
104 weeks in Chinese subjects with subclinical 
atherosclerosis 
Annualized rate of change in mean of the 
maximum (MeanMax) CIMT measurements from 
each of the 12 carotid artery sites based on all scans 
performed during the 104-week study period
2.2
Secondary objectives
Secondary Objective:
Outcome Measure :
To assess the efficacy of rosuvastatin 20 mg 
compared to placebo over 104 weeks on
slowing progression of intima-media 
thickness (IMT) in carotid artery segments and 
on blood lipids in Chinese subjects with 
subclinical atherosclerosis 

Annualized rate of change in the MeanMax IMT 
of the near and far walls of the right and left
common carotid artery (CCA)

Annualized rate of change in the MeanMax IMT 
of the near and far walls of the right and left 
carotid bulb

Annualized rate of change in the MeanMax IMT 
of the near and far walls of the right and left 
internal carotid artery (ICA)

Annualized rate of change in the mean of the 
mean (MeanMean) IMT of the near and far walls 
of the right and left CCA

Change in LDL-C, total cholesterol, HDL-C, 
triglycerides, non-HDL-C, apolipoprotein (Apo) 
B, ApoA-I, non-HDL-C/HDL-C, and 
ApoB/ApoA-I
2.3
Safety objectives
Safety Objective:
Outcome Measure :
To assess the safety and tolerability of 
rosuvastatin 20 mg compared to placebo over 
104 weeks in Chinese subjects with subclinical 
atherosclerosis
Safety assessments will include AEs, serious adverse 
events (SAEs), AEs leading to discontinuation, 
changes in clinical laboratory analyses (chemistry, 
hematology, and urinalysis), vital signs, 12-lead 
electrocardiograms (ECGs), and physical 
examination


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Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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3. SUBJECT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each subject should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule.
3.1
Inclusion criteria
For inclusion in the study, subjects should fulfill the following criteria:
1.
Provision of informed consent prior to any study-specific procedures 
2.
Male aged ≥45 and <70 years or female aged ≥55 and <70 years
3.
Subjects with only hypertension (as defined blood pressure ≥140/90 mmHg or on 
antihypertensive treatment) and age as CVD risk factors and subjects without 
hypertension who have 3 or more other risk factors (including age) must have: 

Fasting LDL C of ≥120 mg/dL (3.1 mmol/L) and <160 mg/dL (4.1 mmol/L)
Subjects without hypertension who have fewer than 3 other risk factors (including 
age) must have:

Fasting LDL-C of ≥120 mg/dL (3.1 mmol/L) and <190 mg/dL (4.9 mmol/L)
4.
Triglycerides <500 mg/dL (5.65 mmol/L) at Visit 1 (Week -6)
5.
HDL-C levels ≤60 mg/dL (1.6 mmol/L) at Visit 1 (Week -6)
6.
Maximum IMT ≥1.2 mm and <3.5 mm at any location in the carotid ultrasound 
scans conducted at both Visit 2 (Week -4) and Visit 3 (Week -2)
7.
Willing to follow all study procedures including study visits, fasting blood draws, 
and compliance with study treatment regimen
3.2
Exclusion criteria
Subjects should not enter the study if any of the following exclusion criteria are fulfilled:
1.
Use of pharmacologic lipid-lowering medications (eg, statins, fibrate derivatives, 
bile acid binding resins, niacin, or its analogues at doses >400 mg or prescribed
Chinese traditional drugs), including cholesterol-absorption inhibitors (CAIs), and 
CAI/statin combination, within 12 months prior to Visit 1 (Week -6) 
2.
Current or recent (within 2 weeks of Visit 1, Week -6) use of supplements known to 
alter lipid metabolism (eg, soluble fibers [including >2 teaspoons Metamucil® or 
psyllium-containing supplement per day] or other dietary fiber supplements, marine 


Clinical Study Protocol
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Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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oils, sterol/stanol products, or other supplement determined at the discretion of the 
investigator)
3.
History of hypersensitivity reactions to other HMG-CoA reductase inhibitors
4.
Pregnant women, women who are breast-feeding, and women of childbearing 
potential who are not using chemical or mechanical contraception or who have a 
positive serum pregnancy test
5.
Clinical evidence of coronary artery disease (CAD) or any other atherosclerotic 
disease such as angina, MI, transient ischemic attack, symptomatic CAD, 
cerebrovascular accident, percutaneous coronary intervention, coronary artery 
bypass graft, peripheral arterial disease, abdominal aortic aneurysm
6.
History of cancer (other than basal cell carcinoma) in the past 2 years
7.
Uncontrolled hypertension defined as either a mean resting diastolic blood pressure 
of ≥110 mmHg or a resting systolic blood pressure of ≥180 mmHg recorded at any 
time during the screening period
8.
History of diabetes mellitus or current diabetes mellitus
9.
Uncontrolled hypothyroidism defined as a thyroid stimulating hormone (TSH) 
>1.5 times the upper limit of normal (ULN) at Visit 1 or subjects whose thyroid 
replacement therapy was initiated within the last 3 months
10.
History of heterozygous or homozygous familial hypercholesterolemia or known 
hyperlipoproteinemia Types I, III, IV, or V (familial dysbetalipoproteinemia)
11.
Use of the disallowed concomitant medications (see Section 7.7.1, except “food    
supplement taken specifically for lipid lowering”) within 12 months prior to Visit 1 
(Week -6)
12.
History of alcohol and/or drug abuse within the past 5 years, that in the 
investigator’s opinion would jeopardize the patient’s participation in the study or 
interpretation of the data
13.
Active liver disease or hepatic dysfunction as defined by elevations of ≥1.5 x ULN 
at Visit 1 (Week -6) in any of the following liver function tests: alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), or bilirubin
14.
Serum creatine kinase (CK) >3 x ULN at Visit 1 (Week -6)
15.
Serum creatinine >2.0 mg/dL (177 mmol/L) recorded during the screening period
16.
Participation in another investigational drug study, and having ingested 
investigational drug ≤4 weeks before enrollment in the screening period


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Study Code D3565C00003
Edition Number 2.0
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17.
Previous randomization in the present study
18.
History of a significant medical or psychological condition that, in the opinion of 
the investigator, would compromise the subject’s safety or successful participation 
in the study 
19.
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site)
For the procedures for withdrawal of incorrectly enrolled subjects, see Section 3.4.
3.3
Subject enrollment and randomization
Investigator(s) should keep a record, the subject screening log, of subjects who entered 
prestudy screening.
The investigator(s) will:
1.
Obtain signed informed consent from the potential subject before any study-specific 
procedures are performed.
2.
Assign each potential subject a unique enrollment number, beginning with “E#” via 
interactive web/voice response system (IWRS/IVRS).
3.
Determine subject eligibility; see Sections 3.1 and 3.2.
4.
Assign each eligible subject a unique randomization code via IWRS/IVRS.
At the start of the screening period, each subject must be allocated an enrollment code 
(E-code)
 
At the end of the screening period, subjects who satisfy the entry criteria will be randomly 
assigned in a 1:1 ratio to 1 of the following 2 treatment groups: rosuvastatin 20 mg or placebo 
(see Section 3.5).  Randomization codes will be assigned strictly sequentially as subjects 
become eligible for randomization.  If a subject withdraws from participation in the study, 
then his/her enrollment/randomization code cannot be reused.  Once a randomization number 
has been assigned, no attempt should be made to use that number again.
3.4
Procedures for handling incorrectly enrolled or randomized subjects
Incorrectly enrolled or randomized subjects will be discontinued from further study treatment 
and assessments.  Subjects who fail to meet the eligibility criteria should not, under any 
circumstances, be enrolled or receive investigational product.  There can be no exceptions to 
this rule.  Subjects who are enrolled, but subsequently found not to meet all the eligibility 
CCI


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Edition Number 2.0
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criteria must not be randomized or initiated on treatment, and must be withdrawn from the 
study.
Where a subject does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the investigator should inform the AstraZeneca study 
physician immediately, and a discussion should occur between the AstraZeneca study 
physician and the investigator regarding whether to continue or discontinue the subject from 
treatment.  The AstraZeneca study physician must ensure all decisions are appropriately 
documented.
3.5
Methods for assigning treatment groups
 
 
 
 
 
 
 
 
3.6
Methods for ensuring blinding
Subjects, the investigator, study site personnel, and Sponsor personnel involved with data 
review and analysis will remain blinded to study treatment throughout the study.
The study treatment will be blinded by providing rosuvastatin and matching placebo tablets, 
which are indistinguishable from each other in appearance and will be presented in the same 
packaging.
Medication will be labelled using a unique kit ID number, which is linked to the 
randomization scheme.  IVRS/IWRS will allocate randomization numbers sequentially when 
sites call the IVRS/IWRS to randomize an eligible subject.  IVRS/IWRS will also allocate the 
kit ID number to be dispensed to the subject.
CCI


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Edition Number 2.0
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The treatment codes will be kept strictly within AstraZeneca to safeguard the integrity of the 
blind of investigator and subjects and hence to minimize any possible bias in data handling.
AstraZeneca patient safety only has access in the cases of emergency whereas AstraZeneca 
drug supply chain has access to enable investigational product supply.  The central laboratory 
vendor will remain unblinded to the results of all laboratory tests.  After screening, subjects
and investigational site personnel will be blinded to blood lipid levels.  A flag placed by the 
central laboratory on laboratory reports will alert site personnel that further action is indicated.
3.7
Methods for unblinding 
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the subject requires knowledge of the treatment randomization.  Only in the 
case of a medical emergency, individual treatment codes, indicating the treatment 
randomization for each randomized subject, will be available to the investigator(s) or 
pharmacists from the IVRS/IWRS.  
Routines for unblinding in the case of an emergency will be described in the IVRS/IWRS user 
manual that will be provided to each center.  The investigator will document and report the 
action to AstraZeneca, without revealing the treatment given to the subject to the AstraZeneca 
staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an investigational product and that potentially require 
expedited reporting to regulatory authorities.  Treatment codes will not be broken for the 
planned analyses of data until all decisions on the evaluability of the data from each individual 
subject have been made and documented.
3.8
Restrictions
Beginning at the screening visit, all subjects will undergo a diet and lifestyle stabilization 
period, and will receive counselling regarding the 2007 China Adult Dyslipidemia 
Management Guidelines TLC diet (see Appendix E).  The following restrictions will be
applied to subjects in this study:

Subjects who were blood donors are not to donate blood during the study or for 
3 months following their last dose of study treatment.

Subjects will fast (water is permitted) and refrain from alcohol consumption for 
8 hours before visits requiring blood collection.

Subjects should refrain from cigarette smoking on the morning of each visit.

Subjects should be advised to maintain their normal physical activities or exercise 
routines during the trial.


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
Subjects should alert the investigator regarding any elective planned surgery or 
extended travel.
3.9
Discontinuation of investigational product
Subjects may be discontinued from investigational product in the following situations, at the 
discretion of the investigator(s):

Subject decision.  The subject is at any time free to discontinue treatment, without 
prejudice to further treatment.

An AE that in the opinion of the investigator warrants subject withdrawal.

Severe non-compliance with the study protocol.

Withdrawal of informed consent.

CK >10 x ULN accompanied by muscle pain, tenderness, or weakness; see 
Appendix D for management of increased creatine kinase.

ALT or AST >3 x ULN; see Appendix C for further instruction on cases of 
increases in liver biochemistry and evaluation of Hy’s Law.

Deterioration in the subject’s condition that in the opinion of the investigator
warrants subject withdrawal.

At investigator’s discretion.

Development of a condition that made the subject high-risk, such as clinical 
atherosclerotic disease (MI, transient ischemic attack, stroke, angina pectoris, 
symptomatic CAD, peripheral arterial disease, abdominal aortic aneurysm) or 
diabetes mellitus.
Subjects will be monitored to ensure that they are within the entry criteria limits for LDL-C 
throughout the study.  Subjects will be discontinued from the treatment in 1 of 2 
circumstances based on a subject’s inclusion criteria:
1.
Subjects with no additional CVD risk factors other than age and hypertension, and
subjects without hypertension who have 3 or more other risk factors (including age) 
will be discontinued from the treatment if their LDL-C levels are ≥160 mg/dL 
(4.1 mmol/L) on 2 consecutive visits during the study.
2.
Subjects without hypertension who have fewer than 3 other risk factors (including 
age) will be discontinued from the treatment if their LDL-C levels are ≥190 mg/dL 
(4.9 mmol/L) on 2 consecutive visits during the study. 


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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The results of the LDL-C determinations will remain unblinded to the central laboratory but 
will be blinded to the investigator and site personnel after screening.  A flag on the central 
laboratory report will notify the investigator that the subject should be removed from the 
study. The subject will be discontinued from the study and complete the Early Termination 
visit procedures.  Subsequent treatment will be advised by the investigator based on local 
guidelines.  
If the subject is discontinued from investigational product, the principal investigator/sub-
investigator will perform the best possible observation(s), test(s) and evaluation(s) as well as 
give appropriate medication and all possible measures for the safety of the subject.  The 
subject will be required to attend the Early Termination visit (see Section 4.2.11) and to return 
all study medication.
In cases where a subject has been removed from study treatment for 2 weeks or longer, the 
AstraZeneca physician or designee needs to be contacted prior to any decision to permanently 
withdraw or resume investigational product.
3.9.1 Procedures for discontinuation of a subject from investigational product 
At any time, subjects are free to discontinue investigational product or withdraw from the 
study (ie, investigational product and assessments – see Section 3.10), without prejudice to 
further treatment.  A subject who decides to discontinue investigational product will always be 
asked about the reason(s) for discontinuation and the presence of any AEs.  If possible, the
subject will be seen and assessed by an investigator(s).  All AEs will be followed up (see 
Section 6), and all investigational products should be returned by the subject.
Subjects who discontinue from the investigational product should complete the Early 
Termination visit procedures.
3.10
Criteria for withdrawal 
3.10.1Screen failures 
Screening failures are subjects who do not fulfill the eligibility criteria for the study, and 
therefore, must not be randomized.  These subjects should have the reason for study 
withdrawal recorded as ‘Incorrect Enrollment’ (ie, subject does not meet the required 
inclusion/exclusion criteria).  This reason for study withdrawal is only valid for screen failures 
(not randomized subjects).
3.10.2Withdrawal of the informed consent
Subjects are free to withdraw from the study at any time (investigational product and 
assessments), without prejudice to further treatment.
A subject who withdraws consent will always be asked about the reason(s) and the presence of 
any AE.  The investigator will follow up AEs outside of the clinical study.


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
31(113)
If a subject withdraws from participation in the study, then his/her enrollment/randomization
code cannot be reused.  Withdrawn subjects will not be replaced.
When a subject is lost to follow-up (ie, fails to return for study visits), a reasonable effort (eg, 
documented by receipts for certified mailings) will be made to contact the subject to 
determine why the subject failed to return and to attempt to schedule the Early Termination 
visit (see Section 4.2.11).
3.11
Discontinuation of the study
The study may be stopped if, in the judgment of AstraZeneca, trial subjects are placed at 
undue risk because of clinically significant findings that:

meet individual stopping criteria or are otherwise considered significant 

are assessed as causally related to investigational product

are not considered to be consistent with continuation of the study
Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the eCRF.  All reasons for discontinuation of 
treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the subjects’ interests.
4. STUDY PLAN AND TIMING OF PROCEDURES
A schedule of trial procedures showing the timing of events is presented in Table 1.


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
32(113)
Table 1
Study plan
Study plan
Screening
Treatment
Visit number
1
2
3
4
5
6
7
8
9
10
11
12 13/ETa
Week number*
-6
-4
-2
0
6
13
26
39
52
65
78
91
104
Informed consent

Randomization

Vital signs








Height

Body weight



Adverse events













Concomitant medications











Medical history

Physical examination


ECG


Chemistry panel
b



c
c
c

Pregnancy test d

Hematology


Urine sample e


Serum lipid profile








ApoA-I and ApoB


Risk assessment

IMT
f
f



g
Dispense investigational 
product








Investigational product 
compliance









TLC counselling h










ALP  Alkaline phosphatase; ALT  Alanine aminotransferase; Apo  Apolipoprotein; AST  Aspartate 
aminotransferase; CK  Creatine kinase; ECG  Electrocardiogram; ET  Early termination; IMT  Intima-media 
thickness; TLC  Therapeutic Lifestyle Changes; TSH  Thyroid stimulating hormone.
* Note:  The visit window for visits5-13 is ±7 days.
a
In the event of early termination, all non-IMT procedures scheduled for Visit 13 (Week 104) are to be 
conducted.  A single IMT is to be performed on any subject who withdraws after 26 weeks.
b
Including TSH at Visit 1.
c
Abbreviated chemistry panel including liver function tests (ALT, AST, bilirubin, ALP), serum creatinine, 
and CK only.
d
Urine pregnancy test conducted at study site.  Required only for premenopausal females.  Those with 
amenorrhea for at least 1 year are exempt.
e
For complete urinalysis.


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
33(113)
f
IMT measurements at Visit 2 (Week -4) and Visit 3 (Week -2) must meet inclusion criteria of maximum 
IMT ≥1.2 mm and <3.5 mm.
g
Final IMT procedures will be scheduled before discontinuation of study treatment.  The second and final 
IMT procedure should occur at or before Visit 13 (Week 104), at the time of discontinuation of the study 
treatment.  The 2 IMT procedures for Visit 13 should be performed on different days when possible.
h
TLC counselling is to be reinforced at each clinic visit.
4.1
Screening period
Procedures will be performed according to the Study Plan shown in Table 1. At screening, 
consenting subjects are assessed to ensure that they meet eligibility criteria.  Subjects who do 
not meet these criteria must not be enrolled in the study. All the assessments and procedures 
for screening period should be performed after informed consent and within 6 weeks prior to 
subject randomization.
4.1.1 Visit 1 (Week -6)
Subjects will be required to fast for 8 hours (water permitted) prior to Visit 1 (Week -6).  
Those subjects who have failed to fast for 8 hours should return for their blood draw following 
an 8-hour fasting period.  At the visit, the following procedures will be performed:

Informed consent

Recording of vital signs

Measurement of height

Measurement of body weight

Recording of AEs

Review of prior and concomitant medications

Medical history

Chemistry panel, including TSH

Pregnancy test for premenopausal females only.  Those with amenorrhea for at least 
1 year are exempt.

Serum lipid profile

Risk assessment, including calculation of body mass index

TLC counselling 


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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4.1.2 Visit 2 (Week -4) and Visit 3 (Week -2)
At Visits 2 and 3, IMT will be performed.  Intima-media thickness measurements at both of
these visits must meet the inclusion criteria of maximum IMT ≥1.2 mm and <3.5 mm, or the 
subject is not eligible for the study.
IMT measurements at Visit 2 and Visit 3 are not mandatory to be performed on Weeks -4 and 
-2, respectively, as long as they are performed on different days after Visit1, and within 6 
weeks prior subject randomization. IMT measurement in Visit 3is to be conducted after Visit 
2 IMT measurement result meets inclusion criteria.
AE needs to be recorded in Visit2 and Visit3.
4.2
Treatment period
During the Treatment Period, the procedures will be performed according to the Study Plan 
shown in Table 1.  There will be 10 visits during the 104-week treatment period (Visits 4, 5, 6, 
7, 8, 9, 10, 11, 12, and 13 at Weeks 0, 6, 13, 26, 39, 52, 65, 78, 91, and 104, respectively).  
Visits5-13 will have a visit window of ±7 days.  
4.2.1 Visit 4 (Week 0; Baseline)
Visit 4 at Week 0 is the Baseline visit.  Subjects will be required to fast for 8 hours (water 
permitted) prior to Visit 4 (Week 0).  Those subjects who have failed to fast for 8 hours should 
return for their blood draw following an 8-hour fasting period.  At the visit, the following 
procedures will be performed:

Randomization 

Recording of vital signs 

Measurement of body weight 

Recording of AEs

Recording of concomitant medications

Physical examination 

Electrocardiogram (ECG)

Chemistry panel 

Hematology

Urine sample for complete urinalysis

Serum lipid profile 


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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
ApoA-I and ApoB 

Dispense investigational product

TLC counselling 
4.2.2 Visit 5 (Week 6)
Subjects will be required to fast for 8 hours (water permitted) prior to Visit 5 (Week 6).  Those 
subjects who have failed to fast for 8 hours should return for their blood draw following an 8-
hour fasting period.  At the visit, the following procedures will be performed:

Recording of vital signs 

Recording of AEs

Recording of concomitant medications

Chemistry panel 

Serum lipid profile 

Investigational product compliance 

TLC counselling 
4.2.3 Visit 6 (Week 13)
Subjects will be required to fast for 8 hours (water permitted) prior to Visit 6 (Week 13).  
Those subjects who have failed to fast for 8 hours should return for their blood draw following 
an 8-hour fasting period.  At the visit, the following procedures will be performed:

Recording of vital signs 

Recording of AEs

Recording of concomitant medications

Chemistry panel 

Serum lipid profile 

Dispense investigational product

Investigational product compliance 

TLC counselling 


Clinical Study Protocol
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Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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4.2.4 Visit 7 (Week 26)
At Visit 7 at Week 26, the following procedures will be performed:

Recording of AEs

Recording of concomitant medications

IMT

Dispense investigational product

Investigational product compliance 

TLC counselling 
4.2.5 Visit 8 (Week 39)
Subjects will be required to fast for 8 hours (water permitted) prior to Visit 8 (Week 39).  
Those subjects who have failed to fast for 8 hours should return for their blood draw following 
an 8-hour fasting period.  At the visit, the following procedures will be performed:

Recording of vital signs 

Recording of AEs

Recording of concomitant medications

Chemistry panel including liver function tests (ALT, AST, bilirubin, ALP), serum 
creatinine, and CK only

Serum lipid profile 

Dispense investigational product

Investigational product compliance 

TLC counselling 
4.2.6 Visit 9 (Week 52)
At Visit 9 at Week 52, the following procedures will be performed:

Recording of AEs

Recording of concomitant medications

IMT


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
37(113)

Dispense investigational product

Investigational product compliance 

TLC counselling 
4.2.7 Visit 10 (Week 65)
Subjects will be required to fast for 8 hours (water permitted) prior to Visit 10 (Week 65).  
Those subjects who have failed to fast for 8 hours should return for their blood draw following 
an 8-hour fasting period.  At the visit, the following procedures will be performed:

Recording of vital signs 

Recording of AEs

Recording of concomitant medications

Chemistry panel including liver function tests (ALT, AST, bilirubin, ALP), serum 
creatinine, and CK only

Serum lipid profile 

Dispense investigational product

Investigational product compliance 

TLC counselling 
4.2.8 Visit 11 (Week 78)
At Visit 11 at Week 78, the following procedures will be performed:

Recording of AEs

Recording of concomitant medications

IMT

Dispense investigational product

Investigational product compliance 

TLC counselling 


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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4.2.9 Visit 12 (Week 91)
Subjects will be required to fast for 8 hours (water permitted) prior to Visit 12 (Week 91).  
Those subjects who have failed to fast for 8 hours should return for their blood draw following 
an 8-hour fasting period.  At the visit, the following procedures will be performed:

Recording of vital signs 

Recording of AEs

Recording of concomitant medications

Chemistry panel  including liver function tests (ALT, AST, bilirubin, ALP), serum 
creatinine, and CK only

Serum lipid profile 

Dispense investigational product

Investigational product compliance 

TLC counselling 
4.2.10Visit 13 (Week 104)
Subjects will be required to fast for 8 hours (water permitted) prior to Visit 13 (Week 104).  
Those subjects who have failed to fast for 8 hours should return for their blood draw following 
an 8-hour fasting period.  If, at the final visit, the subject has failed to fast, the subject should 
remain on investigational product until the blood samples have been drawn.
At this last visit during the treatment period (Visit 13), the following procedures will be 
performed:

Recording of vital signs 

Measurement of body weight 

Recording of AEs

Recording of concomitant medications

Physical examination 

ECG 

Chemistry panel 

Hematology 


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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
Urine sample for complete urinalysis

Serum lipid profile 

ApoA-I and ApoB 

IMT (2 IMT procedures for Visit 13 are to be performed on different days when 
possible with the second IMT procedure occurring on or before Visit 13)

