Treatment of High and Very High riSk Dyslipidemic pAtients for the PreveNTion of CardiOvasculaR Events in Europe - a MultInatioNal ObservatIonal Study (SANTORINI)
Conditions: Dyslipidemia, Cardiovascular Diseases, Hypercholesterolemia, Atherosclerotic Cardiovascular Disease
Sponsor: Daiichi Sankyo Europe, GmbH, a Daiichi Sankyo Company

 
 
 
 
 
 
 
OBSERVATIONAL PLAN 
 
Treatment of High and Very high riSk dyslipidemic 
pAtients for the PreveNTion of CardiOvasculaR Events 
in Europe – a MultInatioNal ObservatIonal Study 
(SANTORINI) 
 
DSE-HCL-01-19 
 
 
Sponsor: 
Daiichi Sankyo Europe GmbH 
Zielstattstrasse 48 
81379 Munich, Germany 
Phone: 
 
Fax: 
 
 
 
Version Number: 2.0 
Date of Version: 26 Aug 2020 
 
 
 
 
 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the 
written consent of Daiichi Sankyo Europe GmbH
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Contents: 
 
1 
Signatures ...................................................................................................................... 5 
Investigator’s Signature .............................................................. Error! Bookmark not defined. 
2 
Glossary ......................................................................................................................... 7 
3 
Responsible Parties ....................................................................................................... 9 
3.1 
Steering Committee ...................................................................................................... 9 
4 
Summary ..................................................................................................................... 10 
5 
Amendments to the Observational Plan ................................................................... 17 
6 
Milestones .................................................................................................................... 17 
7 
Rationale and Background ........................................................................................ 17 
8 
Research Question and Objectives of the observation ............................................ 19 
8.1 
Primary Objective ...................................................................................................... 19 
8.2 
Secondary Objectives ................................................................................................. 19 
9 
Research Methods ...................................................................................................... 19 
9.1 
Study Design................................................................................................................ 19 
9.2 
Setting .......................................................................................................................... 19 
9.2.1 Participating Centers ................................................................................................. 20 
9.2.2 Eligibility Criteria ...................................................................................................... 21 
9.2.3 Patient Groups ............................................................................................................ 21 
9.2.4 Schedule ....................................................................................................................... 21 
9.3 
Variables ...................................................................................................................... 22 
9.4 
Data Sources................................................................................................................ 24 
9.5 
Sample Size Calculation ............................................................................................. 25 
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9.6 
Data Management ...................................................................................................... 26 
Data Entry/Electronic Data Capture .................................................................................... 26 
Source Documents .................................................................................................................. 26 
File Retention and Archiving ................................................................................................ 26 
9.7 
Data Analysis .............................................................................................................. 27 
9.8 
Quality Control/Monitoring ...................................................................................... 28 
9.9 
Limitations of the Research Methods ....................................................................... 28 
10 
Protection of Human Subjects ................................................................................... 29 
10.1 
Review by Ethics Committees/Competent Authorities ........................................... 29 
10.2 
Insurance and Liability .............................................................................................. 29 
10.3 
Patient Information, Informed Consent (if applicable) .......................................... 29 
10.4 
Data Protection ........................................................................................................... 30 
10.5 
Numbering and Identification of Patients ................................................................ 30 
10.6 
Assessments (according to the study type) ............................................................... 30 
11 
Collection and reporting of Adverse Drug Reactions/Adverse Events (IF 
applicable) ................................................................................................................... 30 
11.1 
Definitions ................................................................................................................... 30 
11.2 
Reporting of Suspected ADRs by the Investigator .................................................. 31 
11.3 
Pregnancy .................................................................................................................... 32 
12 
Documentation and Archiving .................................................................................. 32 
13 
Legal Requirements.................................................................................................... 32 
13.1 
Reimbursement ........................................................................................................... 32 
13.2 
Registration ................................................................................................................. 33 
14 
Final Report ................................................................................................................ 33 
15 
Publication................................................................................................................... 33 
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16 
Premature Termination of the NIS/registry ............................................................ 33 
17 
References ................................................................................................................... 34 
 
 
 