Investigational product compliance 
The final 2 IMT procedures will be scheduled before discontinuation of study treatment.  The 
second of the final 2 IMT procedures will occur at or before Visit 13 (Week 104), at the time 
of discontinuation of the study treatment.
4.2.11Early Termination Visit
The term "early termination" refers to a subject’s non-completion of a study whether by his or 
her own choice or the investigator’s decision or due to discontinuation of the study by the 
Sponsor.
In the absence of a medical contraindication or significant protocol violation, every effort will 
be made by the principal investigator to keep the subject in the study.  Should the subject 
decide to withdraw, an attempt will be made to conduct an Early Termination (ET) Visit
within 1 week of discontinuation of study treatment.  The ET visit will include all procedures 
normally done at Visit 13 (Week 104) except the IMT procedures.  A single IMT is to be 
performed on any subject who withdraws after 26 weeks.
The primary reason for a subject withdrawing prematurely should be recorded on the eCRF.
The investigator should notify the Study Physician promptly when a subject is withdrawn, or 
if the study is stopped at their site by the Independent Ethics Committee/Institutional Review 
Board, or if the investigator elects to stop the study.
4.3
Follow-up period
A follow-up period is not planned for this study.
5. STUDY ASSESSMENTS
The Rave Web Based Data Capture (WBDC) system will be used for data collection and 
query handling.  The investigator will ensure that data are recorded on the eCRF as specified 
in the study protocol and in accordance with the instructions provided.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement.  The 


Clinical Study Protocol
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Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
40(113)
investigator will sign the completed eCRFs.  A copy of the completed eCRFs will be archived 
at the study site.
5.1
Efficacy assessments
5.1.1 IMT Assessment
IMT assessment will be conducted at the times indicated in the Study Plan shown in Table 1. 
The images will be centrally evaluated at 
 or
.
Intima-media thickness measurements will be made from ultrasound images of the carotid 
arteries.  The thickness of the intima and media is determined as the distance from the 
interface between the vessel lumen and the intima, to the interface between the media and the 
adventitia.  At each imaging visit, subjects will lie in a supine position with their head turned 
to the opposite side away from the artery that is being examined.  Images will be made of the 
near and far walls of the CCA, the carotid bulb, and the ICA segments of the right and left 
carotid arteries.  The standard protocol requires each of these 12 artery segments to be imaged 
from 3 interrogation angles, each of which differs from the adjacent orientation by 30° of 
angulation (see Appendix G).  The images will be recorded and sent to 
 for evaluation.
For each carotid artery segment, the images recorded at the various interrogation angles will 
be measured to determine the largest IMT in each image.  The maximum IMT measured from 
the individual interrogation angles will be entered as the IMT value for that arterial segment.  
This process is repeated for the 12 carotid arterial segments:  the near and far walls of the 
CCA, the carotid bulb, and the ICA segments of the right and left carotid arteries.
5.1.2 Lipid parameters
Blood samples for analysis of lipid parameters will be collected at the times indicated in the 
Study Plan shown in Table 1.
Subjects must fast for at least 8 hours and must have been sitting for at least 5 minutes before 
blood samples are taken for lipid assays.  If a subject attends a study visit without having 
fasted for 8 hours, he or she must be asked to return at another time within the visit window 
for the study visit.
The central laboratory will provide the investigational sites with all the appropriate materials 
for specimen collection and sample processing, packaging, and shipping to the central 
laboratory.  A central laboratory manual providing detailed instructions will be provided to 
each investigational site before trial start.
The principal investigator will ensure that samples are labelled and shipped in accordance 
with the Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria), 
see Appendix B.  Any samples identified as Infectious Category A materials are not to be 
CCI
CCI
CCI


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
41(113)
shipped, and no further samples will be taken from the subject unless agreed with AstraZeneca 
and appropriate labelling, shipment and containment provisions are approved.
Sample analysis will be carried out in the central laboratory.
5.2
Safety assessments
Safety will be assessed by the incidence of AEs, SAEs, AEs leading to discontinuation,
changes in clinical laboratory analyses (chemistry, hematology, and urinalysis), vital signs, 
12-lead ECGs, and physical examination during treatment with rosuvastatin.  The collection 
of AEs is described in Section 6 and the other safety assessments are detailed below.
5.2.1 Laboratory safety assessments
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis 
will be taken at the times indicated in the Study Plan in Table 1.  A full clinical chemistry will 
be performed at Visit 1 (Week -6), Visit 4 (Week 0), Visit 5 (Week 6), Visit 6 (Week 13), and 
Visit 13 (Week 104), and an abbreviated chemistry panel including liver function tests (ALT, 
AST, bilirubin and ALP), serum creatinine, and CK only will be performed at Visit 8 
(Week 39), Visit 10 (Week 65), and Visit 12 (Week 91).  Additional safety samples may be 
collected if clinically indicated at the discretion of the investigator.  The date and time of 
collection will be recorded on the appropriate eCRF.
All safety laboratory analyses, other than urine pregnancy tests, will be performed by a central 
laboratory.  The safety laboratory samples will be disposed of after analysis.  The central 
laboratory will provide all collection materials and instructions for sample collection, 
packaging, and shipment.  Urine pregnancy tests will be performed at the clinical sites.
The laboratory variables shown in Table 2 will be measured.


Clinical Study Protocol
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Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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Table 2
Laboratory Safety Assessments
Hematology (whole blood)
Clinical Chemistry (serum or 
plasma)
Urinalysis
Hemoglobin
Erythrocytes
Hematocrit
Leukocyte cell count
Platelet count
Red cell distribution width
Mean corpuscular volume
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration
Percentage differential leukocyte 
count
Alanine aminotransferase 
Aspartate aminotransferase 
Creatine kinase 
Gamma-glutamyltransferase
Alkaline phosphatase
Total bilirubin
Sodium
Potassium
Calcium
Total protein
Phosphate
Albumin
Creatinine
Fasting blood glucose
Color
Appearance
Specific gravity
Urine reaction pH
Glucose
Protein (qualitative)
Ketones
Bilirubin
Occult blood
Microscopic analysis of any 
formed elements
The investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities.  The laboratory results should be signed and dated and retained at the 
center as source data for laboratory variables.  For information on how AEs based on 
laboratory tests should be recorded and reported, see Section 6.3.
Note:  If CK is ≥5 x ULN, see Appendix D.
Note:  If a subject has ALT or AST >3 x ULN, it is recommended to discontinue the 
investigational product.  See Appendix C for further instruction on cases of increases in liver 
biochemistry values and evaluation of Hy’s Law.
5.2.2 Medical history and physical examination (including height and weight)
A detailed medical history, including family history of hyperlipidemia, alcohol intake, use of
other medications or drugs, as well as CHD, and risk factors such as smoking, diabetes 
mellitus, and a family history of premature CHD will be recorded on the eCRF at Visit 1
(Week -6).
A full physical examination (including stigmata of hyperlipidemia) including cardiovascular
system, respiratory system, central nervous system, skin, gastrointestinal system, 
musculoskeletal system, endocrine system, ears, nose and throat, eyes, and lymph nodes will
be recorded at the times indicated in the Study Plan in Table 1.  Weight will be recorded at 
Visit 1 (Week -6), Visit 4 (Week 0), and Visit 13 (Week 104), and height will be recorded
only at Visit 1 (Week -6).


Clinical Study Protocol
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Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
43(113)
5.2.3 ECG
A 12-lead ECG will be performed after the subject has been lying down for 5 minutes at the 
times indicated in the Study Plan in Table 1.  Heart rate, P and QRS durations, PR, QT and 
QTc intervals will be recorded from standard lead of the computerized quantitative 12-lead 
ECG.
For information on how AEs based on ECGs should be recorded and reported, see Section 6.3.
5.2.4 Vital signs
Blood pressure and resting heart rate will be measured at the times indicated in the Study 
Plan in Table 1.  Blood pressure will be measured after the subject has been resting for
5 minutes, using a standard non-invasive equipment and recorded.  Heart rate will be taken
manually from the radial pulse.
For information on how AEs based on vital signs should be recorded and reported, see 
Section 6.3.
5.3
Other assessments
5.3.1 Risk assessment
During the screening period at Visit 1 (Week -6), subjects will be evaluated using the risk 
assessment introduced in the 2007 China Adult Dyslipidemia Management Guidelines (see 
Appendix F).  Patients with existing CHD (or a CHD risk equivalent) are at the highest risk 
and will be excluded from participation.  According to the guideline, hypertension plays a role 
equal to that of any 3 other risk factors.  Thus, subjects with hypertension and 3 or more 
additional CVD risk factors will be regarded as at high risk and will be excluded from 
participation.  The risk assessment will be determined according to the counting of categorical 
CVD risk factors of age, hypertension, smoking, obesity, family history of premature CHD, 
and HDL-C (see Appendix F).
5.4
Pharmacokinetics
Pharmacokinetic samples will not be taken during the study.
5.5
Pharmacodynamics
Pharmacodynamic samples will not be taken during the study.
5.6
Pharmacogenetics
Pharmacogenetic samples will not be taken during the study.
5.7
Biomarker analysis 
Biomarkers will not be assessed in this study.


Clinical Study Protocol
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Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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6. SAFETY REPORTING AND MEDICAL MANAGEMENT
The principal investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
6.1
Definition of adverse events
An AE is the development of an undesirable medical condition or the deterioration of a pre-
existing medical condition following or during exposure to a pharmaceutical product, whether 
or not considered causally related to the product.  An undesirable medical condition can be 
symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver) or the abnormal 
results of an investigation (eg, laboratory findings, electrocardiogram).  In clinical studies, an 
AE can include an undesirable medical condition occurring at any time, including run-in or 
washout periods, even if no study treatment has been administered.
The term AE is used to include both serious and non-serious AEs.
6.2
Definitions of serious adverse event
A serious adverse event is an AE occurring during any study phase (ie, screening, treatment, 
follow-up), that fulfills one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-patient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life functions

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardize the subject or may require 
medical intervention to prevent one of the outcomes listed above
For further guidance on the definition of an SAE, see Appendix A.
6.3
Recording of adverse events
6.3.1 Time period for collection of adverse events
All AEs, including SAEs, will be collected from the time of signature of the informed consent
throughout the treatment period and within 10 days after last dose of study drug.
6.3.2 Follow-up of unresolved adverse events
Any AEs that are unresolved at subject’s last visit/ contact in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the eCRF.  


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Study Code D3565C00003
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AstraZeneca retains the right to request additional information for any subject with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary.
6.3.3 Variables 
The following variables will be collected for each AE:

AE (verbatim)

Date and time when the AE started and stopped

Maximum intensity (mild, moderate, or severe)

Whether the AE is serious or not

Investigator causality rating against the investigational product (yes or no)

Action taken with regard to investigational product

AE caused subject’s withdrawal from study (yes or no)

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for serious AE

Date investigator became aware of serious AE

AE is serious due to

Date of hospitalization

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to study procedure(s)

Description of AE
The investigator will rate the intensity of AEs using the following scale:

mild (awareness of sign or symptom, but easily tolerated)


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Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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
moderate (discomfort sufficient to cause interference with normal activities)

severe (incapacitating, with inability to perform normal activities)
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not an SAE unless it meets the criteria 
shown in Section 6.2.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be an SAE when it satisfies the criteria 
shown in Section 6.2.
6.3.4 Causality collection
The investigator will assess causal relationship between investigational product and each AE, 
and answer “yes” or “no” to the question “Do you consider that there is a reasonable 
possibility that the event may have been caused by the investigational product?”
For SAEs, causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes.’
For a guide to the interpretation of the causality question, see Appendix A.
6.3.5 Adverse events based on signs and symptoms
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study personnel: “Have you had any health problems since the previous visit?” or 
revealed by observation will be collected and recorded in the eCRF.  When collecting AEs, 
the recording of diagnoses is preferred (when possible) to recording a list of signs and 
symptoms.  However, if a diagnosis is known and there are other signs or symptoms that are 
not generally part of the diagnosis, the diagnosis and each sign or symptom will be recorded 
separately.
6.3.6 Adverse events based on examinations and tests
The results from protocol-mandated laboratory tests and vital signs will be summarized in the 
clinical study report.  Deterioration as compared to baseline in protocol-mandated laboratory 
values, vital signs, and ECGs should therefore only be reported as AEs if they fulfill any of 
the SAE criteria or are the reason for discontinuation of treatment with the investigational 
product.
If deterioration in a laboratory value/vital sign/ECG is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated laboratory 
result/vital sign will be considered as additional information.  Wherever possible, the 
reporting investigator uses the clinical, rather than the laboratory term (eg, anemia versus low 
hemoglobin value).  In the absence of clinical signs or symptoms, clinically relevant 
deteriorations in non-mandated parameters should be reported as AE(s).


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Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE.
6.3.7 Hy’s Law
Cases where a subject shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥3 x ULN together with total bilirubin ≥2 x ULN will need 
to be reported as SAEs.  See Appendix C for further instruction on cases of increases in liver 
biochemistry and evaluation of Hy’s Law.
6.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s).  All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
the appropriate AstraZeneca representatives within 1 day (ie, immediately but no later than 
24 hours) of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within 1 calendar day (ie, immediately but no later than 24 hours) of when he or she 
becomes aware of it.
Once the investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the investigator or other study site personnel 
reports an SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the investigator/study site personnel how to 
proceed.
6.5
Overdose
There is no specific antidote to rosuvastatin.
Experience of an overdose with other statins is limited; a few cases of an overdose following 
simvastatin have been reported.  In all cases, there were no sequelae.  Monitoring of CK and 
liver enzymes (ALT, AST) is recommended.  Clinical monitoring and general supportive 
measures should be given as appropriate.


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Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module

An overdose without associated symptoms is only reported on the Overdose eCRF 
module
If an overdose on an AstraZeneca investigational product occurs in the course of the study, 
then the investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with an SAE, the standard reporting timelines apply; see Section 6.4.  
For other overdoses, reporting must occur within 30 days.
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.
6.6.1 Maternal exposure
If a subject becomes pregnant during the course of the study, the investigational product 
should be discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication.  
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs.  Elective abortions without complications should not be handled as AEs.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth or congenital abnormality) should be followed up and documented 
even if the subject was discontinued from the study.
If any pregnancy occurs in the course of the study, then the investigator or other site personnel 
informs the appropriate AstraZeneca representative within 1 day (ie, immediately but no later 
than 24 hours) of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the PREGOUT is 
used to report the outcome of the pregnancy.  


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Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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6.6.2 Paternal exposure 
Male subjects should refrain from fathering a child or donating sperm during the study and 
3 months following the last dose.
6.7
Management of investigational product-related toxicities: Dose 
reductions
Dose reductions are not permitted in this study.
7. INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
All investigational products will be supplied to the investigator by AstraZeneca in tablet 
formulation for oral use.
Investigational product
Dosage form and strength
Manufacturer
Rosuvastatin 
20 mg tablets a
AstraZeneca 
Placebo
Matching placebo tablets a
AstraZeneca 
a.
The lot number will be identified in the clinical study report. Rosuvastatin (CRESTOR) Clinical tablets for 
use in clinical trials are identical to CRESTOR commercial tablets in all aspects with the exception of the 
tablet markings.  CRESTOR Clinical tablets are plain (unmarked), while commercial tablets are marked 
(intagliated).
7.2
Dose and treatment regimens
At Visit 4 (Week 0), the subject will be randomized to either rosuvastatin 20 mg or placebo.  
Beginning at Visit 4, subjects will take the investigational product orally with water once daily
for the duration of the 104-week treatment period.  Each dose will consist of 1 tablet.  The 
subject should be encouraged to take the investigational product at the same time each day.
7.3
Labelling
The investigational product will be supplied in subject-specific labelled bottles.  Each labelled
bottle will contain sufficient medication for at least each treatment period plus overage.
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfill GMP Annex 13 requirements for labelling.  
Label text will be translated into local language.
7.4
Storage
All investigational products must be kept in a secure place under appropriate storage 
conditions, as specified on the investigational product label on each bottle.


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Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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The investigational product must be stored in its original container in a lockable storage 
facility until dispensed to the subjects and should be protected from light and moisture.  The 
investigational product must be stored below 25°C and should not be frozen.
7.5
Compliance
Subjects must return all unused medications and empty containers to the investigator.  The 
number of tablets returned at Visits 5 (Week 6), 6 (Week 13), 7 (Week 26), 8 (Week 39), 
9 (Week 52), 10 (Week 65), 11 (Week 78), 12 (Week 91) and 13 (Week 104) must be checked 
against the number of tablets dispensed to determine subject compliance.  
Compliance will be calculated, as follows:
% Compliance = # of tablets dispensed - # of tablets returned
X 100
# of days between visits X # of tablets per daily dose
A subject should be counselled on the importance of taking his or her medication as 
prescribed.  Any subject taking less than 80% of the prescribed investigational product at 
2 consecutive visits will be considered non-compliant.  The subject will continue in the study 
but will be counselled on the importance of taking his or her medication regularly.
In cases where a subject is removed from treatment for 2 weeks or longer, the AstraZeneca 
physician must be contacted prior to resuming therapy.
7.6
Accountability
The investigational products provided for this study will be used only as directed in the study 
protocol.  The investigational products are to be prescribed only by the investigator or his or 
her designee.
Subjects must return all unused medications and empty containers to the investigator.  The 
study personnel will account for all investigational products dispensed to and returned from 
the subject.
The investigator must maintain accurate records to account for the receipt of the 
investigational materials.  This record keeping consists of a dispensing record that includes the 
identification of the person receiving the medication, the date of dispensing, and any unused 
medication returned to the investigator.  The dispensing record, in addition to any drug 
accountability information, must be recorded on the eCRFs.  The delivery records must be 
able to be reconciled with records of usage and returned stocks.  Any discrepancies must be 
reconciled.  Certificates of delivery and returns must be signed by the investigator or 
responsible person.
The investigator will retain the returned medication until AstraZeneca-authorized personnel 
collect it, along with any trial treatments not dispensed.  An AstraZeneca monitor will account 
for all investigational products received at the center, unused investigational products, and 


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Edition Number 2.0
Date 28 Mar 2018
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appropriate destruction (according to local procedures).  Certificates of destruction and/or 
return should be signed.
7.7
Concomitant and other treatments 
The administration of all medication (including investigational products) must be
recorded in the appropriate sections of the eCRF.  Introduction of new concomitant
drugs should be recorded throughout the trial.
Other medication that is considered necessary for the subject’s safety and well-being may be
given at the discretion of the investigator and are acceptable, provided that these 
medications do not conflict with the exclusion criteria (Section 3.2).
Subjects must follow the medication restrictions outlined in the inclusion and exclusion 
criteria (Section 3.1 and Section 3.2, respectively) during the study.
7.7.1 Prohibited medications
With the exception of lipid-regulating drugs, the only other disallowed drugs will be
cyclosporine and tacrolimus, azathioprine sodium, and other potent immunosuppressants as 
listed in Table 3 since use of these agents may increase the risk of AEs during treatment with
rosuvastatin.
Table 3
Disallowed concomitant medications
Class of drug
Generic name
Lipid Regulation
niacin/nicotinic acid (includes vitamins/supplements with >50mg/dayniacin/nicotinic acid)
bile acid sequestrant
probucol
clofibrate
fenofibrate
gemfibrozil (and other fibrates)
all statins, such as (but not exclusively) atorvastatin, lovastatin, pravastatin, rosuvastatin (except 
for study medication), simvastatin, and fluvastatin
cholesterol-absorption inhibitor/ezetimibe
cholestyramine
cholesterol-absorption inhibitor and statins combination/vytorin
any other prescription medicine given to treat dyslipidemia
any other prescription medicine given for lipid lowering
any food supplement taken specifically for lipid lowering
Immunosuppresants
azathioprine sodium 
tacrolimus 
cyclosporine
Protease inhibitors
all protease inhibitors


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Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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7.7.2 Warfarin (including warfarin derivatives and Coumadin)
In 2 clinical studies, one in normal volunteers and the other in subjects receiving a
coumarin anticoagulant, rosuvastatin potentiated the effect of the coumarin anticoagulant.  
With rosuvastatin and other HMG-CoA reductase inhibitors, clinically evident bleeding
and/or increased prothrombin time has been reported in a few subjects taking coumarin
anticoagulants concomitantly.
For this reason, careful monitoring of international normalized ratio (INR) is required when
warfarin and blinded investigational product are co-administered at any time during the
subject’s participation during this trial.  It is suggested that the investigators should, in
accordance with usual practice, measure INR frequently until warfarin dose stabilization is 
achieved, and periodically thereafter in the following situations:

when starting warfarin therapy in a randomized subject

when a subject already receiving warfarin begins randomized trial treatment
To provide current information and advice, investigators should telephone their study monitor 
to discuss the situation with the AstraZeneca Study Team Physician.
7.7.3 Other concomitant treatment
Other medication other than that described above, which is considered necessary for the 
subject’s safety and well-being, may be given at the discretion of the investigator and recorded 
in the appropriate sections of the eCRF.
8. STATISTICAL ANALYSES 
8.1
Statistical considerations
All personnel involved with the analysis of the study will remain blinded until database lock 
and protocol violators are identified.
Analyses will be performed by AstraZeneca or its representatives.
A comprehensive Statistical Analysis Plan will be prepared and any subsequent amendments 
will be documented, with final amendments completed prior to unblinding of the data.
8.2
Sample size estimate
 
 
 
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Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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8.3
Definitions of analysis sets
8.3.1 Efficacy analysis sets
Two analysis sets will be used for efficacy evaluation:

The Intent-to-Treat (ITT) population consists of all randomized subjects.  Subjects 
will be analyzed according to the treatment randomized.

The per-protocol (PP) population is a subset of the ITT population that includes 
subjects without any important protocol deviations.  The criteria for important 
protocol deviations will be defined in the statistical analysis plan.  Subjects will be 
analyzed according to the treatment actually received.
The ITT population will be the primary efficacy analysis population.  The CIMT analysis will 
be performed based on both the ITT and PP populations, and lipid and apolipoprotein analyses 
will be performed on the ITT population only.  
8.3.2 Safety analysis set
The safety analysis set will consist of all subjects who took at least 1 dose of investigational 
product or placebo.  Subjects will be analyzed according to treatment actually received, and 
data in this population will be presented based on treatment actually received.  For subjects 
who received both treatments during the study, the algorithm to be used for assignment of 
treatment will be detailed in the Statistical Analysis Plan.
8.4
Outcome measures for analyses
8.4.1 Primary variable
Maximum CIMT measurements from 3 different angles (Max CIMT) obtained at each of the 
12 carotid artery sites at each measuring timepoint will be provided by the imaging center.  
Max CIMT measurement will be analyzed for estimation of the annualized rate of change in 
MeanMax of the 12 carotid artery sites during the 104-week study period.  The 12 carotid 
artery sites include the near and far walls of the right and left CCA, carotid bulb, and ICA.
8.4.2 Secondary variables
The secondary efficacy variables are as follows:

Max CIMT of the near and far walls of the right and left CCA
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Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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
Max CIMT of the near and far walls of the right and left carotid bulb

Max CIMT of the near and far walls of the right and left ICA

Mean CIMT (mean value of 3 CIMT measurements from the 3 angles) of the near 
and far walls of the right and left CCA.  

Percentage change from baseline in LDL-C, total cholesterol, HDL-C, triglycerides, 
non-HDL-C, Apo B, ApoA-I, non-HDL-C/HDL-C, and ApoB/ApoA-I

Segment specific Max CIMT or Mean CIMT measurement will be analyzed for the 
estimation of the corresponding annualized rate of change as secondary efficacy 
evaluation.
8.4.3 Safety variables
Safety variables are AEs, SAEs, AEs leading to discontinuation, changes in clinical laboratory 
analyses (chemistry, hematology, and urinalysis), vital signs, 12-lead ECGs, and physical 
examination.
8.5
Methods for statistical analyses
All efficacy measures will be summarized by randomized treatment group using descriptive 
statistics or frequency distributions (whichever is appropriate) for the raw data.  For variables 
subject to formal statistical analysis, such as hypothesis testing and statistical modeling, the 
results of the analysis will be presented and interpreted.
8.5.1 Analysis of the primary efficacy variable
A linear mixed-effects model will be used for the primary analysis to assess the difference in 
the annualized rate of change in the CIMT measurements across 12 carotid artery sites 
between rosuvastatin 20 mg and placebo treatment over 104 weeks.  
For the primary efficacy analysis, the dependent variable is the maximum CIMT measurement
from 3 interrogation angles at each of the 12 carotid artery sites at each timepoint of CIMT 
measurement during the 104-week study period.  The model includes fixed effects for 
treatment group, time, time by treatment interaction, ICVD risk stratification (<5%/5% to 
10%), age, sex, centre and scan reader, and random effects for the intercept and slope at the 
individual subject level and carotid artery site within subject.  Ultrasound machine will be 
included as a fixed effect as well if different types of machines are deployed across sites.  For 
time of CIMT measurement, the 2 pre-randomization visits and the final 2 visits at the end-of-
study will be treated as separate time points.  Details will be defined in the Statistical Analysis 
Plan.  Time, as a continuous variable, is the interval from the date of randomization to the date 
of CIMT measurement.  Differences in annualized change between rosuvastatin and placebo 
will be evaluated by testing the time-by-treatment interaction term.


Clinical Study Protocol
Drug Substance Rosuvastatin calcium
Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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In the analysis, let 1 and 2 represent respectively the coefficient parameters for time and 
time by treatment interaction in the mixed effect model.  The annualized rate of change 
(slope) in MeanMax CIMT in placebo will be estimated by the coefficient parameter 1, the 
annualized rate of change (slope) in MeanMax CIMT in rosuvastatin will be estimated by 
1+2, and the difference of annualized rate (slope) of change between 2 groups will be 
estimated by 2.  Then, the null and the alternative primary hypothesis can be expressed as H0:
2=0 vs.  Ha: 2≠0 at a significance level of 0.05 two-sided.
8.5.2 Analysis of the secondary efficacy variables
The same statistical method used for the primary CIMT efficacy analysis will be applied to 
model the segment-specific secondary CIMT efficacy outcome measurements.  The difference 
in the annualized rate of change between rosuvastatin and placebo for the secondary CIMT 
outcome measures will also be evaluated by testing the time-by-treatment interaction term in 
each model fitting.  
Secondary lipid and lipoproteins outcome measures are the percentage change from baseline, 
which will be analyzed by analysis of covariance with terms for treatment in the model.  For 
lipid measurements (LDL-C, total cholesterol, HDL-C, triglycerides, non-HDL-C, 
non-HDL-C/HDL-C), both the analysis of the percent change from baseline at final visit, and 
the analysis of the percent change from baseline to time-weighted average during treatment 
will be performed.  In the evaluation of change from baseline to final visit, missing 
observations will be imputed by last observation carried forward (LOCF).  The time-weighted 
average lipid value is defined as the lipid value multiplied by the number of days since the last 
lipid assessment, summed for all lipid observations and divided by the sum of days between 
all visits.  No imputation will be made for lipid missing values for time-weighted average 
analysis.  For apolipoprotein measurements (ApoB, ApoA-I, ApoB/ApoA-I), the analysis of 
the percent change from baseline to final visit (LOCF) will be performed.
No multiplicity adjustment will be applied to the secondary efficacy analysis.
8.5.3 Safety Analysis
Safety outcome measures including incidence of AEs (including SAEs and AEs leading to 
discontinuation), changes in clinical laboratory analyses (chemistry, hematology, and 
urinalysis), vital signs, 12-lead ECGs, and physical examination will be summarized 
descriptively.  Safety analysis will be conducted using the safety analysis set.  No formal 
statistical test will be performed.
AEs will be categorized according to 2 definitions:

AEs reported during the screening phase

Treatment-emergent AEs
AEs will be reported according to a standard dictionary for body system and preferred term.


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Edition Number 2.0
Date 28 Mar 2018
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8.5.4 Demographics and baseline data 
Descriptive statistics of demographic and other baseline characteristics will be provided.
8.5.5 Subgroup analysis
Subgroup analysis of the primary efficacy measurement will be specified in detail in 
Statistical Analysis Plan.
8.5.6 Interim analysis
No interim analysis is planned.
8.5.7 Sensitivity analysis 
Analysis of CIMT data on the PP population will be performed as a check of the robustness of 
the analysis on the ITT population.
9. STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site personnel
Before the first subject is entered into the study, an AstraZeneca representative will review 
and discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study-specific procedures and system(s) 
utilized.
The principal investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The principal investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).
IMT sonographers from each study center must participate in a uniform training and 
certification program coordinated by
.  
Documentation related to certification is maintained at
 
9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to:

Provide information and support to the investigator(s).

Confirm that facilities remain acceptable.
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Edition Number 2.0
Date 28 Mar 2018
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
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
accordance with the Laboratory Manual. and that investigational product
accountability checks are being performed.

Perform source data verification (a comparison of the data in the eCRF with the 
subject’s medical records at the hospital or practice, and other records relevant to 
the study) including verification of informed consent of participating subjects.  This 
will require direct access to all original records for each subject (eg, clinic charts).

Ensure withdrawal of informed consent to the use of the subject’s biological 
samples is reported and biological samples are identified and disposed of/destroyed 
accordingly, and the action is documented, and reported to the subject.
The AstraZeneca representative will be available between visits if the investigator(s) or other 
staff at the center needs information and advice about the study conduct.
9.2.1 Source data
Refer to the Clinical Study Agreement for location of source data.
9.2.2 Study agreements
The principal investigator at each center should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study.  In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and the 
treatment of subjects and in all other respects, not relating to study conduct or treatment of 
subjects, the terms of the Clinical Study Agreement shall prevail.
Agreements between AstraZeneca and the principal investigator should be in place before any 
study-related procedures can take place, or subjects are enrolled.
9.2.3 Archiving of study documents
The investigator follows the principles outlined in the Clinical Study Agreement.
9.3
Study timetable and end of study
The end of the study is defined as ‘the last visit of the last subject undergoing the study’.
The study is expected to start in 3Q 2015 and to end by 1Q 2019.
The study may be terminated at individual centers if the study procedures are not being 
performed according to Good Clinical Practice (GCP), or if recruitment is slow.  AstraZeneca 
may also terminate the entire study prematurely if concerns for safety arise within this study 
or in any other study with rosuvastatin.


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Study Code D3565C00003
Edition Number 2.0
Date 28 Mar 2018
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9.4
Data management by AstraZeneca 
Data management will be performed by AstraZeneca Data Management Center staff, 
according to the Data Management Plan.  AEs and medical/surgical history will be classified 
according to the terminology of the latest version the Medical Dictionary for Regulatory 
Activities.  Medications will be classified according to the AstraZeneca Drug Dictionary.  All
coding will be performed by the Medical Coding Team at the AstraZeneca Data Management 
Center.
The data collected through third-party sources will be obtained and reconciled against study 
data.
Data queries will be raised for inconsistent, impossible, or missing data.  All entries to the 
study database will be available in an audit trail.
The data will be validated as defined in the Data Management Plan.  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly.  The Data Management Plan will also clarify the roles and 
responsibilities of the various functions and personnel involved in the data management 
process.
When all data have been coded, validated, and locked, a clean file will be declared.  Any 
treatment revealing data may thereafter be added and the final database will be locked.
Serious Adverse Event (SAE) Reconciliation
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site.
10.ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Conference on 
Harmonisation (ICH)/GCP, applicable regulatory requirements, and the AstraZeneca policy 
on Bioethics and Human Biological Samples.
10.2
Subject data protection
The informed consent form will incorporate (or, in some cases, be accompanied by a separate 
document incorporating) wording that complies with relevant data protection and privacy 
legislation.


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10.3
Ethics and regulatory review
An Ethics Committee should approve the final study protocol, including the final version of 
the informed consent form and any other written information and/or materials to be provided 
to the subjects.  The investigator will ensure the distribution of these documents to the 
applicable Ethics Committee and to the study site staff.
The opinion of the Ethics Committee should be given in writing.  The investigator should 
submit the written approval to AstraZeneca before enrollment of any subject into the study.
The Ethics Committee should approve all advertising used to recruit subjects for the study.
AstraZeneca should approve any modifications to the informed consent form that are needed 
to meet local requirements.
Before enrollment of any subject into the study, the final study protocol, including the final 
version of the informed consent form, is approved by the national regulatory authority or a 
notification to the national regulatory authority is done, according to local regulations.
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.
AstraZeneca will provide Regulatory Authorities, Ethics Committees, and principal 
investigators with safety updates/reports according to local requirements.
Each principal investigator is responsible for providing the Ethics Committees/Institutional
Review Board with reports of any serious and unexpected adverse drug reactions from any 
other study conducted with the investigational product.  AstraZeneca will provide this 
information to the principal investigator so that he/she can meet these reporting requirements.
10.4
Informed consent
The principal investigator(s) at each center will:

Ensure each subject is given full and adequate oral and written information about 
the nature, purpose, possible risk, and benefit of the study.

Ensure each subject is notified that he/she is free to discontinue from the study at 
any time.

Ensure that each subject is given the opportunity to ask questions and allowed time 
to consider the information provided.

Ensure each subject provides signed and dated informed consent before conducting 
any procedure specifically for the study.


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
Ensure the original, signed informed consent form(s) is/are stored in the 
investigator’s Study File.

Ensure a copy of the signed informed consent form is given to the subject.

Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are 
described in the informed consent form that is approved by an Ethics Committee.
10.5
Changes to the protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the National 
Coordinating Investigator and AstraZeneca.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol).
The amendment is to be approved by the relevant Ethics Committee and if applicable, also the 
national regulatory authority approval, before implementation.  Local requirements are to be 
followed for revised protocols.
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each principal investigator(s).  For distribution to the Ethics Committee, see Section 10.3.
If a protocol amendment requires a change to a center’s informed consent form, AstraZeneca 
and the center’s Ethics Committee are to approve the revised informed consent form before 
the revised form is used.
If local regulations require, any administrative change will be communicated to or approved 
by each Ethics Committee.
10.6
Audits and inspections
Authorized representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the center, including source data verification.  The 
purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents, to determine whether these activities were conducted, and 
data were recorded, analyzed, and accurately reported according to the protocol, GCP, 
guidelines of the ICH, and any applicable regulatory requirements.  The investigator will 
contact AstraZeneca immediately if contacted by a regulatory agency about an inspection at 
the center.


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11.LIST OF REFERENCES
Baigent et al 2005
Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al. Efficacy and 
safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 
participants in 14 randomised trials of statins. Lancet 2005;366:1267–78.
Belcaro et al 2001
Belcaro G, Nicolaides AN, Ramaswami G, Cesarone MR, De Sanctis M, Incandela L, et al. 
Carotid and femoral ultrasound morphology screening and cardiovascular events in low risk 
subjects: A 10-year follow-up study (the CAFES-CAVE study). Atherosclerosis 
2001;156:379–87.
Chinese Society of Cardiology 2011
Chinese Society of Cardiology of Chinese Medical Association. Chinese guidelines for 
prevention of cardiovascular diseases. Editorial Board of Chinese Journal of Cardiology. 
Zhonghua Xin Xue Guan Bing Za Zhi 2011;39(1):3-22.
Collins et al 2003
Collins R, Armitage J, Parish S, Sleigh P, Peto R. MRC/BHF Heart Protection Study of 
cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-
controlled trial. Lancet 2003;362(9385):361.
Consensus on primary prevention of CVD 2010
Internal Medicine Branch of Cardiovascular Diseases, Chinese Physicians Association. 
Consensus on primary prevention of CVD. Chin J Intern 2010;49(2)174-89.
Crouse et al 2007
Crouse JR 3rd, Raichlen JS, Riley WA, Evans GW, Palmer MK, O'Leary DH, et al; METEOR 
Study Group.  Effect of rosuvastatin on progression of carotid intima-media thickness in low-
risk individuals with subclinical atherosclerosis: the METEOR Trial.  JAMA
2007;297(12):1344-53.
CTT Collaborators 2012
Cholesterol Treatment Trialists’ (CTT) Collaborators. The effects of lowering LDL 
cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of 
individual data from 27 randomised trials. Lancet 2012; 380: 581–90.
Davidson 2002
Davidson MH. Rosuvastatin: a highly efficacious statin for the treatment of dyslipidaemia. 
Expert Opin Investig Drugs 2002;11:125-41
Doneen and Bale 2013
Doneen AL1, Bale BF. Carotid intima-media thickness testing as an asymptomatic 
cardiovascular disease identifier and method for making therapeutic decisions. Postgrad Med 
2013;125(2):108-23.


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Study Code D3565C00003
Edition Number 2.0
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Du et al 2014
Du R, Cai J, Zhao XQ, Wang QJ, Liu DQ, Leng WX, et al. Early decrease in carotid plaque 
lipid content as assessed by magnetic resonance imaging during treatment of rosuvastatin.
BMC Cardiovasc Disord 2014;14:83.
Feng et al 2014
Feng X, Zhang J, Liu M, Li X. Impact on the carotid intima-medial thickness and safety of 
rosuvastatin in Chinese patients with carotid atherosclerosis: a meta-analysis. Zhonghua Xin 
Xue Guan Bing Za Zhi 2014;42(3):247-53
Jones et al 2003
Jones PH, Davidson MH, Stein EA, Bays HE, Mckenney JM, Miller E, et al. Comparison of 
the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across 
doses(STELLAR*Trial). Am J Cardiol 2003;92:152-60.
Espeland et al 2005
Espeland MA, O’Leary DH, Terry JG, Morgan T, Evans G, Mudra H. Carotid intimal-media 
thickness as a surrogate for cardiovascular disease events in trials of HMG-CoA reductase 
inhibitors. Curr Control Trials Cardiovasc Med 2005;6(1):3.
Irie et al 2012
Irie Y, Katakami N, Kaneto H, Kasami R, et al. Maximum carotid intima-media thickness 
improves the prediction ability of coronary artery stenosis in type 2 diabetic patients without 
history of coronary artery disease. Atherosclerosis 2012;221:438-44.
Keo et al 2011
Keo HH, Baumgartner I, Hirsch AT, Duval S, et al. Carotid plaque and intima-media 
thickness and the incidence of ischemic events in patients with atherosclerotic vascular 
disease. Vasc Med 2011;16:323-30.
Lloret et al 2006
Lloret R, Ycas J, Stein M, Haffner S; STARSHIP Study Group. Comparison of rosuvastatin 
versus atorvastatin in Hispanic-Americans with hypercholesterolemia (from the STARSHIP 
trial). Am J Cardiol 2006;98(6):768-73.
NCEP 2001
National Cholesterol Education Program Expert Panel (NCEP) on Detection, Evaluation and 
Treatment of High Blood Cholesterol in Adults.  JAMA 2001;285(19):2486-97.
Onut et al 2012
Onut R, Balanescu AP, Constantinescu D, Calmac L, Marinescu M, Dorobantu PM. Imaging 
Atherosclerosis by Carotid Intima-media Thickness in vivo: How to, Where and in Whom? 
Maedica (Buchar) 2012;7(2):153-62.


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Date 28 Mar 2018
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Ridker et al 2008
Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al; JUPITER 
Study Group.Rosuvastatin to prevent vascular events in men and women with elevated C-
reactive protein. N Engl J Med 2008;359(21):2195-207.
Ross 1999 x
Ross R.  Atherosclerosis — An inflammatory disease.  N Engl J Med 1999;340(2):115-26.
Sever et al 2003
Sever PS, Dahlf B, Poulter NR, Wedel H, Beevers G, Caulfield M, et al. Prevention of 
coronary and stroke events with atorvastatin in hypertensive patients who have average or 
lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes 
Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 
2003;361:1149–58.
Smilde et al 2001
Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF. Effect of 
aggressive versus conventional lipid lowering on atherosclerosis progression in familial 
hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet 
2001;357(9256):577-81.
Strandberg et al 2004
Strandberg TE, Feely J, Sigurdsson EL; DISCOVERY study group. Twelve-week, 
multicenter, randomized, open-label comparison of the effects of rosuvastatin 10 mg/d and 
atorvastatin 10 mg/d in high-risk adults: a DISCOVERY study. Clin Ther 2004(11):1821-33.
Stone et al 2014
Stone N, Robinson J, Lichtenstein A, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 
ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic 
Cardiovascular Risk in Adults: a Report of the American College of Cardiology/American 
Heart Association Task Force on Practice Guidelines. Circulation 2014;63(25 Pt B):3024-5.
Takayama et al 2009
Takayama T, Hiro T, Yamagishi M, Daida H, Hirayama A, Saito S, et al; COSMOS 
Investigators.  Effect of rosuvastatin on coronary atheroma in stable coronary artery disease: 
multicenter coronary atherosclerosis study measuring effects of rosuvastatin using 
intravascular ultrasound in Japanese subjects (COSMOS).  Circ J 2009;73(11):2110-7.
Taylor et al 2002
Taylor AJ, Kent SM, Flaherty PJ, Coyle LC, Markwood TT, Vernalis MN. ARBITER: 
Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: a 
randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima medial 
thickness. Circulation 2002;106(16):2055-60.


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WHO 1998
WHO The world health report 1998. Available online at: 
http://www.who.int/whr/1998/en/index.html
Wu et al 2006
Wu Y, Liu X, Li X, Li Y, Zhao L, Chen Z, et al; USA-PRC Collaborative Study of 
Cardiovascular and Cardiopulmonary Epidemiology Research Group; China Multicenter 
Collaborative Study of Cardiovascular Epidemiology Research Group. Circulation 
2006;114(21):2217-25.
Wu et al 2004
Wu Y, Zhou B, Li Y, Li X, Zhao L, Yang J, et al. Ischemic cardiovascular diseases: a new 
index to reflect the potential risk from dyslipidemia. Chin J Cardiol 2004;32(2):173-6.
Zhu et al 2007
Zhu J and the China Adult Dyslipidemia Management Guidelines Committee. China Adult 
Dyslipidemia Management Guidelines. Chin J Cardiol 2007;35(5):390-419.


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12. APPENDIX


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12.1
Appendix A
Additional Safety Information


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FURTHER GUIDANCE ON THE DEFINITION OF A SERIOUS 
ADVERSE EVENT (SAE)
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important medical event or medical intervention
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious.  
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.
Examples of such events are:

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation

Development of drug dependency or drug abuse


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A GUIDE TO INTERPRETING THE CAUSALITY QUESTION
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.

Time Course.  Exposure to suspect drug.  Has the subject actually received the 
suspect drug?  Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug?

Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience.  Did the AE resolve or improve on stopping or reducing 
the dose of the suspect drug?

No alternative cause.  The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors.

Re-challenge experience.  Did the AE reoccur if the suspected drug was 
reintroduced after having been stopped? AstraZeneca would not normally 
recommend or support a re-challenge.

Laboratory tests.  A specific laboratory investigation (if performed) has confirmed 
the relationship.
In difficult cases, other factors could be considered such as:

Is this a recognized feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.


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12.2
Appendix B
International Airline Transportation Association 
(IATA) 6.2 Guidance Document


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LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) classifies biohazardous agents into 
3 categories.  For transport purposes the classification of infectious substances according to 
risk groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition 
(2005).  Infectious substances are now classified either as Category A, Category B or Exempt.  
There is no direct relationship between Risk Groups and categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are eg, Ebola, Lassa fever virus:

are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2.  They are assigned the following UN 
number and proper shipping name:

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens

Clinical trial samples will fall into Category B or exempt under IATA regulations

Clinical trial samples will routinely be packed and transported at ambient 
temperature in IATA 650 compliant packaging 

Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content

IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as 
applicable

Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times.  The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport 
is used.


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12.3
Appendix C
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law


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12.3.1Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law.  It is not intended to be a comprehensive guide to the management 
of elevated liver biochemistries.
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the study.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than drug induced liver injury (DILI) caused by the investigational 
medicinal product (IMP).
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting adverse events (AE) and serious adverse events (SAE) according to the outcome of 
the review and assessment in line with standard safety reporting processes.
12.3.2Definitions
Potential Hy’s Law (PHL)
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3x upper limit of 
normal (ULN) together with total bilirubin (TBL) ≥2xULN at any point during the study 
following the start of study medication irrespective of an increase in alkaline 
phosphatase (ALP).
Hy’s Law (HL)
AST or ALT ≥3x ULN  together with TBL ≥ 2xULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e. on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
12.3.3Identification of potential hy’s law cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥ 3xULN

AST ≥ 3xULN


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
TBL ≥ 2xULN
When a patient meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to AstraZeneca 
representative). 
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the Investigator will:

Notify the AstraZeneca representative

Request a repeat of the test (new blood draw) by the central laboratory

Complete the appropriate unscheduled laboratory CRF module(s) with the original 
local laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:

Determine whether the patient meets PHL criteria (see Section 12.3.2 of this 
Appendix for definition) by reviewing laboratory reports from all previous visits 
(including both central and local laboratory results)
12.3.4Follow-up
12.3.4.1
Potential Hy’s Law Criteria not met
If the patient does not meet PHL criteria the Investigator will:

Inform the AstraZeneca representative that the patient has not met PHL criteria.

Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.
12.3.4.2
Potential Hy’s Law Criteria met
If the patient does meet PHL criteria the Investigator will:

Notify the AstraZeneca representative who will then inform the central Study Team 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up and the continuous review of data.  Subsequent to 
this contact the Investigator will:

Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated 


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
Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. 

Complete the three Liver CRF Modules as information becomes available 

If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures
12.3.5Review and Assessment of potential hy’s law cases
The instructions in this Section should be followed for all cases where PHL criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP.  The AstraZeneca Medical Science Director and Global Safety Physician will also be 
involved in this review together with other subject matter experts as appropriate.  
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF

If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF 
accordingly and follow the AZ standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:

Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes. 

The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:


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
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above

Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to 
determine whether HL criteria are met.  Update the SAE report according to the 
outcome of the review
12.3.6References
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf


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12.4
Appendix D
Guidance for Management of Muscle Symptoms 
and Increased Creatine Kinase (CK)


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GUIDANCE FOR MANAGEMENT OF MUSCLE SYMPTOMS AND 
INCREASED CREATINE KINASE (CK)

Throughout the study, subjects should be instructed to promptly report unexplained 
muscle pain or weakness, particularly if associated with malaise or fever.  If this 
occurs, creatine kinase (CK) should be measured as soon as possible.  

If CK is found to be elevated ≥5xULN on routine testing, the subject should be 
questioned about muscle symptoms.  

A suitably-experienced physician should be involved in deciding appropriate 
management for the subject. The physician should be alerted to the occurrence of 
unexplained muscle symptoms, and any CK values ≥5xULN and must take immediate 
action if CK >10xULN.  

For CK >10xULN with or without muscle symptoms, discontinue study drug. 

For CK 5-10xULN:

If symptomatic and no alternative explanation exists, withhold therapy

If asymptomatic, or if symptomatic but alternative explanation exists, follow 
symptoms and CK levels weekly until there is no longer medical concern or 
symptoms worsen and meet criteria above

The following questioning and follow-up investigations should be considered:

Clarify the nature, duration and intensity of relevant symptoms

Clarify and document whether the patient was taking study treatment at the 
time of the event, or when the last dose of study treatment was taken.  
Document dosing information in source and report if appropriate (eg, if 
considered an SAE).

Review possible predisposing factors, such as: unaccustomed exercise 
(including decorating, gardening, etc.), heavy alcohol intake, viral illness 
(consider performing serology), concomitant medications (e.g. anesthetics, 
cholesterol -lowering agents – niacin, clofibrate, statins, ezetimibe, 
glucocorticoids, narcotics, chloroquine, etc.) and consider diagnosis of other 
conditions which can cause myopathy

Physical examination for muscle tenderness, weakness and rash 

Measure CK again within a few days 

Measure serum creatinine


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
Urinalysis (including myoglobin and sediment)

Arrange to review the subject again in 4 to 10 days, or earlier if symptoms 
of myopathy appear or worsen, of if the urine becomes very dark

Myopathy is defined as muscle aches or weakness in association with CK increased 
to >10xULN.  If myopathy occurs or if on clinical grounds, statin-induced myopathy 
is diagnosed or suspected, statin therapy should be discontinued.  Myopathy should 
always be recorded as an adverse event, and the AstraZeneca representative must be 
informed.

If study treatment is temporarily disrupted, it is suggested that the AstraZeneca
representative be consulted before restarting study treatment.

The AstraZeneca representative should be consulted prior to permanently 
withdrawing a patient.