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2 
GLOSSARY 
 
ADR  
Adverse Drug Reaction  
Apo B 
Apolipoprotein B 
APS 
All Documented Patient Set 
ASCVD 
Atherosclerotic Cardiovascular Disease 
BAS 
Baseline Analysis Set 
BUN 
Blood Urea Nitrogen 
CA 
Competent Authority 
CHD 
Coronary Heart Disease  
CI 
Confidence Interval 
CRO  
Contract Research Organization  
CV (D) 
Cardiovascular (Disease) 
DM  
Data Manager  
DSE  
Daiichi Sankyo Europe GmbH  
eCRF  
electronic Case Report Form  
ESC/EAS 
European Society of Cardiology / European 
Atherosclerosis Society 
ECG 
Electrocardiography 
EDC  
Electronic Data Capturing  
FAS 
Full Analysis Set 
FPI 
First Patient In 
FU 
Follow Up 
FQ 
Feasibility questionnaire 
GFR  
 Glomerular Filtration Rate 
GPP 
Good Pharmacoepidemiology Practices 
GVP  
Good Pharmacovigilance Practices  
HbA1c 
Hemoglobin A1c 
HDL-C 
High Density Lipoprotein-C 
He FC 
Heterozygous Familial Hypercholesterolemia 
HEOR 
Health Economics Outcome Research 
hsCRP 
High Sensitive C-Reactive Protein 
ICF  
Informed Consent Form  
ICH 
International Council on Harmonization 
ICJME 
International Committee of Medical Journal Editors 
ICU 
Intensive Care Unit 
IEC  
Independent Ethics Committee  
LDL-C 
Low Density Lipoprotein-C 
LFT 
Liver Function Test 
LMT 
Lipid Modifying Therapies 
Lp(a) 
Lipid Protein a 
LPI 
Last Patient In 
LPO 
Last Patient Out 
NIS 
Non-Interventional Study 
PAM 
Patient Activation Measure 
PCSK9 
Proprotein Convertase Subtilisin/Kexin Type 9 
PL 
Project Lead  
PRO 
Patient Reported Outcome 
PTCA 
Percutaneous Transluminal Aoronary Angioplasty 
RCT 
Randomized Clinical Trials 
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SAP 
Statistical Analysis Plan 
SOP  
Standard Operating Procedure  
TC 
Total Cholesterol 
TG 
Triglyceride 
TIA 
Transient Ischemic Attack 
 
 
 
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3 
RESPONSIBLE PARTIES 
 
 
DSE 
 
 
Phone 
 
 
Email 
 
 
DSE 
 
 
Phone 
 
 
Email 
 
 
DSE 
 
 
 
Phone 
 
 
Email 
 
 
 
 
 
DSE 
 
 
Phone 
 
 
Email 
 
 
 
, University of Milano 
 
 
Phone 
 
 
Email 
 
, Imperial College 
London 
 
 
 
Phone 
 
 
Email 
 
  
  
 
Kantar Health: 
 
Phone  
 
Email 
 
Hippocrates: 
 
Phone        
 
 
Email 
 
TFS: 
 
Phone        
 
 
Email 
 
Axonal: 
 
Phone        
 
 
Email 
 
Alpha Bioresearch: 
 
Phone       
 
 
Email 
 
Imperial: 
 
Phone        
 
 
Email 
 
 
3.1 
Steering Committee  
The Steering Committee (SC) will give scientific advice, support with setting up the study 
concept, and will be involved in publications. 
 