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12.5
Appendix E
Therapeutic Lifestyle Changes (TLC) Diet


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THERAPEUTIC LIFESTYLE CHANGES (TLC) DIET
2007 China adult dyslipidemia management guidelines recommend a multifaceted lifestyle 
approach to reduce the risk of cardiovascular disease. 
The recommended essential elements of TLC are listed in the Table below.
Essential elements of the Therapeutic Lifestyle Changes Diet
Essential element
Recommendation
Reduce the nutrient that elevates 
the LDL-C
Saturated Fatty Acids
<7% of total calories
Dietary Cholesterol
<200mg/d
Increase the dietary component that 
lowers LDL-C
Phytosterols
2g/d
Soluble Cellulose
10~25g/d
Total Calories
Balance energy intake and expenditure to maintain 
desirable body weight/prevent weight gain
Physical Activity
Including enough moderate exercise, obliterate 
more than 200kcal of energy per day.
Note: Trans-Fatty Acids also increase the LDL-C. It is unfavourable to intake more


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12.6
Appendix F
Definition of China Adult Dyslipidemia 
Management Guidelines Risk Factors 


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DEFINITION OF CHINA ADULT DYSLIPIDEMIA MANAGEMENT 
GUIDELINES RISK FACTORS

Hypertension (as defined: BP≥140/90 or on antihypertensive treatment)

Smoking

HDL-C < 40 mg/dL

Obesity(body mass index ≥28kg/m2)

Family history of premature CHD (CHD in male first degree relative <55 years of 
age; CHD in female first degree relative <65 years of age)

Age (Male ≥45 years, Females ≥55 years)
Subtract one (1) risk factor if HDL-C ≥60 mg


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12.7
Appendix G
Carotid Ultrasound Process


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Carotid Ultrasound Protocol
&
Quality Assurance Manual
Version 1.0


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List of Abbreviations
BIF or BIFUR
Bifurcation
CCA
Common carotid artery
CIMT
Carotid intima-media thickness
DICOM
Digital Imaging and Communications in Medicine
DVD
Digital video disk
ECA
External carotid artery
ECG
Electrocardiogram
ICA
Internal carotid artery 
ID
Identification
IMT
Intima-media thickness
LA
Left arm
LT
Left 
OAI
Optimal anatomical interrogation angle 
QA
Quality assurance 
QC
Quality control
RA
Right arm 
RL 
Right leg
RT
Right
SOP
Standard Operating Procedure
TFD
Tip of flow divider
USB
Universal serial bus


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12.7.1Ultrasound Training and Certification
12.7.1.1
Introduction
The responsibilities of the research sonographer in this study differ significantly from those 
normally assumed by the clinical sonographer. The off-line reading of the B-mode images 
also requires skills that differ significantly from the routine clinical approach to image 
interpretation and measurement. Consequently, all sonographers and readers must participate 
in a uniform training and certification program coordinated by the QC Center(s).  
Documentation related to certification is maintained at the QC Center(s).
12.7.1.2
Training
Each sonographer and reader first completes a didactic ultrasound training session lead by QC 
Center staff and representatives of equipment manufacturers, as appropriate.  A set of pre-
training materials providing a common background on CIMT measurements and an overview 
of the study specific CIMT scan protocol will be provided to each Imaging Center 
approximately one month before the CIMT carotid ultrasound protocol training session is 
conducted. The primary objective of the central training session is to familiarize the 
sonographer with the general operation of the selected ultrasound instrument with emphasis 
on the use of each important control used in this study protocol and its function. 
Standardization of the equipment settings is stressed. Detailed instruction on scanning of the 
carotid arteries is provided. The specific research scanning protocol is demonstrated to all 
sonographers and readers. Supervised practice of the scanning protocol is conducted on 
volunteers during the training by QC Center personnel.
Following the central training, the sonographers continue scanning practice at their respective 
Imaging Center in order to complete the certification requirements as soon as possible. This 
typically takes two to eight weeks depending upon the experience and effort commitment of 
the sonographer to the study. Ideally, sonographers should practice the protocol for a period of 
two hours per day immediately following the conclusion of the initial training session. 
12.7.1.3
Sonographer Certification 
The sonographer certification requirements consist of submitting a total of up to 20 good 
quality protocol scans on volunteers. We recommend that the last five of these 20 scans are 
done on volunteers in the age group of the study population. These scans are reviewed and 
critiqued by QC Center staff and must demonstrate a high level of proficiency in the carotid 
ultrasound protocol. Each sonographer after completion of the scan carefully reviews the 
recorded images for each certification examination and completes a standard review form (see 
Carotid Ultrasound Training Manual). This is to ensure that images and annotations are 
correctly recorded and to permit a careful self-evaluation of adherence to the scanning 
protocol before sending the scans and forms to the QC Center(s). The QC Center staff will 
evaluate the scans again, and observations and critiques are returned by e-mail within five 
working days after receipt of the ultrasound material to each sonographer to indicate the 
quality of performance and suggestions for improvement. The expectation is that 20 scans are 
needed to demonstrate a high level of proficiency in the performance of the protocol. Less 
than 20 scans are possible when a sufficiently high level of performance is achieved more 


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rapidly or for sonographers experienced in similar protocols. At least three consecutive scans 
(graded as level A) are needed for a sonographer to receive initial certification. 
12.7.1.4
Reader Certification 
The ultrasound readers receive instruction on the operation of the reading station 
instrumentation located at the QC Center(s) and on the performance of the B-mode image 
reading protocol. Readings are then performed on the recordings from the volunteer studies 
submitted for sonographer certification. After completion of 10 satisfactory readings on these 
scans in duplicate that demonstrate a high level of proficiency in the performance of the 
protocol, each reader receives initial certification.  Outcome variable data including within-
reader and between-reader reproducibility are of primary importance in the certification 
process. In general, we aim at having an intra-class correlation coefficient for between 
readings of 0.75 or higher. Certification of readers may be achieved based on less than 10 
readings if a sufficiently high level of performance is demonstrated more rapidly. This may be 
relevant especially for experienced readers, i.e., those who have worked with a similar reading 
protocol in previous studies and have shown in these previous studies to read in a consistent 
and reproducible manner. 
12.7.1.5
Performance and Maintenance of Equipment
It is the primary responsibility of the sonographer and reader to assure that the ultrasound or 
reading equipment is performing optimally prior to each exam or reading. Routine preventive 
maintenance must be provided at the interval recommended by the manufacturer. Any service 
related problems that could reduce data quality during the examination should be documented 
in a service log and rapidly resolved by the equipment manufacturer. The QC Center(s) and 
study sponsor must approve all upgrades, to hardware and software in advance in writing. In 
addition, documentation must be made in the service log. Modification of the scanning or 
reading hardware and software can only be made during the course of the study with prior 
written approval of the QC Center(s) and sponsor to maintain standardization throughout the 
study.
12.7.1.6
Image Data Recording
This study will record digital image data in DICOM format for off-line analysis. The digital 
files may be uploaded directly over the internet or recorded on a digital media (e.g., video disk 
[DVD] or universal serial bus [USB] for transfer to the QC Center[s]). Several scans may be 
recorded on a single DVD or USB. Numbered labels will be used to facilitate tracking of 
digital media.  Detailed instructions of imaging uploading will be provided in the carotid 
ultrasound training manual.  
12.7.1.7
Contact Addresses 
Clinical/imaging sites should refer questions, comments and suggestions related to the Carotid 
Ultrasound Protocol to:
PPD


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PPD


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12.7.2 Ultrasound Exam Summary
The ultrasound scanning protocol describes a standardized examination of the right and left 
carotid arteries including the common carotid artery, the carotid bifurcation and the internal 
carotid artery. After proficiency has been developed in performing the protocol, the duration 
of the examination of both sides should not exceed 30 minutes. All Imaging Centers will use 
an approved ultrasound scanner with uniform image settings that will be indicated in the 
carotid ultrasound training manual. For off-line analysis, real time DICOM image clips will be 
stored on digital media or uploaded via the internet. Copies of digital image files will be 
stored at the Clinical/Imaging Centers and/or at the QC Center(s).Extensive Carotid Disease 
This research protocol has been developed to meet specific research objectives in the study, 
and the protocol differs significantly from the routine clinical examination of the carotid 
arteries performed in clinical subjects. If, as a result of the performance of this research scan 
protocol, severe and/or extensive carotid artery disease is discovered in a participant, this 
information is communicated by the sonographer to the clinical site principal investigator or a 
designated co-investigator.  A more detailed medical history may be obtained on these 
subjects and the extent of follow-up will be determined by the local clinical site principal 
investigator.
12.7.2.2
Carotid Segments
The primary objective of the carotid ultrasound scanning protocol is to acquire high quality 
standardized longitudinal B-mode images in 12 well defined arterial wall segments in both the 
right and left carotid arteries. Each carotid artery has been divided into 3 segments (CCA, 
BIF, ICA) with 6 walls (near wall and far wall of each segment) as shown in Figure 2. The tip 
of the carotid flow divider is an important landmark for the standardization of the horizontal 
positioning of the artery and the definition of the segments. The position of each segment is 
defined relative to this tip of the flow divider (TFD), which is normally the most clearly 
defined anatomical reference in the proximity of the carotid bifurcation. The three segments 
are defined as: the near wall and far wall of the arterial segment extending from 10 mm to 20 
mm proximal to the tip of the flow divider into the common carotid artery (CCA); the near 
wall and far wall of the carotid bifurcation beginning at the tip of the flow divider and 
extending 10 mm proximal to the flow divider tip (BIF); and the near wall and far wall of the 
10 mm of the internal carotid artery (ICA) distal to the tip of the flow divider. Since the 
specific internal anatomy of an individual subject is variable, the near walls and far walls may 
correspond to different anatomical sites. Markers on the ultrasound screen will facilitate the 
correct placement of the segments. 


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Figure 2
Three 10 mm segments (CCA/BIF/ICA), the tip of the flow divider 
(TFD) and the 6 boundaries. Gridlines were used to indicate the 
segments and to position the TFD in a standard way
In many participants, it is often difficult to obtain good images of the internal carotid artery 
further than 10 mm distal to the tip of the flow divider. The length of the bifurcation varies 
significantly between subjects, and 10 mm is an approximate average length. The segment 
containing the common carotid is limited to 10 mm in length so that the segment can be 
imaged with high quality while maintaining the level of the flow divider tip at the appropriate 
gridline.
12.7.2.3
Standardized Interrogation Angles
Besides the standardization of the left-right placement of the artery and clear definition of the 
segments, the angle of interrogation has also been standardized. To achieve this objective a 
carotid arc (Meijer’s Carotid Arc) is used as a reference for the interrogation angle as shown 
Figure 3. Carotid images are selected at 3 predefined angles with 30 degrees increments on 
both sides: 90;120;150 for the right side and 210;240;270 for the left side. 


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Figure 3
The Meijer’s Carotid Arc is used to position the transducer at the 6 
predefined angles
12.7.2.4
Instrumentation
Each participating site will work with the sponsor and appropriate QC Center(s) to identify 
one or more approved ultrasound systems that may be used for study examinations.  In some 
cases, approved equipment may be purchased or leased specifically for study use.  Factors 
considered in the ultrasound equipment approval process will include: year of manufacturing, 
axial and lateral resolution, image field of view and distortion, transducer dimensions and 
weight, ease of use by sonographers, quality control standardization, data storage and 
recording methods, Doppler mode capabilities, engineering staff quality, digital recording 
capabilities (including audio) and service frequency and response time.  We anticipate that 
images will be recorded on digital media to support off-line image frame selection and 
measurement of CIMT. Since even subtle between system differences in performance and 
calibration can inflate the variability of estimated rates of change in CIMT, care should be 
taken to minimize the number of different systems approved for study use. Ideally uniform 
equipment is selected to ensure the highest quality of the carotid IMT image and reading 
process. 


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12.7.2.5
Personnel
Two part-time sonographers are required to perform the ultrasound scanning duties at each 
Imaging Center. All sonographers must complete a uniform CIMT training program 
conducted at the central training meeting.  Sonographers are certified upon satisfactory 
documented completion of the training and certification program.  Sonographers should 
equally share the scanning responsibilities during the course of the study to maintain a high 
skill level and certification requirements. The concept of a “primary” and a “back-up“ 
sonographer in longitudinal studies of this type is inappropriate since the skills must be 
practiced on a regular basis by each sonographer to maintain a high skill level.
12.7.2.6
Administration of Image Data
Numbered labels will be used to keep record of the participant examination data and to track 
media used to store and transfer digital image files. All administrative issues and the 
procedures related to the labeling and transfer of the digital media will be described in detail 
in the carotid ultrasound training manual. 
12.7.2.7
Exclusion Guidelines Based On Carotid Ultrasound
The subjects recruited for this study are asymptomatic adults with evidence of early carotid 
atherosclerosis (a maximum intima-media thickness of at least 1.2 mm [subject to any criteria
change in clinical study protocol] and less than 3.5 mm). Precise longitudinal measurements of 
CIMT are possible only in individuals with early changes in the thickness of the intimal and 
medial layers of the artery wall resulting from atherosclerotic disease.  If in a participant the 
imaging circumstances are very poor with limited boundary visualization or the protocol 
cannot be followed due to anatomical constraints, the participant may be excluded from the 
study. Participants with extensive carotid disease with large calcifications and acoustic 
shadowing that will limit appropriate and adequate visualization of sufficient CIMT 
boundaries should not be enrolled in this study, since this will likely limit the number of 
CIMT measurements. During the circumferential scan, the minimum visualization 
requirement for a participant to be eligible for this study is that both the near and far walls of 
the right and left common carotid arteries be well visualized in addition to at least 4 of the 8 
segments in the right and left BIF and ICA.. Either the sonographer or the QC Center(s) may 
exclude such participants, with details clearly documented on the Ultrasound Requisition 
Form(s) or eligibility form(s) for that participant. 


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12.7.3Ultrasound Protocol
Correct participant demographic information is placed on the ultrasound system image screen 
prior to the beginning of each study. This may include clinical/imaging center ID, subject 
number, visit code, date of birth (yyyy-mm-dd), and sonographer ID. If needed, digital media 
labels are completed after completion of the scan.  In addition, standard equipment settings 
provided during the training (e.g., maximum depth, frame rate, dynamic range, edge detection, 
image persistence, and post processing) must be used in the recording of all images. The 
sonographer scans from the head of the examination table. The participant is placed in a 
supine position on the examination table with the head toward the sonographer.  A pillow is 
placed under the participant’s knees to support the lower back if requested by the participant.  
A towel may also be placed under the head of the participant.  ECG leads are attached to the 
participant according to the system specifications.  An example of ECG lead attachment for an 
ultrasound scanner is illustrated in Figure 4.
Figure 4
Example of ECG placement
Points to remember with the ECG:

The tracing should be positioned at the bottom of the image screen, away from 
arterial interfaces of interest.

The amplitude should be sufficient for the R-wave to be clearly identified.

If artifact is visualized in the tracing, check to be sure that electrodes are not loose 
or dry. Avoid placing electrodes on bone structures. Limit participant movement 
during scan.


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The participant is required to rest for 5 minutes before proceeding with the examination to 
establish a stable physiologic state prior to beginning the examination.  A plastic arc (Meijer’s 
Carotid Arc) marked with an angle scale is positioned under and against the shoulders of the 
participant (illustrated in Figure 5) is used as a reference to read the ultrasound transducer 
interrogation angles during the examination. The sonographer performs the right carotid scan 
holding the probe in the right hand and the left carotid scan holding the probe in the left hand. 
When the sonographer selects each specific image sequence for measurement, an on-screen 
annotation is provided by the sonographer to indicate the angle and carotid segment.
Figure 5
Example of the scan position and arc placement
The examination of both right and left sides consists of an initial exploratory 
transverse/longitudinal scan and a Doppler of the carotid system followed by a detailed 
longitudinal examination of the specific arterial segments illustrated in Figure 2. For the initial 
transverse scan the transducer is always positioned for the right side at 135 degrees and for the 
left side at 225 degrees so that the image presentation is in accordance with the anatomy of the 
participant. This should result in an image in which the right edge of the image is directed 
toward the right side of the participant. For the longitudinal scan the transducer is positioned 
(for both the right and left sides) so that the carotid image is oriented with the participant’s 
head towards the left side of the monitor. The right carotid is scanned first followed by the left 
side.


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12.7.3.1
Exploratory Scout Scan 
Exploratory transverse and longitudinal scans (scout scans) are performed by the sonographer 
prior to the beginning of clip storage of images. This is to enable the sonographer to become 
familiar with the participant’s anatomy. The image quality of the carotid scan is carefully 
examined by the sonographer to determine if the 6 arterial wall boundaries can be adequately 
visualized within the specific arterial segments at the predefined angles. Anatomical features 
that might preclude the serial acquisition of high quality images are noted on the participant
Ultrasound Requisition Form. The minimum visualization requirement for a participant to be 
eligible for this study is that both the near and far walls of the right and left common carotid 
arteries be well visualized during the circumferential scan, in addition to at least 4 of the 8 
segments in the right and left BIF and ICA.
Precise longitudinal measurements of CIMT are possible in individuals with relatively early 
changes in the thickness of the intimal and medial layers of the carotid artery wall. 
Participants that are very difficult to scan or provide images of poor quality because of 
anatomical constraints or severe and/or extensive atherosclerotic disease may be excluded 
from the study at this time and the examination will be terminated (see previous section
12.7.2.7). 
12.7.3.2
Transverse Exploratory Scan
The transverse scan of the right common carotid artery is performed beginning at the clavicle 
with the participant’s head position 45 degrees to the contra-lateral side (225 degrees) and a 
transducer (groove pointing to participant’s left side) interrogation angle of 45 degrees to the 
posterior (135 degrees) as shown in Figure 6. The sonographer uses fine transducer 
angulations to clearly display both the blood-intima boundaries and the media-adventitia 
boundaries on both the near and far walls of the artery, the transducer is slowly moved toward 
the mandible until the lumen area increases with the appearance of the carotid bifurcation 
(also the lumen changes shape from nearly circular to elliptical), and finally the internal and 
external carotid arteries are visualized. The location of these vessels is denoted in the image 
by positioning an indicator near the arterial segment. These indicators greatly assist the reader 
during the reading process.  For the transverse scan, a clip at least 6 seconds in duration is 
saved on the hard drive showing the complete segment of interest, including the orientation of 
the internal and external carotid arteries.  A properly performed transverse scan is 
demonstrated in the training video. The left initial transverse scan is done at 225 degrees with 
the head 45 degrees to the other side (135 degrees).


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Figure 6
Position the head of the participant 45 degrees to the contra-lateral 
side using the Meijer’s Carotid Arc; position the transducer 45 degrees 
to the posterior.
12.7.3.3
OAI (Optimal Anatomical Interrogation) Angle
Using the knowledge acquired of the relative anatomical orientation of the internal and 
external carotid arteries during the transverse scan, the optimal anatomical interrogation (OAI) 
angle which best displays the tip of the flow divider and the “Y” appearance of the two 
arteries in a single longitudinal image can be determined (Figure 7 and Figure 8). This angle 
provides information about the carotid anatomy of this participant.  If both extreme anterior 
and extreme posterior interrogation angles can provide an OAI view, the anterior angle is to 
be preferred. One way to obtain the OAI is to position one vessel on top of the other in the 
transverse scan and then turn longitudinal by a 90 degrees rotation of the transducer to 
demonstrate the “Y” appearance.  (Transducer groove points toward participant’s head.)


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Figure 7
The different transverse orientations of the artery with the degrees of 
movement to obtain the OAI. In the lighter shade orientations the 
movement is towards the anterior.
Figure 8
The scan approach to obtain the OAI from the transverse plane and 
the longitudinal image of that particular scan plane
12.7.3.4
Longitudinal Exploratory Scan
The sonographer remains at or close to the OAI angle with the tip of the flow divider 
positioned on the designated gridline.  A brief Doppler examination is performed to clearly 
distinguish the internal carotid artery from the external carotid artery based on the differences 
in the flow velocity profiles in the two vessels. The entire 30 mm predefined length of the 
carotid system is now scanned longitudinally starting from the most anterior angle and 


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proceeding to the most posterior angle with a brief stop at the predefined angles to explore the 
anatomy. 
12.7.3.5
Preliminary Scan
On each side, the transverse scan (3.2) is stored in a clip at least 6 seconds in duration. At the 
longitudinal scan following the collection of the Doppler signals, a still frame "image store” is 
made of the best image displaying the carotid bifurcation (“Y”) with identification of the 
internal carotid artery and the angle of interrogation.  The sonographer should demonstrate 
with annotation the relative positions of these two vessels when imaged from the OAI angle 
(shallow or deep). The indicator is placed within the lumen of the internal vessel close to the 
flow divider wall at the level of the tip of the flow divider. This information will be used at the 
QC Center(s) to confirm proper artery identification and anatomical relationship. 
12.7.3.6
Longitudinal Scan for 12 Selections at Defined Angles
This scan always starts with the anterior scanning angle of 150 degrees at the RT CCA. The 
flow divider is positioned approximately 1.5 cm from the left edge of the screen on the 
designated gridline. To check the position of the tip of the flow divider, the transducer should 
be rocked backward and forward to visualize the off spring (origin) of the internal and 
external carotid arteries.  On-screen indicators are used to identify the angle and vessel wall 
segment under interrogation as shown in Figure 9.  The right pictogram is placed on the left of 
the image screen when the right side is being scanned. The left pictogram is placed on the 
right of the image when the left side is being scanned. The images are acquired from 3 defined 
interrogation angles on both sides.


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Figure 9
Example of 3 selections: Text and/or on-screen indicators are placed to 
confirm the segment of interest and the scan angle
Example:
A. CCA near and far wall:  CCA NF
B. Bifurcation far wall:  BIF F
C. Internal near wall:  ICA N
At the first CCA selection (150 degrees), a video clip containing approximately 5 consecutive 
cardiac cycles that clearly visualize both the near wall and far wall boundaries in the same 
image frames are stored on the hard drive of the ultrasound machine. The annotation is placed 
appropriately before the digital storage is recorded.  Following the CCA the sonographer 
continues with the next segment BIF (near wall) and then the ICA (near wall) at that angle in a 
similar way. Then the focus of the sonographer is shifted to the ICA (far wall), followed by 


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the BIF (far wall). The annotation and caliper should be placed correctly for optimization of 
the image and identification of the segment and angle of interrogation. This sequence of image 
selections is illustrated in Figure 2 and Figure 10.
The transducer is then positioned on the next angle (120 degrees) and the same sequence of 
images is acquired. In a similar way images are also selected at the angle of 90 degrees 
marked on the plastic arc when scanning the right side. For the left side, corresponding angles 
of interrogation are 210, 240 and 270 degrees. 
ACI
150 = OAI
90
ICA
ECA
Right side
OAI
CCA
BIFUR
TIP of flow divider
120
ACE
2
1
3
5
6
4
Sequence of selections
Figure 10
Schematic overview of the carotid artery with the sequence of image 
selections illustrated
12.7.3.7
Confirmation of Tip of Flow Divider, Boundary Optimization and Focus 
Setting
At the beginning of the selection of each segment, the position of the tip is being confirmed by 
rocking the transducer to visualize the origin of the internal and external carotid arteries, while 
maintaining the locations of surrounding tissues (drifting from the desired segment location is 
avoided). Considerable effort is shown to optimize (horizontalize) the boundaries and to 
maintain the position of the level of the flow divider at the TFD reference gridline on the 
screen. 


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12.7.4Comprehensive Protocol Overview/Summary
The carotid artery is divided into three segments (CCA/BIF/ICA) of each 10 mm length with 
tip of flow divider being the reference point.  
The tip of the flow divider will be placed at the designated gridline. 
Doppler will be used to differentiate the ICA and ECA.  At the 3 consecutive defined angles 
on the Meijer’s Carotid Arc, the image selections of the carotid walls are acquired and stored 
on hard drive.  The carotid arc will help to guide the sonographer through the multi-angle 
acquisition protocol ensuring that multiple sites are investigated.
On-screen annotations and/or indicators placed by the sonographer will provide the necessary 
information about the vessel segment, the angle, and the vessel wall under interrogation. 
Near and far wall images of 6 carotid segments are acquired at the 3 different defined angles. 
To have a good understanding of the anatomy of the right and left carotid arteries in each 
individual, the angle where the tip of the flow divider is clearly imaged (OAI) is documented. 
At the training, the sonographer will be instructed on completing data sheets.
12.7.4.1
Sonographer Work Protocol

Start with the transverse scan on the right side at the level of the clavicle and scan at 
an angle of 45 degrees posterior from the 180 degrees angle (135 degrees). 
Optimize the boundaries during the scan and locate the orientation of the bifurcation 
to obtain the “Y” for vessel identification in the longitudinal images later on. Store 
one image clip at least 6 seconds in duration to illustrate the anatomy.