 
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4 
SUMMARY 
 
 
Study/Registry Title 
Treatment of High and Very high riSk dyslipidemic pAtients for the 
PreveNTion of cardiOvasculaR Events in Europe – a MultInatioNal 
ObservatIonal Study (SANTORINI)  
Observational plan 
version identifier 
Version 2.0 
Date of last 
observational plan 
version 
28 Nov 2019 
Marketing 
Authorization Holder  
NA 
Main Authors 
,  
,  
both DSE 
Rationale and 
Background 
Dyslipidemia is a major and costly health concern in Europe. 
Appropriate medical treatment lowers low-density lipoprotein 
cholesterol (LDL-C) and reduces the incidence of clinical 
cardiovascular events (morbidity, mortality), and their associated 
costs. 
A number of drug classes are available to decrease circulating LDL-
C in Very High Risk and High Risk patients with the statins being the 
most widely prescribed of these. However, many patients remain 
inadequately treated or even untreated, and some lipid-lowering 
drugs may be associated with an increase in the incidence of diabetes. 
Furthermore, high sensitivity C-reactive protein (hsCRP), in addition 
to the atherogenic lipids, is of growing interest as a putative 
independent predictor of CV mortality. 
Gaining further insight into current real-life European medical 
practice with respect to the management of dyslipidemic patients is 
considered to be of interest, and may contribute to an improvement 
in the management of dyslipidemic patients and to an associated 
reduction in the clinical and economic burden associated with the 
management of atherosclerotic cardiovascular disease (ASCVD). 
Research Question and 
Objectives  
To assess the characteristics and management of Very High Risk and 
High Risk patients requiring Lipid Modifying Therapies (LMTs) and 
the use of healthcare resources associated with current patient 
management strategies, particularly with respect to the prevention of 
clinical cardiovascular events. 
 
Data collection methodology: 
As this is a non-interventional study, only data from routine clinical 
practice will be documented. Physicians will not be required to 
perform any mandatory assessment outside the routine clinical 
practice for this study. To facilitate accurate recording of data, 
patients can optionally fill in a memory aid to note important details.  
 
 
 
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Primary objective: 
The primary objective is to document, in the real-world setting, the 
effectiveness of current treatment modalities in managing plasma 
levels of LDL-C in Very High Risk and High Risk patients requiring 
LMTs  
 
Secondary objectives: 
 The secondary effectiveness objectives are to document: 
 The relationship between treatment modalities and plasma 
levels of other potentially ASCVD-modifying cholesterol 
fragments, namely, HDL-C, non-HDL-C, TC, apoB, TGs and 
Lp(a) 
 Changes in the inflammatory marker hsCRP over time 
 Changes in the patients´ overall CV risk assessment over time 
measured through CV risk score calculators  
 
The secondary safety objectives are to document: 
 Clinical events associated with the treatment modalities: 
o Laboratory abnormalities 
o Muscle-associated symptoms 
o New onset and/or worsening diabetes 
o Changes in the patients´ glycemic status over time  
o Adverse Drug Reactions associated with Bempedoic 
Acid and/or fixed dose combination with ezetimibe 
 
Additional secondary objectives are to document: 
 The characteristics of the sites and physicians caring for Very 
High Risk and High Risk patients 
 The patients’ use of lipid-modifying treatment, especially 
with regard to a switch from one drug class to another, a dose 
modification of a given drug, a switch from one statin to 
another, any evidence of statin intolerance or insufficient 
responsiveness to a statin, including a maximally tolerated 
statin, and any use of combination drug therapy 
 Various HEOR parameters associated with the management 
of the dyslipidemic patients such as PRO outcomes, 
healthcare resource use and patients disease awareness.  
 Study Design  
Multinational, 
multicenter, 
prospective 
observational, 
non-
interventional study 
Population 
Setting: 
8000 patients from different countries and care settings (primary care 
and secondary care and different specialties). 
 
At each study site, the patients will be enrolled consecutively. 
Patients will be stratified for High and Very High Risk as well as for 
previously and newly treated patients. Sites will be required to 
complete a patient screening log of eligible patients for this disease 
registry at their treatment centers. This log will document how 
patients came to be included or excluded from the study, in order to 
assess the representativeness of the study population. Minimal 
information will be recorded for all patients who are screened for 
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study enrolment, but no patient-identifiable information should be 
recorded. Those patients who provide their informed consent will be 
enrolled into the study. 
The study population consists of Very High Risk and High Risk 
patients previously diagnosed and treated as well as newly treated 
patients receiving their first LMT. 
At baseline data collection point, baseline characteristics 
(demography, sociodemography), medical history including LDL-C 
and other lipid parameters, CV risk assessment and relevant  CV 
medical history (CV events such as myocardial infarction and 
stroke), concomitant diseases such as diabetes, and certain HEOR 
variables and patient reported outcomes (EQ-5D-5L and PAM-13) 
will be documented.  
In addition, for the previously diagnosed and treated patients, details 
on the lipid modifying treatment during the year before enrolment 
will be collected. 
 