Now move the transducer over the neck until the vessels are projected on top of 
each other. When this is the case rotate the transducer 90 degrees to a longitudinal 
projection so the vessels are displayed on top of each other and the bifurcation and 
tip of the flow divider can clearly be seen. The TFD should be placed at the left side 
of the screen at the designated gridline. 
At this longitudinal angle identify the internal vessel with Doppler, place caliper within vessel 
and store the image.
12.7.4.2
Start of the 12 Selections
At the CCA segment start the scan at 150 degrees on the arc; place the text indicating the 
angle of interrogation on the screen. Position the tip of the flow divider on the designated 
gridline and keep this position during all selections. Horizontalize the vessel optimizing both 
boundaries. When both boundaries are clearly seen, store a video clip.  


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
After the CCA segment, move to the near wall of the bifurcation segment.  
Change annotations accordingly, check the tip position, then optimize the boundary, 
and store the video clip. 

Move to the near wall of the internal segment.  Change annotations accordingly, 
check the tip position, then optimize the boundary, and store the video clip. 

Move to the far wall of the internal segment.  Change annotations accordingly, 
check the tip position, then optimize the boundary, and store the video clip.

Move to the far wall of the bifurcation segment.  Change annotations accordingly, 
check the tip position, then optimize the boundary, and store the video clip.

Move the transducer to the next angle on the arc (120 degrees) and repeat the 
procedure as described above.  Hereafter continue with the 90 degree angle using 
the same procedure.

Repeat the same procedure on the left side at angles 210, 240 and 270. 
When the scan is completed the stored image clips of the entire scan may be uploaded to the
QC Center(s) over the internet.


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12.7.5Ultrasound Image Reading
After the ultrasonic B-mode and Doppler data are recorded, the digital files are transferred to 
the QC Center(s). The individual image frames selected for measurement are stored in digital 
format for long term retention.
12.7.5.1
Reading Protocol
The primary objective of the carotid ultrasound B-mode image reading protocol is to measure 
the mean CIMT in the common carotid artery and the maximum CIMT in each of the twelve 
arterial segments as defined in Figure 2 and Figure 10. When present, a plaque can extend 
over more than one of the defined segments. In this case, more than one maximum thickness 
measurement may arise from a single extended plaque.  The reading process is described 
briefly below.  Additional details are given in the Reading Station Operator’s manual. 
12.7.5.2
Reading Station Instrumentation
The B-mode image reading station consists of the following instrumentation:  monitor, 
personal computer, and hardware and software for multiple image frame capture, CIMT 
measurement and data storage.  Measurement software will include semi-automated edge 
detection algorithms with tracings that can be easily modified by the reader as required.
12.7.5.3
Personnel
The exact number of readers required will be determined by the reading load, but four to eight 
readers is typical for moderate to large studies.  The time to read a scan is between 1 and 3 
hours.  Limitations are placed on the number of hours of reading permitted per session to 
minimize reader fatigue and to help ensure that all studies are read according to the 
standardized reading protocol. All ultrasound readers are certified after satisfactory 
completion of a standardized training program described in Section 1.4 of this protocol.
12.7.5.4
Acquisition of B-mode Image Measurement Data
The data from each of the twelve predefined arterial segments (mean and maximum CIMT) 
that are required to compute the primary and secondary outcome parameters are obtained 
using the standardized procedure described below.
12.7.5.5
Image Frame Selection from Digital Files
From the digital files, the image sequences obtained from several interrogation angles in each 
segment correctly coded in the image and accompanied by annotations are carefully reviewed 
frame by frame to select the best quality images for measurement. The reader searches for 
those end diastolic image frames from each segment which most clearly outline the maximum 
CIMT within the near wall and/or far wall boundaries within the predefined segments.  
Following each measurement, the image frame selected is stored on the reading station hard 
drive or directly to the network of the QC Center(s). The measurement data, the images from 
which the CIMT measurements were taken, the outlines traced on the images and the digital 
file contents will be stored and archived for long term retention. 


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12.7.5.6
Marking of Arterial Boundaries
On each image frame, the visualized blood-intima and media-adventitia boundaries are 
marked using the study specific software. These segments are defined relative to the tip of the 
flow divider, which has been maintained by the sonographer at the TFD reference gridline on 
the screen as shown in Figure 2. For CIMT measurements, the trailing edges are traced on the 
near wall boundaries and the leading edges on the far wall boundaries.  When measurements 
of lumen diameter are made in the common carotid artery, the trailing edge of the near wall 
and the leading edge of the far wall blood-intima boundaries are marked. After all boundaries 
in a given segment have been traced, the mean of the 10 mm segment and/or maximum CIMT 
are computed and stored in a data file. Images from all segments are read in an identical 
manner.  The standardized procedure used in making CIMT measurements is illustrated in the 
training video.
12.7.5.7
Doppler Data Analysis 
The results of the brief Doppler examination performed on the internal and external carotid 
arteries at the OAI angle following the transverse scan are only used to confirm correct artery 
identification and anatomical orientation.  No quantitative flow measurements are made from 
the Doppler results. 
12.7.5.8
Primary CIMT Outcome 
The primary CIMT outcome for the study is change in the average maximum CIMT over 12 
carotid segments defined by the near and far walls of the CCA, BIF and ICA on the right and 
left sides.  We refer to this parameter as the MeanMax CIMT.  For each participant visit, the 
12 segment specific maximum CIMT values are obtained by combining data across the 3 
interrogation angles and selecting the largest CIMT measurement.  Participant and visit 
specific estimates of MeanMax CIMT are computed for descriptive and QA/QC purposes by 
averaging the observed maximum CIMT values for the 12 carotid segments.  For statistical 
analysis, however, the segment specific maximum CIMT values are treated as dependent 
variables in a repeated measures analysis of variance and maximum likelihood estimates of 
the change in MeanMax CIMT are computed within the statistical model. 
12.7.5.9
Secondary CIMT Outcomes 
Segment specific estimates of change in MeanMax CIMT will be examined based on subsets 
of the 4 maximum CIMT formed by the near and far walls on the right and left sides within 
the CCA, BIF and ICA, respectively.  
In addition, change in the MeanMean CCA will be evaluated based on 4 Mean CIMT values 
for the near and far walls of the right and left CCA formed by averaging mean CIMT values 
across the 3 angles of interrogation.
12.7.5.10
Transmission of Data
Outcome parameter data to be incorporated into the study database for analysis are transmitted 
using a secure upload procedure or bonded courier from the QC Center(s) to the sponsor or 
their designated vendor at specified intervals. 


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12.7.6Timing of the Reading Process
12.7.6.1
Screening Scans
Two screening exams will be performed for all eligible participants approximately 4 and 2 
weeks prior to randomization.  These will be full examinations consistent with the scanning 
protocol described in sections 2-4 above and will be read as they are received to determine 
participant eligibility.  Based on the results, the reader will generate and return to the 
Clinical/Imaging Center an eligibility certificate for each scan, clearly indicating whether the 
participant meets the eligibility requirements described in section 12.7.2.7 or not. The QC 
Center staff will make every effort to return eligibility certificates to the respective 
Clinical/Imaging Centers within 2-4 business days of receipt of the scan.  Participants must 
satisfy the criteria described in section 12.7.2.7 for both scans to be eligible for the study.
12.7.6.2
Initial Follow-up Scans
CIMT has been used as an endpoint in clinical trials for more than 20 years and a wealth of 
information is now available regarding the trade-offs between sample size and a number of 
techniques intended to minimize within-subject variability including the length of follow-up, 
the number and timing of scans, and the number of measurements collected per scan.  
Generally, the longer the duration of follow-up, the larger the number of scans and the larger 
the number of measurements per scan, the smaller the sample size required to detect a 
clinically significant difference in CIMT change.  For example, the METEOR study was 
designed for 2 years of follow-up, 7 scans per participant and 60 sets of measurements per 
scan, with a targeted sample size of 840 participants.  In this study design, there is a period of 
months or even years between the completion of recruitment and the beginning of close-out 
visits.  Since this study design will also employ batch reading processes to minimize between 
reader and temporal reading variability, there will be a period during initial follow-up when 
scans are being performed and sent to the QC Center(s), but no readings are performed.  
Special QA activities as described in sections 12.7.7.3 and 12.7.7.4 may be required to 
maintain data quality in these cases.  
12.7.6.3
Batch Readings at Close-out
Experience suggests that both systematic differences between readers and temporal drift in 
measurements can influence CIMT reading results.  To minimize these influences, all the 
scans for a given participant can be read together as a batch by a single reader over a relatively 
short period of time as each participant finishes the study. Details of the batch reading process 
will be negotiated with the sponsor and described in a batch reading SOP.  Unfortunately, it is 
generally not practical to fully blind the reader to information about scan order during batch 
reading.  Typically, however, scans within a batch will be read in a random order over a 
period of 2 -4 weeks and may be comingled with readings from other participant batches to 
minimize any bias resulting from the reader’s access to information about the order in which 
scans were obtained.  


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12.7.7Quality Control/Quality Assurance Procedures
Throughout the study, the QC Center(s) continuously monitors the quality of the images 
submitted from the routine studies and the outcome variable data obtained from the within-
and between-sonographer and within- and between-reader QC studies.  Should low quality 
images related to scanning technique be observed, these observations are immediately 
reported to the sonographers. Reasons for the low quality are identified and remedied in 
consultation with the sonographer. Should low quality studies related to the reading process be 
observed, these observations are immediately reported to the reader.  Reasons for the low 
quality are identified and remedied in consultation with the reader.  Sonographers and readers 
that repeatedly produce low quality studies may be decertified and prohibited from scanning 
or reading scans from study participants.
12.7.7.1
Purpose of QC/QA Programs
The purpose of the quality control/quality assurance program is to ensure that the ultrasound 
data collected for this study are of consistently high quality and are collected according to the 
study protocol.  The foundation of the quality control/quality assurance program rests on a 
well defined protocol, standardization of equipment and procedures, and uniform training and 
certification of sonographers and B-mode image readers.  Training and certification 
procedures are detailed in Section 12.7.1 of this document, and the standardized ultrasound 
protocol is detailed in Section 12.7.3. Additional components of the quality assurance program 
include:

monitoring the performance of the ultrasound scanning system selected for use in 
this study

monitoring sonographer performance to assure consistent acquisition of ultrasound 
B-mode images

monitoring reader performance and equipment to assure consistent measurement of 
arterial dimensions from the B-mode images

assessment of temporal changes in data collection processes

preparation of an ultrasound database
A detailed description of the individual quality assurance program components is provided 
below:
12.7.7.2
Monitoring Ultrasound Equipment Performance 
During the trial, the ultrasound system hardware and software may not be upgraded without 
prior approval from the QC Center(s) and sponsor.  Each Imaging Center should maintain a 
service log to track the timing, reason, and result of all service visits. Following each service 
visit, including regularly scheduled preventive maintenance, a service report should be sent to 
the QC Center(s) detailing the reason for the visit, any problems identified, and all actions 
taken. Monitors will compare these service reports against each site's service log during 


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regular site visits to ensure the accuracy and completeness of the service record 
documentation.
12.7.7.3
Monitoring Sonographer Performance
The QC Center(s) will employ a variety of qualitative and quantitative approaches to 
monitoring sonographer performance, including monthly performance reviews, site visits, and 
evaluation of study data.

Monthly and Quarterly Performance Reviews: 
One scan per sonographer per month will be reviewed by the sonographer and at the QC 
Center(s) using a standard review form for the first three months post certification.  After 
three months the sonographer will send in a self review form on a participant or on a volunteer 
(only during times of low activity) on a quarterly basis. The QC Center(s) will provide a 
schedule to the sonographers showing the months in which they must submit a quarterly 
review. The standard review used in the evaluation of the sonographers’ scans allows for a 
detailed review of the preliminary and arterial segment scans on the right and left carotid 
arteries for sonographer recertification purposes, and provides an overall performance grade 
of:
A) Satisfactory - the sonographer has followed protocol and used available tools to 
maximize image quality. 
B) Marginal - the sonographer has followed the protocol, or has only minor 
deviations that have minimal impact on the availability and/or quality of 
arterial measurements.
C) Unsatisfactory - the sonographer has deviated from the protocol in a manner 
likely to affect the availability and/or quality of arterial measurements.
Results and critiques from these performance reviews will be provided to sonographers on a 
regular basis. Sonographer receiving a grade of "C" will automatically have a second study 
reviewed. If successive "C" grades are received, the QC Center(s) will contact the site to 
develop a plan for remedial training and reassessment.  If no improvement is achieved, the 
sonographer may be decertified.  
The QC Center(s) will also randomly select studies for review to help ensure quality remains 
high throughout the study.  The sonographer’s imaging skills will be evaluated using the 
standard review form.  These random evaluations will assure that each sonographer is 
evaluated on study subjects and remove any prior knowledge on the sonographer’s part that a 
review will take place.  Weighted selection processes may be employed to oversample 
sonographers or sites with indications of quality deficits based on other metrics.  

Low Scan Activity During the Study


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If a certified sonographer does not perform a subject scan during one calendar month within 
the first three months post-certification or does not perform any subject scan during one 
quarter after the first three months following certification, the sonographer will be required to 
make a full scan on a volunteer, complete the Sonographer Scan Review Form, log it in the 
Sonographer Recertification Scan Review Form Log, and send the digital file and a copy of 
the Sonographer Scan Review Form to the QC Center(s).

Quick Scan Reviews
Each scan will be subject to a quick review upon receipt by the QC Center(s).   The purpose of 
this quick review is to confirm that participant demographics are as expected, the scanning 
equipment was functioning correctly, instrument settings were appropriate, the scan is 
complete and visualization of arterial interfaces is sufficient to provide high quality data for 
analysis.  Any deviations noted will be communicated back to the Imaging Center to allow 
them to attempt to reschedule the participant for a replacement scan or make the necessary 
corrections for future scans. Note that the quick reviews are especially important if there is a 
gap between the end of recruitment and the beginning of batch reading, to help prevent 
problems with equipment or sonographer performance from affecting multiple scans before 
they can be detected by quarterly reviews.  

Site Visits and Annual Meetings
At regular intervals, monitors will visit each Imaging Center to monitor ultrasound records 
and verify equipment service history. Remedial site visits will be performed by staff from QC 
Center(s) to review scanning procedures and suggest methods for improvement. The 
frequency of remedial site visits will be determined by findings from sonographers reviews, 
repeat scans and study data as well as communications between the QC Center(s) and Imaging 
Center staff regarding scanning procedures or other issues affecting ultrasound image quality 
and protocol implementation. 
All sonographers should plan to attend group quality control meetings to review study data 
and to maintain a high degree of standardization of the data collection process throughout the 
study. The number and timing of these group meetings will depend on the study design, but 
one will typically be held prior to beginning close-out scans.   
12.7.7.4
Monitoring Reader Performance 
Readers for this study will use a standard reading station with hardware and software funded 
by the sponsor to minimize differences in data acquisition. Upgrades or additions to the 
reading systems are not permitted unless mutually agreed upon by the QC Center(s) and the 
sponsor.  All readers should also plan to attend group quality control meetings as described 
above.
QC Center(s) will employ regular performance reviews, inter- and intra- reader repeat 
readings, and evaluation of study data as necessary to ensure consistent collection of arterial 
measurements between readers within that Center as outlined below. 


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During the batch reading process, approximately 1 batch per quarter will be randomly selected 
for use as a QC batch.  For QC batches, the two screening scans and the two close-out scans 
will be read by all active readers, allowing for a detailed evaluation of within and between 
reader differences in both cross-sectional and longitudinal estimates of CIMT.  Performance 
thresholds for the batch QC readings will be established, and outliers will be subject to 
remedial training and possible decertification.
A similar process will be used during recruitment, with QC batches consisting of the two 
screening scans for a single participant.
12.7.7.5
Use of Study Data
Study data on mean and maximum arterial dimensions, number of sites selected, average 
number of visualized interfaces, and average length of visualized interfaces will be evaluated 
to identify potential differences between sonographers and readers in the application of the 
study protocol.  Caution must be exercised in comparing study data results for sonographers in 
different Imaging Centers, since these comparisons may be confounded by differences in 
patient populations (in contrast to repeat scans that automatically control for participant 
effects).  Nevertheless, the study data available for these comparisons offers increased 
sensitivity to identify issues that merit further investigation, providing a powerful supplement 
to other approaches for assessing sonographer and reader differences.  
12.7.7.6
Safety Monitoring
Safety monitoring of ultrasound results will be the responsibility of the individual 
Clinical/Imaging Centers. The research protocol employed in this study is intended to allow 
precise estimation of average CIMT progression rates at specific arterial sites in groups of 
participants, and differs substantially from more clinically oriented evaluations.  As a result, 
the QC Center(s) are not able to adequately assess the clinical significance of atherosclerotic 
disease in individual patients. Subjects with severe and/or extensive carotid artery disease 
should be reported by the sonographer to the principal investigator and reviewed by medical 
practitioners at each site and referred for clinical evaluations as appropriate.
12.7.8Archival of Ultrasound Material 
All digital media will be labeled with the study name, clinical/imaging center ID and a 
consecutive follow-up number. The digital media will be stored following completion of the 
study and the sponsor will be consulted prior to destruction of any material.
The B-mode images from which the measurements of carotid intima-media thickness were 
derived are stored in a digital format.  In addition, the lines drawn on the images (outlines) are 
stored digitally as well as the measurement data. These files are processed on a local PC and 
subsequently stored on the network of the QC Center(s). Specific file naming conventions and 
file locations are described in the user requirements specification and data management 
standard operation procedures on file at each reading center.


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There will be no ultrasound scan paperwork received at the QC Centers.  Paperwork generated 
by the QC Centers will be archived. 


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12.8
Appendix H
Assumptions for Sample Size Calculation


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therefore independent of number of assessments and duration of study and reflects natural
 
 
 
     
  
 
 
 
 
 
 
 
 
 
 
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SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d3565c00003-csp-v-2
Document Title:
D3565C00003 Clinical Study Protocol version 2.0
Document ID:
Doc ID-002132590
Version Label:
3.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
04-Apr-2018 22:01 UTC
Barry traxler
Content Approval
04-Apr-2018 11:05 UTC
Larrye Loss
Content Approval
04-Apr-2018 11:29 UTC
Torbjorn Lundstrom
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.

SAP_001.pdf: 
Statistical Analysis Plan, GEL2.0Released Week Commencing: 02 January 2012LDMS_001_00026934LDMS_001_00073734
Statistical Analysis Plan
Study Code
D3565C00003
Edition Number
3.0
Date
06Mar2019
A Randomized, Double-blind, Placebo-controlled, Multicenter Parallel
Group Phase 3 Study Measuring the Effect of Rosuvastatin 20 mg on
Carotid Intima-Media Thickness in Chinese Subjects


PPD


Statistical Analysis Plan
Study Code D3565C00003
Edition Number 3.0
Date 05Mar20 9
A Randomized, Double-blind, Placebo-controlled, Multicenter Parallel
Group Phase 3 Study Measuring the Effect of Rosuvastatin 20 mg on
Carotid Intima-Media Thickness in Chinese Subjects
IQVIA A&R Statistician
Date
3
PPD


PPD


Statistical Analysis Plan 
Study Code D3565C00003
Edition Number 3.0
Date 06Mar2019
5
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
SIGNATURE OF STUDY STATISTICIAN........................................................2
SIGNATURE OF STUDY STATISTICIAN........................................................3
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN ..................................4
TABLE OF CONTENTS.....................................................................................5
LIST OF ABBREVIATIONS ..............................................................................8
AMENDMENT HISTORY................................................................................ 10
1.
STUDY DETAILS............................................................................................. 12
1.1
Study objectives................................................................................................. 12
1.1.1
Primary objective............................................................................................... 12
1.1.2
Secondary objective ........................................................................................... 12
1.1.3
Safety objective.................................................................................................. 12
1.2
Study design ...................................................................................................... 12
1.3
Number of subjects ............................................................................................ 13
2.
ANALYSIS SETS ............................................................................................. 13
2.1
Definition of analysis sets .................................................................................. 13
2.1.1
Intent-To-Treat (ITT) analysis set ...................................................................... 13
2.1.2
Per-protocol analysis set..................................................................................... 13
2.1.3
Safety analysis set.............................................................................................. 13
2.2
Violations and deviations ................................................................................... 14
3.
PRIMARY AND SECONDARY VARIABLES................................................. 15
3.1
Description of CIMT data .................................................................................. 15
3.1.1
Primary efficacy variable ................................................................................... 17
3.1.2
Secondary efficacy variables.............................................................................. 17
3.2
Safety and tolerability ........................................................................................ 18
4.
ANALYSIS METHODS.................................................................................... 18
4.1
General principles.............................................................................................. 18
4.1.1
Baseline values .................................................................................................. 20
4.1.2
Change and percent change from baseline.......................................................... 20
4.1.3
Creatinine clearance........................................................................................... 20
4.1.4
Last observation carried forward (LOCF)........................................................... 21


Statistical Analysis Plan 
Study Code D3565C00003
Edition Number 3.0
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4.1.5
Analysis of covariance (ANCOVA) model for percentage change from 
baseline.............................................................................................................. 21
4.1.6
Time weighted average lipid value..................................................................... 22
4.1.7
Summaries of continuous variables .................................................................... 22
4.1.8
Summaries of categorical variables .................................................................... 22
4.1.9
Summaries of shifts from baseline in categorical variables................................. 22
4.2
Analysis methods............................................................................................... 23
4.2.1
Subject disposition............................................................................................. 23
4.2.2
Protocol Violations and Deviations .................................................................... 23
4.2.3
Demographic and baseline characteristics .......................................................... 23
4.2.4
Medical and surgical history .............................................................................. 24
4.2.5
Duration of exposure.......................................................................................... 25
4.2.5.1
Study therapy..................................................................................................... 25
4.2.5.2
Prior and concomitant medications..................................................................... 25
4.2.5.3
Treatment compliance........................................................................................ 26
4.3
Efficacy analysis ................................................................................................ 26
4.3.1
Estimates of effects and tests of statistical significance for trial objectives .........27
4.3.2
Justification of the model-based approach.......................................................... 27
4.3.3
Details of the statistical models .......................................................................... 28
4.3.4
Main and supportive between-group analyses of primary and secondary 
endpoints ........................................................................................................... 29
4.3.5
Laboratory data.................................................................................................. 30
4.3.6
Other analyses.................................................................................................... 30
4.3.7
Subgroup analyses ............................................................................................. 31
4.3.8
Exploratory analyses.......................................................................................... 32
4.4
Safety variables.................................................................................................. 32
4.4.1
Adverse events................................................................................................... 32
4.4.2
All adverse events.............................................................................................. 34
4.4.3
Deaths................................................................................................................ 34
4.4.4
Serious adverse events ....................................................................................... 34
4.4.5
Related adverse events ....................................................................................... 35
4.4.6
Adverse events leading to discontinuation.......................................................... 35
4.4.7
Other adverse events analyses ............................................................................ 35
4.5
Clinical laboratory tests evaluation..................................................................... 35
4.5.1
Summary of laboratory variables over time ........................................................ 36
4.5.2
Shift tables and summary of subjects with specific laboratory values ................. 36
4.5.3
ECG................................................................................................................... 37
4.5.4
Vital signs.......................................................................................................... 38
4.5.5
Weight ............................................................................................................... 38
4.5.6
Physical examination ......................................................................................... 38
4.6
Conventions....................................................................................................... 39
4.6.1
Study period start and end dates ......................................................................... 39
4.6.2
Duplicate assessments........................................................................................ 39


Statistical Analysis Plan 
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4.6.3
Post-dosing efficacy observations ...................................................................... 39
4.6.4
Post-dosing Safety Observations ........................................................................ 39
4.6.5
Missing Start and Stop dates for Adverse Events................................................ 40
4.6.6
Calculation of Body Mass Index ........................................................................ 40
4.6.7
Missing Dates Assignment for Concomitant Medications................................... 40
5.
INTERIM ANALYSES ..................................................................................... 41
6.
CHANGES OF ANALYSIS FROM PROTOCOL ............................................. 41
7.
REFERENCES .................................................................................................. 41
LIST OF TABLES
Table 1
Summaries of baseline characteristics ...................................................23
Table 2
Changes of analysis from protocol ........................................................41
LIST OF FIGURES
Figure 1
Study flow Chart...................................................................................12
Figure 2
Summary for CIMT endpoints...............................................................17
LIST OF APPENDICES
Appendix A
Subset of important protocol deviations that will affect study 
results interpretation and the Per-Protocol population............................43
Appendix B
Efficacy objectives and outcome variable relating to each 
objective ...............................................................................................46
Appendix C
SAS codes for statistical models used in the efficacy analysis. ..............48
Appendix D
Assumptions for sample size calculation. ..............................................49
Appendix E
Method Comparison between two generation of reagent for 
measuring Low Density LDL-C in Serum Samples for 
Homogeneous Enzymatic Colorimetric Assay using Roche 
Modular and Cobas series .....................................................................50


Statistical Analysis Plan 
Study Code D3565C00003
Edition Number 3.0
Date 06Mar2019
8
LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
AE
Adverse event
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
Apo
Apolipoprotein
AST
Aspartate aminotransferase
BL2
IMT assessment at Visit 2
BL3
IMT assessment at Visit 3
CAI
Cholesterol - absorption inhibitor
CCA
Common carotid artery
CHD
Coronary heart disease
CIMT
Carotid intima-media thickness
CrCl
Creatinine clearance
CVD
Cardiovascular disease
ECG
Electrocardiogram
eCRF
Electronic case report form
HDL-C
High-density lipoprotein cholesterol
ICA
Internal carotid artery
ICVD
Ischemic cardiovascular disease
IMT
Intima-media thickness
ITT
Intent-to-treat
IxRS
Interactive Voice/Web Response System
LDL-C
Low-density lipoprotein cholesterol
LOCF
Last observation carried forward
MeanMax
Mean of the maximum
MeanMean
Mean of the mean
MedDRA
Medical Dictionary for Regulatory Activities
PP
Per-protocol
PT
Preferred term


Statistical Analysis Plan 
Study Code D3565C00003
Edition Number 3.0
Date 06Mar2019
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Abbreviation or 
special term
Explanation
SAE
Serious adverse event
Statin
HMG-CoA reductase inhibitor
SOC
System organ class
TG
Triglycerides 
ULN
Upper limit of normal


Statistical Analysis Plan 
Study Code D3565C00003
Edition Number 3.0
Date 06Mar2019
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AMENDMENT HISTORY
Date
Brief description of change
26Jun2018
Updated following BDR1 comments and internal review

Clarification added to ensure that if a subject meets inclusion
criteria during a re-test between visits 1 and 2, this is not 
considered a deviation (Appendix A)

Windowing removed

Additional CIMT outputs detailed; summaries by cohort and 
outputs to show quality control of scanning and reading of 
results (section 4.3.6).
14Aug2018
Updated after direct LDL measurement transitioned from 2nd 
generation reagents to 3rd generation reagents (section 4.1)
07Sep2018
Updated following AZ global and upper management team review
23Oct2018
Updated following some additional output requests, an update request 
from the safety physician, and an update following the review of the 
CSR prototype (section 4.2.1 and 4.3.5).
01Feb2019
Updated following BDR2 comments: 

Minor cosmetic/formatting updates throughout.