At the follow-up data collection point at 1 year (± 2 months), 
available information on the patients’ routine management between 
baseline and this data collection point, and efficacy and safety 
variables will be collected including (LDL-C and other lipid 
parameters, CV risk assessment and relevant CV medical events such 
as myocardial infarction and stroke), changes in concomitant diseases 
such as diabetes, and certain HEOR variables. 
As an additional assessment, quality-of-life questionnaires will be 
completed by the patient preferably in the physician’s office.  
Approximately 800 sites / physicians - office-based or hospital-
based, general practitioners, internists, lipidologists, diabetologists, 
and cardiologists - in Ireland, UK, Portugal, Spain, France, Belgium, 
the Netherlands, Denmark, Germany, Switzerland, Italy, and Austria, 
as well as Norway and/or Sweden and/or Finland. 
It is estimated that each site will contribute 10 patients. Nonetheless, 
additional patients – subject to approval – may be considered. 
Inclusion/exclusion 
criteria 
Key inclusion criteria: 
 Very High Risk and High Risk patients requiring LMTs 
 ≥ 18 years of age 
  not simultaneously participating in any interventional study 
 providing written informed consent for participation in the 
study (ICF) 
 life expectancy > 1 year   
Patients will be stratified for High and Very High Risk as well as for 
previously and newly treated patients. 
 
As this is a non-interventional study, no explicit exclusion criteria are 
defined. The prescribing behavior will not be influenced. 
 
 
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Variables 
(Observation Criteria) 
Parameters to be recorded (if available) during the observation 
period: 
To be documented at baseline (if available): 
o Eligibility 
o Demographic and sociodemographic variables  
o Vital signs 
o Medical history, including CVD risk status-related 
medical history: 
o CV risk assessment with or without utilization 
of risk score 
o history/diagnosis 
and 
current 
status 
of 
dyslipidemia 
o heterozygous familial hypercholesterolemia 
(HeFH) 
o documented ASCVD either clinical or 
unequivocal on imaging  
o Concomitant diseases  
o For diabetic patients 
o disease type and date of diagnosis 
o treatment 
o microvascular complications 
o Current concomitant medication for CVD 
o Previous / current dietary restrictions 
o Previous / current use of lipid-modifying treatment 
Previous / current use of lipid-modifying treatment 
including details of dose, dose modification, switching, 
combination 
therapy, 
drug 
intolerance, 
insufficient 
responsiveness, investigators and patients assessment on 
compliance  
o Statin(s)  
o Bile acid sequestrant(s) 
o Cholesterol absorption inhibitor (Ezetimibe) 
o PCSK9 inhibitor(s) 
o Nicotinic acid 
o Drug combinations 
o Bempedoic acid and/or bempedoic acid fixed 
dose combination with ezetimibe 
o Other 
o Laboratory parameters (at baseline or  last available 
measurement) 
o Lipid variables 
o LDL-C 
o HDL-C, non-HDL-C, TC, apoB, TG, Lp(a) 
o Diabetes-related parameters 
o fasting glucose 
o HbA1c 
o Inflammatory status 
o hsCRP 
o Renal function parameters (GFR, serum creatinine, 
blood urea nitrogen (BUN)) 
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o Other laboratory parameters (liver function, serum 
chemistry, hematology) 
o HEOR parameters 
o Hospital admissions  
o Length of hospital stay  
o Number of days in ICU  
o Interventions  
o Other HEOR parameters  
o Adherence to former and current treatment  
o Patient reported outcomes (EQ-5D-5L, PAM-
13) 
  