Information around disallowed medication and CIMT deviation 
clarified (section 2.2).

Clarification added around use of CIMT scans from randomized 
subjects not treated, with no post-randomisation CIMT scans
(section 3.1)

Baseline definition for subjects not treated clarified (section 
4.1.1).

Definition of a completer clarified (section 4.2.1)

Compliance calculation updated and a definition of dose 
interruption added (section 4.2.5.3)

Subgroups for on-treatment LDL-C clarified (section 4.3.8)

Definition of AEs to be included as ischaemic cardiovascular 
AEs updated (section 4.4.2).

Definition of ‘consecutive occasions’ clarified (section 4.5.2)

Derivation of QTcF added (section 4.5.3)

Clarification added on handling multiple early termination 
CIMT assessments (section 4.6.2).

Appendix E added


Statistical Analysis Plan 
Study Code D3565C00003
Edition Number 3.0
Date 06Mar2019
11
Date
Brief description of change
26Feb2019
Minor cosmetic updates and more detail provided to amendment section
28Feb2019
Minor updates following review of v2.9:

"global METEOR", updated to "global METEOR 
(D3565C00088)" (Section 1.3) and "US Meteor" updated to 
"global METEOR"  (Section 4.3.3)

Section 4.2.5.3, in sentence "no medication it taken at site at this 
visit". "it" should be "is".

Section 6, added compliance calculation to the change from 
protocol analysis table.
05Mar2019
Compliance calculation updated to only calculate overall compliance 
and not by-visit compliance (section 4.2.5.3) and IPD for compliance 
updated for consistency (Appendix A)


Statistical Analysis Plan 
Study Code D3565C00003
Edition Number 3.0
Date 06Mar2019
12
1.
STUDY DETAILS
1.1
Study objectives
1.1.1
Primary objective
The primary objective of this study is to assess the efficacy of rosuvastatin 20 mg compared to 
placebo on slowing progression of carotid intima-media thickness (CIMT) over 104 weeks in 
Chinese subjects with subclinical atherosclerosis.
1.1.2
Secondary objective
The secondary objective is to assess the efficacy of rosuvastatin 20 mg compared to placebo 
over 104 weeks on slowing progression of intima-media thickness (IMT) in carotid artery 
segments and on blood lipids in Chinese subjects with subclinical atherosclerosis.
1.1.3
Safety objective 
The safety objective is to assess the safety and tolerability of rosuvastatin 20 mg compared to 
placebo over 104 weeks in Chinese subjects with subclinical atherosclerosis.
1.2
Study design
This study is a randomized, double-blind, placebo-controlled, multicenter parallel group study 
assessing the effects of rosuvastatin 20 mg treatment for 104 weeks on the change in CIMT of 
the common carotid artery (CCA), carotid bulb, and internal carotid artery (ICA) in adult
Chinese subjects with subclinical atherosclerosis. 
The timing of IMT measurements is detailed in section 3.1. Blood samples for analysis of 
lipid parameters will be collected at weeks -6, 0, 6, 13, 39, 65, 91 and at the time of
discontinuation of study treatment (on or before week 104).
Figure 1
Study flow Chart


Statistical Analysis Plan 
Study Code D3565C00003
Edition Number 3.0
Date 06Mar2019
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1.3
Number of subjects
 
 
 
 
2.
ANALYSIS SETS
2.1
Definition of analysis sets
Two analysis sets will be used for efficacy evaluation:
2.1.1
Intent-To-Treat (ITT) analysis set
The primary and secondary efficacy endpoints will be analyzed using the intent-to-treat (ITT) 
analysis set. The ITT population consists of all randomized subjects. Subjects will be analyzed
according to the treatment randomized.
2.1.2
Per-protocol analysis set
Supportive analyses of CIMT data will be carried out using the per-protocol (PP) analysis set.
The PP analysis set is a subset of the ITT population that includes subjects without any 
important protocol deviations that may affect the study outcome significantly or the 
interpretability of the study results. The criteria for such important protocol deviations are 
defined in the section 2.2 and Appendix A. Subjects will be analyzed according to the 
treatment actually received.
The exclusions from the PP analysis set will include, but will not be limited to, the subjects 
who took prohibited concomitant medications, who were non-compliant in taking the
investigational product (or who’s compliance could not be calculated, see section 4.2.5.3), or 
who had major deviations of study procedures.  These exclusions for the PP analysis set are 
explicitly defined in section 2.2 and Appendix A. The list of prohibited medications is given 
in section 7.7.1 of the protocol.
2.1.3
Safety analysis set
The safety analysis set will consist of all subjects who take at least 1 dose of investigational 
product or placebo. Subjects will be analyzed according to treatment actually received. For 
subjects who received both treatments during the study, for instance, erroneously treated for a 
CCI


Statistical Analysis Plan 
Study Code D3565C00003
Edition Number 3.0
Date 06Mar2019
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period of time and then switched back to correct treatment, the subject will be analyzed
according to the first dose administered at baseline.
2.2
Violations and deviations
All protocol deviations need to be appropriately monitored and addressed at the site 
monitoring/management level.  
For reporting purpose, however, only the “important protocol deviations” as assessed by study 
team will be included in the CSR. All important deviations related to study inclusion or 
exclusion criteria, conduct of the trial, subject management or subject assessment should be 
described.  The "major/minor" terminology should no longer be used in CSRs.  Protocol 
deviations that the study team considered to be unimportant should not be tabulated or listed, 
among which might include lack of compliance with visit schedule and subjects who have dose 
reductions or interruptions.
The following categories are used to describe important protocol deviations, and to be 
summarized and listed in CSR.

Eligibility criteria not fulfilled; 

Subjects randomized but subsequently discover they failed the eligibility criteria; 

Disallowed concomitant medication taken during the study (medications with an ATC 
code of C10AA (HMG COA REDUCTASE INHIBITORS), C10 (LIPID MODIFYING 
AGENTS), or C10AX (OTHER LIPID MODIFYING AGENTS) or ‘Reason for Therapy’ 
is recording on the eCRF as ‘Control for dyslipidemia’, ‘Hyperlipidemia’ or 
‘Hypolipidemic’ are only considered disallowed if they are used for more than 3 months
across the study period before last dose date.); 

CIMT data taken more than 31 days after the last dose of study medication; 

Received incorrect study drug. 
Refer to appendix A for details.
IQVIA will identify any protocol deviators, in conjunction with study team physician and flag 
all important deviations to AZ study team for exclusion in any relevant populations and output 
programs 
• Important deviations that may affect the study outcome significantly and the 
interpretability of the study results will be programmatically derived by the A&R provider
where possible.
• One report will be available to identify the list of all important protocol deviations.
An
 report will be sent from the AZ study lead in Excel. The MARS lead statistician 
and AZ study physician will work together to review the list manually and flag which are 
important and add into the data sets. Of note, the lead statistician from the MARS provider will 
review this list only to identify the deviations that are programmable and will not classify the 
deviations as major or minor. Non-programmable deviations will be taken from the 
 
report directly for the summary of important protocol deviations.
CCI
CCI


Statistical Analysis Plan 
Study Code D3565C00003
Edition Number 3.0
Date 06Mar2019
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A subset of important deviations that may affect the study outcome significantly and the 
interpretability of the study results will be identified and documented prior to unblinding by 
study team, and defines the per-protocol analysis by excluding data completely or partially as 
outlined in Appendix A.
3.
PRIMARY AND SECONDARY VARIABLES
3.1
Description of CIMT data
CIMT measurements are made from ultrasound images of the carotid arteries. The thickness 
of the intima and media is determined as the distance from the interface between the vessel 
lumen and the intima, to the interface between the media and the adventitia. At each imaging 
visit, subjects will lie in a supine position with their head turned to the opposite side away 
from the artery that is being examined. Images are made of the near and far walls of the CCA, 
the carotid bulb, and the ICA sites of the right and left carotid arteries. The standard protocol 
requires each of these 12 artery sites to be imaged from 3 interrogation angles, each of which 
differs from the adjacent orientation by 30° of angulation (see Appendix H of the protocol). 
The images will be recorded and sent to 
 or
 for evaluation.
For each of the 12 carotid artery sites at each visit, the 3 images recorded at the various 
interrogation angles will be measured to determine the minimum, mean and maximum of the 
CIMT for a specific angle in that site. The maximum CIMT measured from the 3 interrogation 
angles will be entered as the maxCIMT value for that arterial site. This process is repeated for 
the 12 carotid arterial sites: the near and far walls of the CCA, the carotid bulb, and the ICA 
sites of the right and left (near and far walls) carotid arteries.
Additionally, the means of the CIMT measurements of the 4 CCA sites over the 3 
interrogation angles will also be recorded as the meanCIMT values for each of the 4 sites 
(right and left, near and far walls).
We use the following convention to describe the 12 carotid artery sites mentioned above:

L or R to denote left or right carotid

B, C or I to denote the bulb, common or ICA segment

F or N to denote far or near wall
Consequently, the 12 carotid artery sites are
'LBF','LBN','LCF','LCN','LIF','LIN','RBF','RBN','RCF','RCN','RIF' and 'RIN'.
For each subject, IMT assessment from ultrasound scan will be done 7 times: twice before 
randomization, at weeks 26, 52, 78, and twice at the time of discontinuation of study treatment 
(on or before week 104). Each scan will yield a set of IMT measurements described above. 
CCI
CCI


Statistical Analysis Plan 
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Edition Number 3.0
Date 06Mar2019
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The two IMT measurements taken before randomization must meet inclusion criteria of 
maximum IMT ≥ 1.2 mm and < 3.5 mm. The final two IMT procedures should be performed 
on different days when possible. The second of the final IMT procedures should occur at or 
before week 104, at the time of discontinuation of study treatment. 
Batch reading of all the 7 scans (2 before and 5 after randomization) of a given subject will be 
done by the same reader over a short period of time for each randomized and treated subject 
upon completion of (or premature discontinuation from) the 2-year treatment. This will reduce 
the influence of between reader variability and temporal drift in measurements. Only batch-
read CIMT data will be used for statistical analysis of efficacy because of its greater accuracy. 
However, for randomized subjects who did not receive study medication with no post-
randomisation scans, if the two scans before randomization are not be batch read, the 
eligibility CIMT reading data will be used instead for statistical analysis of efficacy.  For 
randomized subjects who did receive study medication with no post-baseline scans, the same 
approach will apply.
Since the subjects may miss visits or prematurely withdraw before 2 years, we may have 
incomplete efficacy observations. Also, IMT measurement from ultrasound scan may 
occasionally be immeasurable at all 3 angles for some carotid sites.
Following is a summary diagram describing the CIMT measure, data derivation, and data 
analysis process in terms of dependent variable and summary statistics.


Statistical Analysis Plan 
Study Code D3565C00003
Edition Number 3.0
Date 06Mar2019
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Figure 2
Summary for CIMT endpoints
*For CCA only.
3.1.1
Primary efficacy variable
The primary efficacy variable is the annualized rate of change in mean of the maximum 
(MeanMax) CIMT measurements from each of the 12 carotid artery sites based on all scans 
performed during the 104-week study period. The maxCIMT value for each site will be the 
dependent variable in mixed effects model.
3.1.2
Secondary efficacy variables
The secondary outcome variables are

Annualized rate of change in the MeanMax CIMT of the near and far walls of the 
right and left CCA, using maxCIMT value from CCA as the dependent variable.

Annualized rate of change in the MeanMax CIMT of the near and far walls of the 
right and left carotid bulb, using maxCIMT value from carotid artery bulb as the 
dependent variable.
Mean
Max
Min
Max
Mean
Min
Max
Mean
Min
Angle 1
Angle 2
Angle 3
Each site 
Each visit
Data 
transfer
Derivation takes 
single maximum or 
average
Dependent 
variable
Mixed 
effects 
model
Summary 
statistics
MaxCIMT
MeanCIMT*
MeanMax - Change 
in maximum CIMT 
for 12 carotid sites 
(mm/yr)
MeanMean -            
Change in mean CIMT
for 4 common carotid 
sites (mm/yr)


Statistical Analysis Plan 
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Edition Number 3.0
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
Annualized rate of change in the MeanMax CIMT of the near and far walls of the 
right and left ICA, using maxCIMT value from ICA as the dependent variable.

Annualized rate of change in the mean of the mean (MeanMean) CIMT of the near 
and far walls of the right and left CCA, using meanCIMT value from CCA as the 
dependent variable.

Percentage change from baseline to final visit in low-density lipoprotein cholesterol 
(LDL-C) (using converted results – see section 4.1), total cholesterol, high-density 
lipoprotein cholesterol (HDL-C), triglycerides (TG), non-HDL-C, apolipoprotein 
(Apo) B, ApoA-I, non-HDL-C/HDL-C, and ApoB/ApoA-I
Please refer to Appendix B for description of efficacy objectives and outcome variables 
corresponding to each objective.
3.2
Safety and tolerability
No formal statistical testing of the safety and tolerability variables will be carried out.  The 
safety and tolerability variables will be individually summarized using the safety analysis set. 
The safety and tolerability variables are:

Adverse events (AEs)

Serious adverse events (SAEs)

Changes in clinical laboratory values (hematology, chemistry, and urinalysis)

12-lead electrocardiograms (ECGs)

Vital signs 

Physical examinations
4.
ANALYSIS METHODS
4.1
General principles
All statistical evaluation, as well as summaries and tabulations will be done by qualified
personnel at IQVIA. Before breaking the treatment codes, following clean file declaration,
all decisions made on the evaluability of the data for each individual subject will be 
documented and each subject will be assigned to the appropriate analysis data set.
The primary analysis for efficacy variables will be based on the ITT analysis set. The CIMT 
analysis will be performed on the PP population as a robustness check of the analysis on ITT 
analysis set.


Statistical Analysis Plan 
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Edition Number 3.0
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A multilevel, repeated measures, linear mixed effects model will be used for the analysis of 
the primary and secondary CIMT end points. Rationale for the choice of the model follows 
Espeland et al (1992 and 1999) and Pitt et al (2000). Details of the model are given in section
4.3.3.
No multiplicity adjustment will be applied to the secondary efficacy analysis.
Lipid and Apo analyses will be performed on the ITT analysis set only. The definition of 
baseline for laboratory endpoint variables is given in section 4.1.1.
Secondary lipid and lipoproteins outcome measures are the percentage change from baseline,
which will be analyzed by analysis of covariance (ANCOVA) with terms for treatment as a 
factor and baseline value as a covariate in the model. For lipid measurements (LDL-C, total 
cholesterol, HDL-C, TG, non-HDL-C, non-HDL-C/HDL-C), both the analysis of the percent 
change from baseline at final visit, and the analysis of the percent change from baseline to 
time-weighted average during treatment will be performed. In the evaluation of change from 
baseline to final visit, missing observations will be imputed by last observation carried 
forward (LOCF) method. No imputation will be made for missing lipid values for time-
weighted average analysis. 
During the study, LDL-C measurement was transitioned from 2nd generation reagent to 3rd 
generation reagent by direct assay. Post-baseline LDL-C values will be affected. To evaluate 
the consistency of different measurement reagents, all post-baseline LDL-C related analysis 
will be performed on two sets of data.

LDL-C values as collected, regardless of the type of reagent.

LDL-C converted, where values which used 3rd generation reagent (i.e. all values 
collect on or after the 8th March 2018) are converted to 2nd generation values using 
the formula X=0.0626+0.882*Y, where X is the LDL-C value (in SI units, mmol/L) 
using 3rd generation reagent, Y is the LDL-C value using 2nd generation reagent.
(see Appendix E for details).
For Apo measurements (ApoB, ApoA-I, ApoB/ApoA-I), the analysis of the percent change 
from baseline to final visit (LOCF) will be performed.
Statistical significance will be set at α=0.05
The day of first dose of double-blind study medication (day 1) will be defined as the reference
start date for the randomized treatment period and will be displayed in the listings where an 
assessment date or event date appears when appropriate.

If the date of the event is on or after the reference date, then: Study Day = (date of
event – reference date) + 1.


Statistical Analysis Plan 
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Edition Number 3.0
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
If the date of the event is prior to the reference date, then: Study Day = (date of
event – reference date).
Duration of an event is calculated as stop date-start date + 1. For example, time on treatment 
(days) = Date of last dose - date of first dose + 1.
No analysis visit windows will be derived. All by-visit data will be presented by protocol 
scheduled nominal visits. Listings will include unscheduled visits.
4.1.1
Baseline values
Baseline is the last measurement collected (including measurements taken at unscheduled 
visits) prior to the date and time of first dose of study medication at randomization visit (visit 
4, week 0), or last measurement collected prior to randomization visit, for subjects who are 
randomized but do not receive any study medication.  For in-clinic assessments with 
assessment date equal to the first dose of study medication and time not available, the 
assessment will be assigned to the baseline period since all assessments are to be done prior to 
dispensing study medication according to the protocol.  For AEs and concomitant medications 
with start date equal to the first dose of study medication and time not available, the event will 
be considered post-baseline.  
4.1.2
Change and percent change from baseline
Change in any measurement (CM) from baseline to any randomized treatment period Week t
is defined as follows:
CMWeek t = MWeek t - Mbaseline,
where:

CMWeek t is the change in the measurement from baseline at Week t,

MWeek t is the measurement at Week t,

Mbaseline is the baseline measurement.
Percent change in any measurement (PCM) from baseline to any randomized treatment period 
Week t is defined as follows:
PCMWeek t =100 × (MWeek t - Mbaseline) / Mbaseline.
4.1.3
Creatinine clearance
Creatinine clearance (CrCl) from serum creatinine will be calculated using the following 
formulae


Statistical Analysis Plan 
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Edition Number 3.0
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4.1.4
Last observation carried forward (LOCF)
In LOCF analyses at Week t, the measurement designated as the Week t measurement will be 
used. If no Week t measurement is available, the last available earlier post-baseline 
measurement will be used.
4.1.5
Analysis of covariance (ANCOVA) model for percentage change 
from baseline
For the secondary efficacy analyses of lipid and lipoprotein outcome measures in the study, 
the ANCOVA model of percentage change from baseline to Week 104 (or last visit during 
treatment) efficacy will include treatment as a main effect and baseline value as a covariate. 
The following model will be used:
Cij = intercept + β Mbaseline,ij + τj + εij,
Where -  

Cij is the percent change from baseline to Week 104 of subject i in treatment 
group j

β is the slope of Cij regressing on the baseline measurement 

Mbaseline, ij is the baseline measurement of subject i, in treatment group j  

τj is the main effect of treatment group j  

εij is random error
The ANCOVA will present least squares (LS) mean estimates and 2-sided 95% confidence 
intervals (CIs) for mean percent changes from baseline within and (when warranted) between 
the rosuvastatin and placebo treatments groups.  In addition, t-statistics corresponding to the 
Type III sums of squares for the difference in the LS means will be used to obtain p-values for 
treatment group comparisons for certain efficacy analyses.


Statistical Analysis Plan 
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Edition Number 3.0
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4.1.6
Time weighted average lipid value
The time-weighted average lipid value is defined as the lipid value multiplied by the number 
of days since the last lipid assessment, summed for all lipid observations (this includes
observations made at unscheduled visits), and divided by the sum of days between all visits. 
No imputation will be made for lipid missing values for the time-weighted average analysis.
TWA=
n
n
n
t
t
t
t
x
t
x
t
x






......
......
2
1
2
2
1
1
, where
i
x s are the lipid values measured at times i=1, 2, …, n, it s are the number of days between 
visit i and visit (i-1).
And 
nt
t
t
T




......
2
1
is the total number of days over which the assessments took place.
This will be calculated for both sets of LDL-C values (collected and converted) described in 
section 4.1.
4.1.7
Summaries of continuous variables
Continuous variables will be summarized using number of observations, mean, SD, median, 
minimum and maximum, and will be presented by visit when applicable. Summaries for 
continuous endpoints known to have skewed distributions will also include quartiles and the 
interquartile range.
Minimum and maximum values will be reported to the same degree of precision as the raw 
data unless otherwise stated. Mean and median will be reported to one further degree of 
precision. SD will be reported to two further degrees of precision compared to the raw data.
4.1.8
Summaries of categorical variables
Categorical variables will be summarized with number of observations and percentage of 
subjects in each category.
4.1.9
Summaries of shifts from baseline in categorical variables
Changes from baseline in certain categorical variables will be summarized using shift tables. 
Frequencies and percentages of subjects within each treatment group will be generated for 
levels of cross-classifications of baseline and the on-treatment value of the variable. The on-
treatment value can be either the value at a certain time point, or the minimum or maximum 
value in the direction of toxicity that has been observed during a study period (e.g., laboratory 
tests). Treatment group differences will not be assessed in summaries of shifts.