To be documented at 1-year follow-up (if available): 
o Vital signs 
o CVD risk status: 
o CV risk assessment with or without utilization 
of risk score 
o history/diagnosis 
and 
current 
status 
of 
dyslipidemia 
o heterozygous familial hypercholesterolemia 
(HeFH) 
o documented ASCVD either clinical or 
unequivocal on imaging  
o Concomitant diseases  
o For diabetic patients 
o disease type and date of diagnosis 
o treatment 
o microvascular complications 
o Current concomitant medication for CVD 
o Previous / current dietary restrictions 
 
o Previous / current use of lipid-modifying treatment 
Previous / current use of lipid-modifying treatment 
including details of dose, dose modification, switching, 
combination 
therapy, 
drug 
intolerance, 
insufficient 
responsiveness, investigators and patients assessment on 
compliance  
o Statin(s)  
o Bile acid sequestrant(s) 
o Cholesterol absorption inhibitor (Ezetimibe) 
o PCSK9 inhibitor(s) 
o Nicotinic acid 
o Drug combinations 
o Bempedoic acid and/or bempedoic acid fixed 
dose combination with ezetimibe 
o Other 
o Clinical events associated with the lipid modifying 
treatment modalities: 
o Insufficient lipid lowering efficacy 
o Muscle-associated symptoms 
o New-onset diabetes mellitus 
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o Reduced kidney function 
o Drug-drug interaction 
o Noncompliance 
o Neurocognitive impairment 
o Other 
o Laboratory parameters  
o Lipid variables 
o LDL-C 
o HDL-C, non-HDL-C, TC, apoB, TG, Lp(a) 
o Diabetes-related parameters 
o fasting glucose 
o HbA1c 
o Inflammatory status 
o hsCRP 
o Renal function parameters (GFR, serum creatinine, 
blood urea nitrogen (BUN)) 
o Other laboratory parameters (liver function, serum 
chemistry, hematology) 
o HEOR parameters 
o Hospital admissions  
o Length of hospital stay  
o Number of days in ICU  
o Interventions  
o Other HEOR parameters (e.g. insurance 
status , employment status, education) 
o Adherence to former and current treatment  
o Patient reported outcomes (EQ-5D-5L, PAM-
13)  
Data Sources 
As this is a non-interventional study, only data on routine clinical  
practice will be documented. To facilitate accurate recording of data, 
patients can optionally fill in a memory aid (patient diary to note 
important details).  
Study Size 
Sample size considerations: 
As this registry is intended to collect data under real-life conditions 
and the statistical analysis will be performed in a purely explorative 
way, no primary parameter has been defined for the sample size 
calculation. On a pragmatic basis, data of approximately 8000 
patients will be collected, whose data is to be documented both 
retrospectively and prospectively (over a period of 1 year). This 
sample size of 8000 patients will provide sufficient precision 
(measured by width of 95% confidence interval) for the rates of CV 
death, nonfatal MI, nonfatal stroke, and coronary revascularization 
during one year follow-up. Assuming an absolute reduction of LDL-
C across all treatment modalities in a real-life setting of 0.9 mmol/L, 
the sample size shall provide information for an expected change in 
the relative risk of major vascular events with an absolute precision 
of ± 13% (relative precision ± 16%). 
Data Analysis 
Three populations will be defined: (1) The All-Documented Patient 
Set (APS) consists of all patients with any eCRF documentation. (2) 
patients with adequately completed recruitment information 
(Baseline Analysis Set / BAS population); (3) patients having 
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completed 1-year follow-up (Full Analysis Set / FAS population). (4) 
The Safety Set (SAF) includes all patients who received at least one 
dose of bempedoic acid and/or bempedoic acid fixed dose 
combination according to their documentation in the eCRF. For BAS, 
FAS and SAF binary, categorical, and ordinal parameters will be 
summarized by means of absolute and percentage numbers within the 
various categories (including ‘missing data’ and ‘not performed in 
the center’ as valid category at baseline). Numerical data will be 
summarized by means of standard statistics (i.e. number of available 
data, number of missing data, mean, standard deviation, minimum, 
median, maximum, lower and upper quartile). 
At the final analysis the differences in the CV risk score for Very 
High Risk and for High Risk patients will be calculated. 
In addition, adequate graphs (e.g. bar charts, box-whisker plots) may 
be presented to summarize the results for some parameters. 
Analysis of changes in numerical parameters (as the differences in 
Score risk between baseline and 1-year follow up) will be done by 
paired Wilcoxon signed rank test and paired t-test if assumptions of 
parametric tests will be met. Comparison of these 1-year changes 
between subgroups will be done by Kruskal-Wallis test and ANOVA 
test if assumptions of parametric tests will be met. Also adjusted 
analyses for age, sex and country effects will be done.   
Time-to-event variables will be analyzed via a Cox proportional 
hazard regression model presenting hazard ratios and the 
corresponding 95% confidence intervals. Additionally, adjusted Cox 
models for age, sex and country effects will be presented.  In addition, 
Kaplan-Meier curves will be presented for time-to-event variables. 
Two-sided 95%-CI will be presented for important parameters, but 
should be interpreted in an exploratory descriptive way. 
All statistical testing (including hazard ratios, relative risks etc.) will 
be performed in an exploratory manner only. Details regarding 
statistical analyses will be described in the SAP and in the statistical 
section of the report. 
Quality Control 
This study will be conducted according to the rules of ‘Good 
Pharmacoepidemiology Practice’ (GPP) and the ‘Guideline on good 
pharmacovigilance practices’ (GVP). Related quality control 
mechanisms (eg, data plausibility checks, monitoring of data) will be 
performed accordingly.  
Milestones  
First Patient In (FPI) / Start of Data Collection:       Q1/2020  
Last Patient In (LPI):                                                Q4/2020 
Last Patient Out (LPO) / End of Data Collection:    Q4/2021 
Final Report:                                                             Q4/2022 
Timelines may be adapted in case some countries experience major 
delays of ethics approvals. 
 
 
 
 
 
 
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5 
AMENDMENTS TO THE OBSERVATIONAL PLAN 
In case of essential changes of an existing observational plan the investigators have to be 
informed as well as the respective local and/or competent authorities and Independent Ethics 
Committees if required by local laws or regulations. 
 
6 
MILESTONES 
 
 
Start of data collection: Q1/2020 
 
Planned snapshots: 2 for baseline data, 2 for follow-up data 
 
Planned end of data collection (planned): Q4/2021 
 
Final report of study results (planned): Q4/2022 
 
7 
RATIONALE AND BACKGROUND 
 
Rationale 
The current understanding of real-world medical practice in the management of dyslipidemia 
is incomplete. Relevant and detailed treatment guidelines, based to a considerable extent on the 
outcomes of randomized clinical trials (RCTs), offer health care providers advice and direction 
with respect to the management of their dyslipidemic patients. However, there are a number of 
reasons – including the strictly controlled RCT environment with respect to inclusion and 
exclusion criteria, the provision of treatment, patient follow up and compliance with therapy 
and dosing – why all of these aspects are very different in the real world. The observational 
study (registry) is increasingly looked upon as a valid and meaningful tool for supplementing 
RCTs with respect to real world information1.  
A better understanding of current medical practice in the field of dyslipidemia across European 
countries may contribute to an improvement in patient management and to an associated 
reduction in the clinical and economic burden of atherosclerotic cardiovascular disease 
(ASCVD) in Europe. 
  
Background 
Cardiovascular disease (CVD), especially its management and associated costs, is a topic of 
major interest in Europe as well as globally. The economic burden of CVD is enormous. CVD 
has been estimated to cost the EU economy €210 billion a year. Of this amount, €111 billion is 
due to direct health care costs, €54 billion to productivity losses, and €45 billion to the informal 
care of people with CVD2.  
 
CVD is the leading cause of death worldwide3, and a direct correlation between circulating 
levels of low-density lipoprotein cholesterol (LDL-C) and the incidence of CVD has been 
established beyond doubt4. Life-style measures such as improved diet, exercise, and loss of 
weight are in some cases effective in lowering LDL-C and, consequently, in reducing the risk 
of CVD but, ultimately, drug therapy is required in many dyslipidemia patients. While a number 
of classes of lipid-lowering drugs are available, statins have become the gold standard and are 
acknowledged as first-line therapy. They are recommended as such by the current ESC/EAS 
Guidelines for the Management of dyslipidemias for the reduction of circulating levels of 
atherogenic lipoproteins as well as for the reduction of risk of clinical cardiovascular events in 
both primary and secondary prevention5,6.  
  