Statistical Analysis Plan 
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Edition Number 3.0
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4.2
Analysis methods
4.2.1
Subject disposition
A summary of subject disposition will display the number of subjects enrolled, i.e., signed 
informed consent, as well as the number of subjects randomized and who comprised each 
analysis set by treatment group and overall.  In addition, the number and percent of subjects 
who completed the study (identified on the eCRF as having completed the study – ‘Was 
subject prematurely withdrawn from study’ =No), discontinued from the study, and reasons 
for discontinuation from the study will be summarized by treatment group and overall. An 
accompanying listing of subjects who prematurely discontinued from the study will be 
provided. 
The exclusions from the PP analysis set will include, but will not be limited to, the subjects 
who took prohibited concomitant medications, who were non-compliant in taking the 
investigational product, or who had major deviations of study procedures.  These exclusions 
for the PP analysis set are explicitly defined in Section 2.2 and Appendix A.
A listing will be produced for all enrolled subjects in the ITT analysis set.
4.2.2
Protocol Violations and Deviations
Important protocol deviations will be summarized and listed by treatment group for the ITT 
analysis set.
4.2.3
Demographic and baseline characteristics
Demographic and other baseline characteristics will be summarized by treatment group and 
overall, for the ITT analysis set.
Baseline height and weight will be summarized as continuous variables. Sex and race will be 
summarized as categorical variables. Age at time of informed consent will be summarized as a 
continuous variable, and by grouping subjects according to age categories (< 65 and ≥ 65 
years). Baseline BMI will be summarized as a continuous variable, and by grouping subjects 
according to BMI categories (< 25 kg/m2, 25- < 28 kg/m2 and 28 kg/m2). 
Other baseline characteristics to be summarized are listed in the following table:
Table 1
Summaries of baseline characteristics
Characteristic
Summarized as
Categories
Smoking status
Categorical
Former, Current, Never
Alcohol use
Categorical
Former, Current, Never
China Adult Dyslipidemia 
Management Guidelines Risk1
Categorical
10-year Ischemic cardiovascular 
disease (ICVD) risk < 5%
10-year ICVD risk ≥5% - <10%
CrCl
Continuous


Statistical Analysis Plan 
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Characteristic
Summarized as
Categories
CrCl
Normal 
CrCl > 80 (ml/min)
Mild impairment
CrCl 50 – 80 (ml/min)
Moderate impairment
CrCl 30-<50 (ml/min)
Severe impairment
CrCl <30 (ml/min)
Maximum IMT (Visit 2 and 3)
Continuous
Major risk factors for ICVD2
Categorical
Hypertension
Smoking 
HDL-C < 40 mg/dL
Obesity (body mass index ≥28kg/m2)
Family history of premature coronary 
heart disease (CHD)
Age Male ≥45 years, Females ≥55 
years)
1Summary will be provided for both interactive voice/web response system (IxRS) data and electronic case report 
form (eCRF) data.
2 Total number of risk factors (0 - 6) will also be summarised, with a sub-category under 2 risk factors of 
with/without hypertension.
All summaries of continuous characteristics will be based on non-missing observations. For 
categorical characteristics, percentages will be calculated out of the total number of subjects in 
the data set, overall and by treatment group (i.e., each denominator includes the number of 
subjects with missing/unknown values for the endpoint).
Demographic and baseline disease characteristics will be presented in listings for all 
randomized subjects.
4.2.4
Medical and surgical history
Medical history will be coded using the latest Medical Dictionary for Regulatory Activities 
(MedDRA) version available at the time of database lock.  
Past and current medical history will be summarized together by system organ class (SOC), 
preferred term (PT), and treatment group for the ITT analysis set.  Surgical histories will be 
summarized in the same way.
The numbers and percentages of subjects with general medical history findings will be 
provided using the ITT analysis set. Surgical histories will be summarized in the same way.
Medical and surgical histories will be listed for the ITT analysis set.


Statistical Analysis Plan 
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4.2.5
Duration of exposure
4.2.5.1
Study therapy
Duration of exposure is defined as the number of days between the start and the end dates of 
study therapy, where the start date of study therapy is the date of the first dose of 
investigational drug or placebo, and the end date of study therapy is the last known dose of 
investigational drug or placebo during the double-blind treatment period, i.e., Duration of 
exposure = Last dosing date - First dosing date + 1. Duration of exposure, excluding 
interruptions is defined in the same way, but only days where dose taken is greater than 0 are 
included.
Duration of exposure will be summarized using all subjects treated (safety analysis set),
presenting the numbers and percentages of subjects with a duration of exposure within the 
following week ranges by treatment group: less than 1 week, 1 to less than 7 weeks, 7 to  less 
than 14 weeks, 14 to less than 21 weeks, 21 to less than 28 weeks, 28 to less than 35 weeks,  
35 to less than 42 weeks, 42 to less than 49 weeks, 49 to less than 56 weeks, 56 to less than 63 
weeks, 63 to less than 70 weeks, 70 to less than 77 weeks, 77 to less than 84 weeks, 84 to less 
than 91 weeks, 91 to less than 98 weeks, 98 to less than 104 weeks and 104 weeks or more. 
The cumulative exposure will be summarized for all subjects in the safety analysis set and
separately for subjects who prematurely discontinued. The numbers and percentages of 
subjects with duration of exposure of at least the following number of weeks will be presented 
by treatment group:
Up to 1 week, 1 week or more, 7 weeks or more, 14 weeks or more, 21 weeks or more, 28 
weeks or more, 35 weeks or more, 42 weeks or more, 49 weeks or more, 56 weeks or more, 
63 weeks or more, 70 weeks or more, 77 weeks or more, 84 weeks or more, 91 weeks or 
more, 98 weeks or more and 104 weeks or more.
Also, the mean, SD, median and range of duration of exposure (days) will be presented by 
treatment group for all subjects in the safety analysis set and separately for subjects who 
prematurely discontinued. 
Duration of exposure for the investigational product will be listed by subject using the safety 
analysis set. Additionally, a listing of subjects by batch number of investigational product will 
be produced. 
4.2.5.2
Prior and concomitant medications
All medications will be coded using the latest AstraZeneca Drug Dictionary at the time of 
database lock.  
Prior medication is defined as medication with a stop date before the date of the first dose of 
study medication.  
A medication will be regarded as concomitant if the start date is on or after the date of first 
dose, or if it started prior to the date of first dose and was ongoing after the date of first dose.


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Concomitant rescue medications will be summarized separately.  Partial date imputation for
medications is described in Section 4.6.7.
Prior and concomitant medications will be summarized by treatment group for the safety 
analysis set by drug class (anatomic class and therapeutic class), and generic drug name for 
each treatment group.  
Prior and concomitant medications will be listed together.  
Vitamin K antagonists including warfarin derivatives and coumadin will be listed by subject.  
These will be identified using ATC code B01AA.
4.2.5.3
Treatment compliance
Overall treatment compliance percent is calculated during the double-blind treatment period
for the blinded study medication (rosuvastatin 20 mg and placebo) as follows:
Compliance (%) =
 	
   	 	
   
	
 
	  	 
 100
If no tablets have been returned during the treatment period, the compliance will be set to 
missing (these subjects will also be excluded from the PP analysis set). If a subject does not 
return study mediation at the last visit, the last visit date will be used as the last return date for 
the compliance calculation. If the number of tablets returned is missing, the subject is assumed 
to have taken the treatment as prescribed by the CSP. If the return date is missing for a 
dispensed kit during the treatment period, the return date for that kit will be imputed to the 
next dispensed date, and the subject is assumed to have taken the treatment as prescribed by 
the CSP (i.e. 1 tablet per day, to a maximum of the dispensed dose). 
Treatment compliance will also be displayed in a listing.
4.3
Efficacy analysis
CIMT Data
In this study the CIMT data has a hierarchical (or multilevel) structure. The levels for the data 
are defined by 1) the study participants and 2) carotid artery sites within the participants. The 
repeated measure is time. 
A multi-level, linear mixed-effects model will be used for the primary analysis to assess the 
difference in the annualized rate of change in the CIMT measurements across 12 carotid artery 
sites between rosuvastatin 20 mg and placebo treatment over 104 weeks. The model is 
specified in terms of fixed effects for randomized treatment group, time, time by treatment 
interaction, ICVD risk stratification (<5%/5%-10%) – based on IxRS data, carotid artery site,


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age, sex, centre, and scan reader (In the unlikely event that the model does not converge it 
may be necessary to drop fixed effects for reader, sex and age in that order). Random effects 
within the model are the intercept and slope for individual subjects. Time in the model is a 
continuous measure and is the interval in years from date of randomization to date of CIMT 
measurement and its effect is linear. 
4.3.1
Estimates of effects and tests of statistical significance for trial 
objectives
Between-group comparisons
In the analysis, let β1 and β2 represent respectively the coefficient parameters for time and
time by treatment interaction in the mixed effects model. The dependent variable is maximum 
CIMT. 
The annualized rate of change (slope) in MeanMax CIMT in placebo will be estimated by the 
coefficient parameter β1, the annualized rate of change (slope) in MeanMax CIMT in the 
rosuvastatin group will be estimated by β1+ β2, and the difference of annualized rate (slope) of 
change between 2 groups will be estimated by β2. Then, the null and the alternative primary 
hypotheses can be expressed as 
H0 : β2=0 vs. Ha : β2≠0 at a significance level of α=0.05.
In other words, the change in MeanMax CIMT from time zero, measured in mm per year, can 
be estimated from the model as β1 (Time) for the placebo group and β1 (Time) + β2 (Time x 
Treatment) for the rosuvastatin group. The estimate of the absolute difference in mm in
MeanMax CIMT at 2 years between the treatment groups is β3 (Treatment) +2 β2 (Time x 
Treatment) and change from baseline at 2 years is 2 β2 (Time x Treatment).
The treatment effect is based on the Time x Treatment term and represents the difference in
slopes in mm/year. The between-group test of statistical significance is the p-value associated
with this term in the model.
Further details of the analyses and model are given in the following sections.
4.3.2
Justification of the model-based approach
An essential feature of the model is that it fits regression lines to profiles of CIMT values
consisting of two pre-randomization values, three values from visits during the treatment
period, and two end-of-study visits. In the event that a subject withdraws with an incomplete
profile after the pre-randomization ultrasound visits, an advantage of this approach is that 
regression lines can still be fitted to the data available. This regression approach is appropriate 
because CIMT values (and therefore primary and secondary endpoints based on them) are 
expected to change in a linear fashion over time. Analysis of CIMT data and presentation of 
results as annualized progression or regression rates is conventional, see for example Espeland 
2005.


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4.3.3
Details of the statistical models
The statistical model (i) reflects the multilevel repeated measures structure of the data, (ii)
focuses on the time-profile of CIMT values, (iii) uses all available data by including subjects
with incomplete data, and (iv) is consistent with pre-planned statistical analyses described in
the protocol. Objectives for analysis are to estimate and test the statistical significance of the 
treatment effect (rosuvastatin compared with placebo). For time of CIMT measurement, the 2 
pre-randomization visits and the final 2 visits at the end-of-study will be treated as separate 
time points.
The two pre-randomization CIMT scans, denoted by BL2 and BL3, are expected to be highly
predictive of CIMT values post-randomization, and the way in which they are included in the
statistical model is therefore important (Cnaan et al 1997). A model which has BL2 and BL3
as baseline covariates has greater flexibility in allowing a difference between changes from 
baseline to the first post-randomization assessment of CIMT (six months) and change from six 
months on, however the disadvantage is that only change from 6 months to two years is 
estimated by the model. For this reason, a model which has BL2 and BL3 as part of the 
response profile is preferred because BL2 and BL3 then contribute to estimation of regression 
lines at the subject-site level. Furthermore, this model reflects what is believed (and supported 
by the results in the global Meteor study) to be the behavior of CIMT over time, in other 
words changes over the 2-year treatment period in both treatment groups are expected to be 
small and smoothly continuous with time. Further advantages are that terms in the model 
(Time and
Time x Treatment) estimate changes over the entire treatment period from baseline up to
2 years, and all estimates of effects and p-values for the between-group comparisons can be 
obtained from a single model by comparing and testing slopes and interactions.
Random effects in the model will consist of subject intercepts and slopes. Thus, random 
effects in the model allow subjects to have different intercepts and slopes. The model assumes 
the treatment-time effect will be the same for all carotid sites. This is consistent with the 
expected effect of rosuvastatin or placebo on carotid artery sites.
An unstructured covariance matrix is used by default to give maximum flexibility in model 
fitting. If the unstructured covariance matrix results in a lack of convergence, alternative 
covariance structures, i.e., compound symmetry, will be used.
The adequacy of the basic model will be assessed by including additional terms for time-
squared and time-squared by treatment interaction. This is to explore non-linearity in the 
effect of time. These terms will be assessed using likelihood ratio tests comparing models 
fitted by maximum likelihood. The additional terms will not be included in the final model if 
they are not statistically significant at the 0.05 level.
Consistency of the treatment effect in individual carotid artery sites will be demonstrated by 
means of summary statistics for CIMT values at each visit for each treatment group.


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4.3.4
Main and supportive between-group analyses of primary and 
secondary endpoints
Results from main analyses (based on ITT analysis set) will be considered definitive, and the 
purpose of supportive analyses (based on PP analysis set) is to demonstrate robustness of 
results from main analyses with different statistical models and in different subject
populations. In the event that results from main and supportive analyses differ substantially 
further exploratory work will be carried out to explain the differences.
Primary Endpoint
The main analysis which gives a between-group assessment will be carried out using the 
mixed effects model as previously defined on subjects in the ITT analysis set population using 
maxCIMT data for all carotid artery sites.
A Supportive analysis will also be carried out in a similar way using only subjects in the PP 
population.
Secondary Endpoints

MeanMax CCA CIMT
The main and supportive analyses will be as for the main and supportive analyses of the
primary endpoint but using maxCIMT data only for sites in the CCA.

MeanMax Bulb CIMT
The main and supportive analyses will be as for the main and supportive analyses of the
primary endpoint but using maxCIMT data only for sites in the carotid artery bulb.

MeanMax ICA CIMT
The main and supportive analyses will be as for the main and supportive analyses of the
primary endpoint but using maxCIMT data only for sites in the ICA.

MeanMean CCA CIMT
The main and supportive analyses will be as for the main and supportive analyses of the
primary endpoint but using meanCIMT values measured in the CCA.


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
Percentage change from baseline to final visit in LDL-C (converted values, see 
section 4.1), total cholesterol, HDL-C, TG, non-HDL-C, ApoB, ApoA-I, non-HDL-
C/HDL-C, and ApoB/ApoA-I.
See section 4.3.5 for details.
4.3.5
Laboratory data
Analyses of percentage change from baseline in lipids and lipoproteins will be carried out for 
the ITT population using ANCOVA with terms for treatment and baseline value as a covariate
in the model. For LDL-C, this will be analysed for both sets of LDL-C values (collected and 
converted) described in section 4.1. However, the converted values will be considered as the 
secondary endpoint while the collected values will be used for supportive analysis.
The assumptions of normality and homogeneity of variance will be explored using probability
and residual plots. If assumptions are found to be violated, rank ANCOVA approach (Quade 
1967) will be used.
4.3.6
Other analyses
For each subject in the ITT analysis set (with at least baseline and one post-baseline scan), the 
slope of the regression line fitted to the profiles of CIMT values for all 12 carotid artery sites 
will be estimated in mm/year using a fixed effects model with terms for intercept, site, and 
time applied to each subject’s data. The estimate for slope will be determined from the 
coefficient of time. A positive slope will indicate progression and a negative slope will 
indicate regression.
The number and percent of subjects with regression will be summarized for each treatment 
group.
Summaries of MeanMax CIMT, MeanMax CCA CIMT, MeanMax Bulb CIMT, MeanMax 
ICA CIMT and MeanMean CCA CIMT (mm) by cohort of assessments completed and visit 
will be provided. Cohorts of assessments will be Completer - 2 years, non-completer but 
completed up to 18 months, non-completer but completed up to 12 months, non-completer but 
completed up to 6 months.
The following outputs will be included to assess quality control of scanning and reading of 
results.

Summary of number of carotid artery sites measured per scan by visit

Distribution of number of carotid artery sites measured per scan at each visit

Number (%) of subjects read by reader

Number of measurements obtained at each carotid artery site and percentage out of 
maximum possible


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4.3.7
Subgroup analyses
The effects of rosuvastatin in following subgroups of subjects will be evaluated,
1.
Age: < 65 and ≥ 65 years
2.
Sex
3.
BMI: < 28 vs ≥ 28 kg/m2
4.
China Adult Dyslipidemia Management Guidelines ICVD risk categories (see 4.2.2 
for definitions)
5.
History of hypertension (Yes/No)
6.
Baseline LDL-C: below and above or equal to the mean
7.
Baseline TC: below and above or equal to the mean
8.
Baseline HDL-C: below and above or equal to the mean
9.
Baseline TG: above and below the mean (If TG are not normally distributed, 
groupings above and below the median value will be considered).
10.
Baseline non-HDL-C: below and above or equal to the mean
11.
Baseline non-HDL-C/HDL-C: below and above or equal to the mean
12.
Baseline ApoB: below and above or equal to the mean
13.
Baseline ApoA-I: below and above or equal to the mean
14.
Baseline ApoB/ApoA-I: below and above or equal to the mean
15.
Smoking: never, current/former
The treatment-by-subgroup interaction will be examined by adding the subgroup variable and 
the interaction term of treatment-by-subgroup as covariates to multilevel, repeated measures, 
linear mixed effects model as described for the primary analysis (section 4.3).  Similar output 
will be presented for each subgroup as for the primary analysis. When the subgroups are also 
stratification factors, the eCRF values will be used rather than the values from IxRS used for 
randomization.
For smoking subgroup, if there is any category with less than 10% of the population in a 
review prior to unblinding the study, the subgroup may be re-categorized or eliminated before 
unblinding. 
These analyses will use the ITT analysis set.


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4.3.8
Exploratory analyses
Slope of the regression line, as defined in section 4.3.6, will be summarised (means, SD, N) 
for rosuvastatin treatment group only in each of the following subgroups (for only the 
converted LDL-C values, as described in section 4.1) to investigate the relevance of a
reduction of LDL-C:
1.            % change from baseline to time-weighted average during treatment in LDL-C:
below and above or equal to the mean.
2.
On-Treatment LDL-C (time-weighted average value):

below and above or equal to the mean

<100 mg/dL and ≥ 100 mg/dL

<70 mg/dL and ≥ 70 mg/dL

<70, (>=70- <100), and ≥100 mg/dL
3.
Loess plot of annualized rate of change in MeanMax CIMT in mm/year by % 
change in LDL-C and by on-treatment LDL-C (time-weighted average values).
4.4
Safety variables
This section describes safety analyses to be conducted on all subjects who enter the screening 
phase.  All analyses of safety data will present descriptive statistics.  Formal statistical 
comparisons will not be performed.  
The baseline value of each safety lab test, ECG, or physical exam endpoint is defined as the 
last assessment before or including Study Day 1 (i.e., day of first dose of double-blind study 
drug).  AEs occurring on Study Day 1 (the day that the first dose of randomized study 
medication was taken) will be counted during the double-blind treatment period. For subjects 
who are randomized but do not receive any double-blind study drug, baseline is defined as the
last assessment before randomization. AEs and other safety measures occurring after the last 
dose of randomized treatment are described in section 4.6.4.
4.4.1
Adverse events
All AEs, including SAEs, will be collected from the time of signature of the informed consent
throughout the treatment period and within 10 days after last dose of study drug.
AEs will be categorized according to 2 definitions:


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
AEs reported during the screening phase

Treatment Emergent AEs
Treatment emergent AEs are defined as all AEs which start on or after the first dose of study 
drug.  An AE that was present at treatment initiation but resolved and then reappeared while 
the subject was on treatment, is a treatment emergent AE (regardless of the intensity of the AE 
when the treatment was initiated). AEs reported through 10 days after the last dose of study 
drug will be included in the double-blind treatment period summaries.
AEs will be reported according to the latest MedDRA version available at the time of database 
lock.
The selection criteria of AEs for counting are as follows:
1.
Where a subject has the same AE, based on PT, reported multiple times in a single 
analysis period, the subject will only be counted once at the preferred terminology 
level in AE frequency tables.
2.
When a subject has the same AE, based on PT, reported multiple times in a single 
analysis period, the following criteria, in order of precedence, will be used to select 
the event to be included in summary tables:

Relationship to study medication: Related events will take precedence over
unrelated events in determining the event to include in summary tables. Missing 
relationship will be considered a related event.

Intensity of event: More intense events will take precedence over less intense
events in determining the event to include in summary tables. Missing intensity will 
be considered the least intense event.

Onset date: Earlier onset date events will take precedence over later onset date 
events in determining the event to include in summary tables.
3.
When reporting AEs by intensity, in addition to providing a summary table based 
on the event selection criteria detailed in item 2 above, summary tables will also be 
provided based on the most intense event during the analysis period - independent 
of relationship to study medication. For these tables, the following criteria, in order 
of precedence, will be used to select the event to be included in summary tables:

Intensity of event

Onset date 


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In summaries by SOC and PT, AEs will be sorted by decreasing frequency of each PT and 
SOC, within SOC, according to the “Rosuvastatin 20 mg group” subject incidence. In 
summaries by PT, AEs will be sorted by decreasing frequency of PT according to the 
“Rosuvastatin 20 mg” subject incidence.
4.4.2
All adverse events
The subject incidence of AEs reported during the screening phase will be summarised by all 
AEs, Deaths, SAEs, and withdrawal from study due to AE.
The subject incidence of treatment emergent AEs will be summarized by treatment group in 
the following ways:

All AEs, (by severity)

AEs classified as related to study drug

Deaths

SAEs (by severity, and excluding where the outcome was death)

AEs leading to study discontinuation
The subject incidence of treatment emergent AEs will be summarized separately by SOC, PT 
and treatment group for the double-blind treatment period. 
The subject incidence of the most common (reported in at least 2% of the subjects in any
treatment group) treatment emergent AEs will be presented by SOC, PT and treatment group. 
Also, the subject incidence of treatment emergent AEs will be presented by PT, intensity and 
treatment group. The subject incidence of ischaemic cardiovascular AEs will also be presented 
by PT. Ischaemic cardiovascular AEs will be identified using key words of ‘myocardial 
infarction’, ‘acute coronary syndrome’, ‘unstable angina’(or angina unstable), ‘stroke’ 
(excluding heat stroke), ‘cerebrovascular accident’, ‘cerebral infarction’. A subject listing of 
all reported AEs during the screening and the double-blind treatment period will be produced.
4.4.3
Deaths
All deaths recorded on the TERM page, the AE page, or SAE page (with a death date, cause
of death, outcome or SAE categorization present) of the CRF will be considered a death in the
analyses. All deaths will be summarized by SOC and PT for the safety analysis. A listing of 
all deaths during screening and double-blind treatment period will be produced.
4.4.4
Serious adverse events
The subject incidence of treatment emergent SAEs will be presented by SOC, PT and 
treatment group. In addition, the subject incidence of related treatment emergent SAEs will be 
presented by SOC, PT, and treatment group for the safety analysis. A listing of all SAEs 
during screening and double-blind treatment period will be produced. If we cannot determine 
whether an AE is serious, it will be considered an SAE.


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4.4.5
Related adverse events
The subject incidence of related treatment emergent AEs will be presented by SOC, PT and 
treatment group for safety analysis. 
The subject incidence of most common related treatment emergent AEs (reported in at least 
2% of the subjects in any treatment group) during the double-blind treatment period will be 
presented by PT and treatment group for safety analysis. 
4.4.6
Adverse events leading to discontinuation
Number of subjects who discontinue during the screening phase due to an AE will be listed.
Treatment emergent AEs leading to study treatment discontinuation will be summarized by
SOC, PT, and treatment group for safety analysis.
In addition, a subject listing of discontinuations due to AEs will be presented for screening
and double-blind treatment period.
4.4.7
Other adverse events analyses
Treatment emergent AEs in subjects with any of the following at any time during the 
treatment phase will be listed:

CK > 10x upper limit or normal (ULN)

Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) ≥ 3 x ULN 
and TBL ≥2 x ULN on one occasion

Serum creatinine increase > 100% from baseline and > ULN

Shift in urine protein from none/trace at baseline to ++ or greater

Shift in urine blood from none/trace at baseline to ++ or greater

Subjects with proteinuria, hematuria or both at any time
4.5
Clinical laboratory tests evaluation
All scheduled laboratory evaluations are performed by central laboratories. Evaluations done
by local laboratories, if any, will not be included in summary tables nor in the listings. 
All safety measurements will use all available data for analyses, including data from 
unscheduled visits and repeated measurements. For lab assessment summary by visit, the data 
will be summarized according to the protocol-scheduled week for that visit. For lab 


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summaries that are not visit-based, all visits including unscheduled and repeat visits will be 
included. 
Laboratory parameters will be presented both in SI and conventional units where appropriate.
If a laboratory test is reported as above or below the limit of quantification (i.e., result 
includes operator >, ≥, <, or ≤), the limit of quantification will be used for analysis. The result 
with the operator will be reported in listings.     
4.5.1
Summary of laboratory variables over time
Descriptive statistics (number of observations, mean, SD, minimum, median and maximum 
values) for collected values, change from baseline, and percentage change from baseline will 
be summarized for clinical laboratory tests (hematology, chemistry, urinalysis, lipid profile) at 
each protocol scheduled nominal visit and at the last non-missing post-baseline visit, across 
treatment groups.  
Hepatic biochemistry and CK values as well as their changes from baseline, plus change from 
baseline and percentage change from baseline in creatinine, will be summarised using 
descriptive statistics at each visit.
Hematology, hepatic biochemistry (including CK) and clinical chemistry values outside the
laboratory reference ranges will be flagged and summarised.
Urinalysis data including pH and specific gravity will be summarised by mean, median, SD,
minimum, maximum, and number of subjects for each treatment group at each visit.
4.5.2
Shift tables and summary of subjects with specific laboratory values
The hematology and chemistry data will also be summarized in shift tables comparing results 
of extreme values over the duration of the double-blind treatment period against the baseline, 
based on normal range categories. 
Urine blood and urine protein will be summarised by 
(1) category of most abnormal result and
(2) by category at the final visit, relative to baseline categories (shift tables) for each 
treatment group. 
Numbers and percent of subjects who developed proteinuria (defined as an increase in the
dipstick urine protein measurement of at least ++ from baseline to any visit after baseline (e.g.
negative/trace to ++, + to +++, ++ to ++++) will be presented by treatment group. Similar 
summaries will be made of hematuria (defined as an increase in the dipstick urine blood 
measurement of at least ++ from baseline to any visit after baseline (e.g. negative/trace to ++, 
+ to +++, ++ to ++++) and concurrent proteinuria and hematuria.


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Similar tables will summarise shift in urine protein/blood categories from none or trace at 
baseline to the categories of urine protein/blood at the last visit.
Elevations of ALT [≥3 times the ULN on single occasions and two consecutive occasions
(defined as any 2 assessments taken on, at either a scheduled or unscheduled visit)] and CK (
≥5 times and ≥10 times the ULN) and percentage increases from baseline in creatinine 
(including >30% and ≤50%; >50% and ≤100%; and > 100%, split by ≤ULN and > ULN) 
at any time point during the treatment phase will be highlighted and summarised by treatment 
group at time of occurrence.
Elevated ALT and/or AST and Total Bilirubin
The following criteria will be summarized in examination of elevated ALT and/or
AST and total bilirubin (TBL):
AST or ALT ≥3 x ULN together with TBL ≥2 x ULN at any point during the study 
following the start of study medication irrespective of an increase in ALP.
4.5.3
ECG
A 12-lead ECG will be recorded at Baseline and Week 104 (or early termination). The overall 
ECG investigator interpretations will be summarized using a shift table comparing Baseline to 
endpoint for the safety analysis set. The ECG interpretations will be reported as “Normal”, 
“Abnormal NCS (Not Clinically Significant)”, or “Abnormal CS (Clinically Significant)”. 
The denominators for the percentages will be the numbers of subjects with ECG data at both 
the baseline and at endpoint in each treatment group by parameter.
QTcF will be derived during creation of the reporting database using the reported ECG values
(RR and QT) with the following formula:
 ( !) = ( ( !))/∛(&&)
where RR=60/heart rate.
Absolute and change from baseline values for heart rate, P and QRS duration, PR and QT 
intervals and corrected QTc interval (unspecified and QTcF) will be summarized by protocol 
scheduled nominal visit and the last non-missing post-baseline visit for each treatment group 
using descriptive statistics.
The number and percentage of subjects presenting in each of the following categories of QTcF 
will be presented.

QTcF value above 450ms, 480ms, and 500ms at any time during treatment


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
Change from baseline (increase) in QTcF by more than 30ms, 60ms, and 90ms at any 
time during treatment

Change from baseline (decrease) in QTcF by more than 30ms, 60ms, and 90ms at any 
time during treatment

QTcF value above 450 ms and an increase of more than 30ms at any time during 
treatment.

QTcF value above 500 ms and an increase of more than 60ms at any time during 
treatment.
A subject listing will be presented for those had post-baseline abnormal CS (Clinically 
Significant).
4.5.4
Vital signs
Vital signs to be analyzed and presented are systolic and diastolic blood pressures and sitting
pulse. Vital signs and their changes from baseline values at post-baseline visits will be 
summarized by protocol scheduled nominal visit and the last non-missing post-baseline visit
for each treatment group using descriptive statistics.
Vital sign measurements will be presented by subject, visit and parameter in a data listing.
4.5.5
Weight 
Body weight and their changes from baseline values at post-baseline visits will be summarized 
by protocol scheduled nominal visit and the last non-missing post-baseline visit for each 
treatment group using descriptive statistics.
Weight will also be presented by subject and visit in a data listing.
4.5.6
Physical examination
The physical examination will be performed at Baseline and Week 104 (or early termination).
Frequency tables of the number and percentage of subjects presenting normal/abnormal 
physical examinations will be presented by protocol scheduled nominal visit. The variables 
collected are: general appearance, skin, head and neck, lymph nodes, thyroid, 
musculoskeletal/extremities, cardiovascular, respiratory, abdomen, neurological, and 
genital/rectal. For subjects reporting abnormalities post-baseline they will be summarized as 
“the same as baseline” if the abnormality was present, or “new or aggravated abnormality” if 
it is a new abnormality or has worsened.


Statistical Analysis Plan 
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Edition Number 3.0
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4.6
Conventions
4.6.1
Study period start and end dates
Double-blind treatment period
The randomized treatment period is assumed to start at the date of the first randomized 
double-blind dose, and to end at the last dose of double-blind study drug as recorded in the 
DOSE CRF module.
4.6.2
Duplicate assessments
When a subject has multiple assessments for the same laboratory, vital signs or the numeric 
ECG parameter reported as drawn/assessed on the same date, these multiple assessments will 
be replaced by a single one, the value of which will be the latest assessment prior to first dose 
of study drug for baseline and the worst observation for post-baseline by-visit and LOCF 
analysis. The worst observation will be determined by examining the proximity of all multiple 
observations to the upper/lower reference ranges. In the situation where there is only one 
observation outside the reference ranges, this value will be considered as the worst.
If there are multiple ECG interpretation or physical exam results on the same date, and any of 
these interpretations are abnormal, the abnormal interpretation will be used for 
analyses/summaries.
If a subject has prematurely discontinued and has CIMT data from ultrasound scans for more
than one early termination visit, only the earliest assessment will be used in analyses and 
summaries. Both visits will be listed
4.6.3
Post-dosing efficacy observations
During randomized treatment period, efficacy and safety laboratory observations will be listed 
regardless of whether the subject was taking blinded study drug. Observations will contribute 
to summaries only if the subject’s last dose of blinded drug was as follows:

CIMT data from ultrasound scans taken more than 31 days after the last dose of 
study medication will be excluded from the efficacy analysis based on PP 
population. All CIMT assessments regardless of collection date relative to last dose 
of study drug will be included in the analysis of primary and secondary endpoints 
based on ITT population.

Lipid and lipoprotein measurements will be summarized only if measured on or 
before the 10th day after the last randomized, double-blind drug dose date.
4.6.4
Post-dosing Safety Observations
The following conventions are for the safety analysis during the 104-week randomized 
double-blind treatment period.


Statistical Analysis Plan 
Study Code D3565C00003
Edition Number 3.0
Date 06Mar2019
40
Randomized treatment period safety observations will be listed regardless of whether the 
subject was taking blinded study drug. However, safety observations will not contribute to 
summaries if the subject’s last dose of blinded drug was as follows:

All AEs, including SAEs, will be summarized only if their onset dates were within 
10 days after last dose of study drug.

Vital signs, physical examination, safety laboratory and ECG results will be 
summarized only if measured on or before the 14th day after the last blinded drug 
dosing date.
4.6.5
Missing Start and Stop dates for Adverse Events
Partial start dates and stop dates for AEs are not allowed per eCRF design.  If an AE start date 
is fully missing, the start date will be imputed as the date of first dose of study medication.  
Imputed dates will not appear on the listings.  Fully missing AE stop dates will not be 
imputed.  
4.6.6
Calculation of Body Mass Index
IQVIA will calculate BMI as the ratio of subject’s weight (in kilograms) to the square of the 
subject’s height (in meters): BMI (kg/m²) = weight (kg)/height^2 (m²).  
4.6.7
Missing Dates Assignment for Concomitant Medications
Start and stop dates for all concomitant medications are collected on the CRF. However, in 
case of missing or partial information in these dates, the following rules will be used:
If start date is missing or partial:

if month is missing, use January (01)

if day is missing, use the 1st (01)

if year is missing, use year of the entry visit (consent date for those missing entry 
visit)

if entire date is missing, use consent date 
If stop date is missing, partial or “continuing:”

if month is missing, use December (12)

if day is missing, use the last day of the month under consideration

if year or the entire date is missing or if “continuing”, set to missing.


Statistical Analysis Plan 
Study Code D3565C00003
Edition Number 3.0
Date 06Mar2019
41
5.
INTERIM ANALYSES
No interim analysis is planned for this study.
6.
CHANGES OF ANALYSIS FROM PROTOCOL
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.
REFERENCES
Cockcroft D, Gault MK. Prediction of Creatinine Clearance from Serum Creatinine. Nephron 
16:31-41, 1976.
Cnaan, A., Laird, N. A., and Slasor, P.,’Using the general linear mixed model to analyze
unbalanced repeated measures and longitudinal data’. Statistics in Medicine, 16, 2349-2380,
1997.
Espeland MA, Byington RP, Hire D, Davis VG, Hartwell T, Probstfield J. Analysis strategies
for serial multivariate ultrasonographic data that are incomplete. Statistics in Medicine, 1992
Jun 15; 11(8):1041-56.
CCI


Statistical Analysis Plan 
Study Code D3565C00003
Edition Number 3.0
Date 06Mar2019
42
Espeland MA, Craven TE, Miller ME, D'Agostino R Jr. 1996 Remington lecture: modeling
multivariate longitudinal data that are incomplete.Ann Epidemiol. 1999 Apr; 9(3):196-205.
Espeland MA et al, ‘Carotid intimal-media thickness as a surrogate for cardiovascular disease
events in trials of HMG-CoA reductase inhibitors’. Current Controlled Trials in
Cardiovascular Medicine, 6, 3, 2005 Mar 10.
Furberg, CD et al, ‘Effect of Lovastatin on early carotid atherosclerosis and cardiovascular
events’. Circulation. 90, 1679-1687, 1994.
Lai, H. L., and Helser, T., ‘Linear mixed-effects models for weight-length relationships’.
Fisheries Research, 70, 377-387, 2004.
Little, R. J., and Raghunathan, T. ‘On summary measures analysis of the linear mixed effects
model for repeated measures when data are not missing completely at random’. Statistics in
Medicine, 18, 2465-2478, 1999.
Pitt B, Byington RP, Furberg CD, Hunninghake DB, Mancini GB, Miller ME,Riley W. Effect
of amlodipine on the progression of atherosclerosis and the occurrence of clinical events.
PREVENT Investigators. Circulation.2000 Sep 26;102(13):1503-10.
Pinheiro JC and Bates DM, Mixed Effects Models in S and S-PLUS. Springer, 2000.
Quade D, ‘Rank Analysis of Covariance’. Journal of the American Statistical Association, 62, 
1187-1200, 1967.
Rubin, DB, ‘Inference and Missing Data’ Biometrika, 63, 581-592, 1976.
Ubels FL, Terpstra WF and Smit AJ. ‘Carotid intima-media thickness: influence of drug
treatment and clinical implications’, The Netherlands Journal of Medicine 55, 188-195, 1999).
Crouse III,  John R., MD et al, ‘Effect of Rosuvastatin on progression of carotid intima media 
thickness in low-risk individuals with subclinical atherosclerosis’ JAMA,  297(12), 1344-53, 
Mar 28, 2007.


Statistical Analysis Plan 
Study Code D3565C00003
Edition Number 3.0
Date 06Mar2019
43
Appendix A
Subset of important protocol deviations that will affect study 
results interpretation and the Per-Protocol population
Number
Important protocol deviations / Criteria
Complete/partial data 
exclusion
Inclusion Criteria
1.
Enrolled, for male, subject < 45 years or ≥ 70 
years
for female, subject < 55 years or ≥ 70 years 
Complete data exclusion.
2.
Enrolled, even though subject did not meet the 
criteria below:
Subjects with only hypertension (as defined blood 
pressure ≥140/90 mmHg or on antihypertensive 
treatment) and age as cardiovascular disease 
(CVD) risk factors and also subjects without 
hypertension who have 3 or more other risk factors 
(including age) must have:
–
Fasting LDL C of ≥120 mg/dL (3.1 
mmol/L) and < 160 mg/dL (4.1 mmol/L)
(Note: if a subject meets this criteria during 
a re-test between visit 1 and 2, this is not 
considered a deviation)
Subjects without hypertension who have fewer 
than 3 other risk factors (including age) must have:  
–
Fasting LDL-C of ≥120 mg/dL (3.1 
mmol/L) and < 190 mg/dL (4.9 mmol/L)
(Note: if a subject meets this criteria during 
a re-test between visit 1 and 2, this is not 
considered a deviation)
Subjects with hypertension and age as CVD risk 
factors, along with at least one other risk factor, 
will be considered as having an important protocol
deviation, regardless of fasting LDL-C values at 
screening.
Complete data exclusion.


Statistical Analysis Plan 
Study Code D3565C00003
Edition Number 3.0
Date 06Mar2019
44
Number
Important protocol deviations / Criteria
Complete/partial data 
exclusion
3
Enrolled, even though subject did not meet the 
criteria below:
TG < 500 mg/dL (5.65 mmol/L) at visit 1 (week -
6)
(Note: if a subject meets this criteria during a re-
test between visit 1 and 2, this is not considered a 
deviation)
Complete data exclusion.
4
Enrolled, even though subject did not meet the 
criteria below:
HDL cholesterol levels ≤60 mg/dL (1.6 mmol/L) 
at visit 1 (week -6)
(Note: if a subject meets this criteria during a re-
test between visit 1 and 2, this is not considered a 
deviation)
Complete data exclusion.
5
Enrolled, even though subject did not meet the 
criteria below:
Maximum IMT ≥1.2 mm and < 3.5 mm in the 
carotid ultrasound studies conducted at both visit 2
(week -4) and visit 3 (week -2).
Complete data exclusion.
Exclusion criteria
6
Enrolled, even though subject met the exclusion 
criteria below:
Use of pharmacologic lipid-lowering medications 
(eg, statins, fibrate derivatives, bile acid binding 
resins, niacin or its analogues at doses > 400 mg or 
prescribed Chinese traditional drugs), including 
cholesterol-absorption inhibitors (CAIs), and
CAI/statin combination, within 12 months prior to 
Visit 1 (Week -6)
Complete data exclusion.
Major deviations:
8
Overall compliance during the double-blind 
treatment period <80% of the prescribed drug
Complete data exclusion.


Statistical Analysis Plan 
Study Code D3565C00003
Edition Number 3.0
Date 06Mar2019
45
Number
Important protocol deviations / Criteria
Complete/partial data 
exclusion
9
Use of prohibited/disallowed medication during 
the double-blind treatment period (medications 
with an ATC code of C10AA, C10, or C10AX or 
‘Reason for Therapy’ is recording on the eCRF as 
‘Control for dyslipidemia’, ‘Hyperlipidemia’ or 
‘Hypolipidemic’ are only considered disallowed if
they are used for more than 3 months across the 
study period before last dose date).
Partial data exclusion: 
Data at the affected visit 
and subsequent visits will 
be excluded. These 
concomitant medications 
are the lipid lowering 
agents listed in appendix 
7.7.1 of the protocol.
10
CIMT data from ultrasound scans taken more than 
31 days after the last dose of study medication.
Partial data exclusion: 
Data at the affected visit 
and subsequent visits will 
be excluded.
11
Subject randomly allocated a treatment out of 
sequence or inadvertently receives the wrong 
treatment.
Complete data exclusion.


Statistical Analysis Plan 
Study Code D3565C00003
Edition Number 3.0
Date 06Mar2019
46
Appendix B
Efficacy objectives and outcome variable relating to each 
objective
Objectives
Variables
Summary 
outcome 
variables for 
analyses
Analysis 
sets
Description of 
planned analysis
Primary
To assess the 
efficacy of 
rosuvastatin 20 mg
treatment for 104
weeks on the change
in the mean of the 
maximum intima
media thickness of
the 12 carotid artery
sites. The subjects
randomized to
rosuvastatin will be
compared to the
subjects randomized
to placebo.
Annualized 
rate of 
change in the 
MeanMax 
CIMT
measurement 
for each of 
the 12 carotid 
artery sites.
For each subject
an annualized 
rate of change 
(slope) of Max 
CIMT will be 
estimated from 
the 12 sites 
using a 
multilevel 
mixed effects 
model. The 
estimates will be 
summarized by 
treatment group.
ITT, PP
Statistical 
significance of the 
MeanMax CIMT 
annualized rate of 
change (slope) 
between placebo and 
rosuvastatin will be 
evaluated using the 
time-by-treatment 
interaction term in 
the multilevel mixed 
effects model.
Secondary
To assess the 
efficacy of 
rosuvastatin 20 mg 
treatment for 104 
weeks on the change 
in the mean of the 
maximum intima
media thickness of 
the 4 CCA sites. The 
subjects randomized 
to rosuvastatin will 
be compared to the 
subjects randomized
to placebo.
Annualized 
rate of 
change in 
MeanMax
CIMT for 
each of the 4 
common 
carotid sites.
For each subject
an annualized 
rate of change 
(slope) of 
MaxCIMT will
be estimated 
from the 4 sites 
using a 
multilevel 
mixed effects 
model. The 
estimates will be 
summarized by 
treatment group.
ITT, PP
Statistical 
significance of the 
MeanMax CIMT 
annualized rate of 
change (slope) 
between placebo and 
rosuvastatin will be 
evaluated using the 
time-by-treatment 
interaction term in 
the multilevel mixed 
effects model.


Statistical Analysis Plan 
Study Code D3565C00003
Edition Number 3.0
Date 06Mar2019
47
To assess the 
efficacy of 
rosuvastatin 20 mg 
treatment for 104 
weeks on the change 
in the mean of the 
maximum intima
media thickness of 
the 4 carotid bulb
sites. The subjects 
randomized to
rosuvastatin will be 
compared to the 
subjects randomized
to placebo.
Annualized 
rate of 
change in 
MeanMax
CIMT for 
each of the 
12 carotid 
bulb sites.
For each subject
an annualized 
rate of change 
(slope) of 
MaxCIMT will 
be estimated 
from the 4 sites 
using a 
multilevel 
mixed effects 
model. The 
estimates will be 
summarized by 
treatment group.
ITT, PP
Statistical 
significance of the 
MeanMax CIMT 
annualized rate of 
change (slope) 
between placebo and 
rosuvastatin will be 
evaluated using the 
time-by-treatment 
interaction term in 
the multilevel mixed 
effects model.
To assess the 
efficacy of 
rosuvastatin 20 mg 
treatment for 104 
weeks on the change 
in the mean of the 
maximum intima
media thickness of 
the 4 ICA sites. The 
subjects randomized 
to rosuvastatin will 
be compared to the 
subjects randomized
to placebo.
Annualized 
rate of 
Change in 
MeanMax
CIMT for 
each of the 4 
ICA sites.
For each subject
an annualized 
rate of change 
(slope) of 
MaxCIMT will 
be estimated 
from the 4 sites 
using a 
multilevel 
mixed effects 
model. The 
estimates will be 
summarized by 
treatment group.
ITT, PP
Statistical 
significance of the 
MeanMax CIMT 
annualized rate of 
change (slope) 
between placebo and 
rosuvastatin will be 
evaluated using the 
time-by-treatment 
interaction term in 
the multilevel mixed 
effects model.
To assess the 
efficacy of 
rosuvastatin 20 mg 
treatment for 104 
weeks on the change 
in the mean of the
mean intima media 
thickness of the 4 
CCA sites. The 
subjects randomized 
to rosuvastatin will 
be compared to the 
subjects randomized
to placebo.
Annualized 
rate of 
change in
MeanMean
CIMT for 
each of the 4 
CCA sites.
For each subject
an annualized 
rate of change 
(slope) of Mean 
CIMT will be 
estimated from 
the 4 sites using 
a multilevel 
mixed effects 
model. The 
estimates will be 
summarized by 
treatment group.
ITT, PP
Statistical 
significance of the 
MeanMean CIMT 
annualized rate of 
change (slope) 
between placebo and 
rosuvastatin will be 
evaluated using the 
time-by-treatment 
interaction term in 
the multilevel mixed 
effects model.


Statistical Analysis Plan 
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Edition Number 3.0
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To evaluate change 
in lipids and 
lipoproteins
LDL-C
(converted 
results), 
HDL-C, TG, 
Non-HDL-C, 
Non-HDL-
C/HDL-C
Percent change 
from baseline to 
week 104 in 
lipid parameters
ITT
(Observed 
and LOCF 
data)
ANCOVA with 
treatment as a factor 
and baseline value 
as a covariate
Percent change 
from baseline to 
time-weighted 
average in lipid 
parameters
ITT
(Observed 
data)
ANCOVA with 
treatment as a factor 
and baseline value 
as a covariate
To evaluate change 
in Apo
ApoB,
ApoA-I, 
ApoB/ApoA/
I
Percent change 
from baseline to 
week 104 in 
lipoprotein 
parameters
ITT
(Observed 
and LOCF 
data)
ANCOVA with 
treatment as a factor 
and baseline value 
as a covariate
Appendix C
SAS codes for statistical models used in the efficacy analysis.
Multi-level linear mixed effects model for primary efficacy analysis:
PROC MIXED;  
CLASS TRT SITE SUBJID ICVD SEX READER CENTRE; 
MODEL RESPONSE = TRT TIME TRT*TIME ICVD SITE CENTRE AGE SEX READER
/ SOLUTION DDFM = KR CL COVB;
RANDOM INTERCEPT TIME /SUB = SUBJID TYPE = UN;
RUN;
Note: The maxCIMT value for each site will be the dependent variable (RESPONSE) in the 
mixed effects model. Time is a continuous variable per the protocol and will be the interval in 
years from date of randomization to date of the CIMT measurement. The fixed effect Time in 
the MODEL statement is not declared as a class variable; thus it models a linear trend in time.
We want to see the change in slope over time for the difference between rosuvastatin and 
placebo across all sites. 
The TYPE=UN option in the RANDOM statement specifies an unstructured covariance 
matrix for the random intercept and slope effects at the individual subject level.


Statistical Analysis Plan 
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Edition Number 3.0
Date 06Mar2019
49
ANCOVA analyses for the laboratory efficacy endpoints:
PROC GLM;
CLASS TRT;
MODEL PER_CHG = TRT BASE /CLPARM;
LSMEANS TRT / STDERR PDIFF CL;
ESTIMATE ‘ROSUVASTATIN 20 MG VS PLACEBO’ TRT 1 –1/CL;
RUN;
PER_CHG = Percentage change from baseline
TRT = Randomized treatment
BASE = Baseline value
Appendix D
Assumptions for sample size calculation.
 
 
 
 
 
 
 
 
 
CCI


Statistical Analysis Plan 
Study Code D3565C00003
Edition Number 3.0
Date 06Mar2019

 
 
 
 
 
 
 
 
 
 
 
 
Appendix E
Method Comparison between two generation of reagent for measuring 
Low Density LDL-C in Serum Samples for Homogeneous Enzymatic 
Colorimetric Assay using Roche Modular and Cobas series
LDL-direct-3rdGen_
20171018- Final vers
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