Nonetheless, and in spite of the widespread availability and broad use of statins, and of the 
availability of other older (as well as newer) drug classes (such as bile acid sequestrants, 
cholesterol absorption inhibitors, Proprotein convertase subtilisin/kexin type 9 (PCSK9) 
inhibitors, nicotinic acid, and their various combinations), a substantial proportion of patients 
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with dyslipidemia remains inadequately treated. These patients are, consequently, at higher risk 
than they would otherwise be. The reasons for this include: insufficient efficacy of the drugs 
(even, in some cases, high-intensity statins at their maximally authorized doses); the caution 
required for their use in certain patient populations (e.g., established diabetes or risk thereof, 
renal insufficiency, hepatic disease and/or LFT elevations), PCSK9 inhibitor market access 
restrictions and poor patient compliance. In the case of statins, the latter is related to the 
complex phenomenon of statin intolerance and, in particular, the muscle-associated side effects 
of these medicines. The most common reason given for statin discontinuation is muscle pain7, 
8. 
 
With respect to statins, poor patient compliance is a major factor in the suboptimal outcomes, 
but its extent and underlying causes are not fully understood. While data from RCTs suggest 
that the rate of statin noncompliance is quite low, e.g., in the range of 1-2%9, data from real-
life studies present a very different picture, with estimates ranging from 10-50% and even 
higher10, 11, 12, 13. Discontinuation rates after 1 year have been variously reported as being in the 
range of 30%14, 15 to almost 50%16,17. 
 
Importantly, poor adherence to statin therapy is associated with a significantly increased risk of 
cardiovascular events, death and decreased survival18, 19, 20 and, consequently, with increased 
healthcare costs21 22. 
 
A further relevant issue impacting on CV outcomes is the relatively very low percentage of 
patients – about 70-80%, according to a number of recent European observational trials – who 
reach their LDL-C target. In a study involving > 4000 Familial Hypercholesterolemia (FH) 
patients, most of whom were on maximally tolerated statins, it was found that only 11% reached 
their LDL-C goal of < 100 mg/dl23. In a pan-European study in almost 7000 CHD patients on 
all intensities of statins (or none at all), 19% achieved their target values of < 70 mg/dl at 1 
year24. In a multi-ethnic study of close to 2000 subjects likely to have FH, statins (half of which 
were high-intensity statins) were prescribed to 83% and only 10% overall and 29% of those 
with ASCVD attained their LDL-C targets25. In a very recent observational study on High and 
Very High Risk patients in central and Eastern Europe, LDL-C success rates of 11-42% 
(depending on the patient characteristics) were reported26. 
 
High and Very High Risk CV patient journeys seems to vary from country to country, and 
current understanding of the process is incomplete. A real-life observational study which 
documents meaningful patient journey-related parameters can be expected to provide 
meaningful insight into the care process, country-by-country.  
 
With the aforementioned considerations in mind, it was deemed of interest to conduct an 
observational study enrolling a broad range of patients at High and Very High risk in various 
settings: in primary and secondary care, treated by general practitioners as well as specialists, 
in the office and the hospital sector. It will document the current management of dyslipidemic 
patients in Europe, including medical outcomes and outcomes relevant to HEOR. This will 
contribute to an understanding the management of dyslipidemic patients and, ultimately, help 
to characterize the clinical and economic burden associated with the management of 
atherosclerotic cardiovascular disease (ASCVD) in Europe. 
 
 
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8 
RESEARCH QUESTION AND OBJECTIVES OF THE OBSERVATION 
 
8.1 
Primary Objective 
The primary objective is to document, in the real-world setting, the effectiveness of current 
treatment modalities in managing plasma levels of LDL-C in Very High Risk and High Risk 
(e.g. SMART score for Very High Risk patients and Framingham risk score for High Risk 
patients) patients requiring LMTs 
 
8.2 
Secondary Objectives 
The secondary effectiveness objectives are to document: 
 The relationship between the above-mentioned treatment modalities and plasma 
levels of other potentially ASCVD-modifying cholesterol fragments, namely HDL-
C, non-HDL-C, TC, apoB, TGs, and Lp(a). 
 Changes in the inflammatory marker hsCRP over time 
Changes in the patient´s overall CV risk assessment over time measured through CV 
risk score calculators  
The secondary safety objectives are to document: 
 Clinical events associated with the various treatment modalities: 
o Laboratory abnormalities 
o Muscle-associated symptoms 
o New onset and/or worsening diabetes 
o Changes in the patients´ glycemic status over time 
o Adverse Drug Reactions associated with bempedoic acid and/or fixed dose 
combination with ezetimibe 
 
 
Additional secondary objectives are to document: 
 The characteristics of the sites and physicians caring for Very High Risk and High 
Risk patients  
 The patients´ use of lipid-modifying treatment, especially with regard to a switch 
from one drug class to another, a dose modification of a given drug, a switch from 
one statin to another, any evidence of statin intolerance or insufficient 
responsiveness to a statin, including a maximally tolerated statin, and any use of 
combination drug therapy 
 Various HEOR parameters associated with the management of dyslipidemic 
patients, such as PRO and healthcare resource use.   
 
9 
RESEARCH METHODS 
 
9.1 
Study Design 
Multinational, multicenter, prospective, observational, non-interventional study  
 
9.2 
Setting 
Approximately 8000 patients from different care settings (primary care and secondary care, 
different specialties) will be enrolled consecutively at a total of approximately 800 sites. It is 
estimated that each site will contribute 10 patients, although additional patients - subject to 
approval - may be considered. At each study site, the patients will be enrolled consecutively. 
Patients will be stratified for High and Very High Risk (per physicians’ assessment) as well as 
for previously and newly treated patients. Sites will be required to complete a patient screening 
log of eligible patients for this disease registry at their treatment centers. This log will document 
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how patients came to be included or excluded from the study, in order to assess the 
representativeness of the study population. Minimal information will be recorded for all patients 
who are screened for study enrolment, but no patient-identifiable information should be 
recorded. Those patients who provide their informed consent will be enrolled into the study. 
Study population: 
The study population consists of Very High Risk and High Risk dyslipidemic patients 
previously diagnosed and treated as well as newly treated patients receiving their first LMT. 
At baseline data collection point, baseline characteristics (LDL-C and other lipid parameters, 
CV risk assessment, concomitant diseases such as diabetes and congestive heart failure, certain 
HEOR variables) and relevant medical history (CV events such as myocardial infarction and 
stroke) will be documented.  
In addition, for the previously diagnosed and treated patients, details on the lipid modifying 
treatment during the year before enrolment will be collected. 
 
This information will be collected from the patients´ chart from all dyslipidemia-related visits 
at which the patient has been seen by the physician, starting from date of diagnosis. 
At the follow-up data collection point at 1 year (± 2 months), available information on the 
patients’ routine management between baseline and this data collection point, and efficacy and 
safety variables will be collected: LDL-C and the other lipid parameters, inflammatory status, 
overall CV risk scores (SMART and Framingham risk scores will be calculated centrally based 
on collected patient information), CV events such as myocardial infarction and stroke, diabetes 
related parameters, renal function parameters, and the lipid-modifying therapy. As an optional 
assessment, PRO questionnaires will be completed by the patient preferably in the physician’s 
office. 
Electronic data capture (EDC) will be used for the recording of the information.   
 
As this is a non-interventional study, only data that is based on routine clinical practice will be 
documented. Treatment pattern and treatment initiation, continuation or changes are solely at 
the discretion of the physician and the patient. There will be no attempt to influence the 
prescribing patterns of any individual treating physician. All medication will be prescribed 
according to usual standard of care and will not be provided by the study sponsor. Participation 
in the study will in no way influence payment or reimbursement for any treatment received by 
patients during the study. 
 
Participating Centers 
Patients will be recruited from approximately 800 sites in Ireland, UK, Portugal, Spain, France, 
Belgium, the Netherlands, Denmark, Germany, Switzerland, Italy, and Austria, as well as 
Norway and/or Sweden and/or Finland. The sites may be office-based or hospital-based, and 
may be involved with either primary or specialized care, the latter including cardiology, 
diabetes, lipidology.  
 
Different databases are used to put a site list of potential sites together (DSE internal database, 
local CRO databases, external databases as available). At least 3 times the targeted number of 
active sites are contacted by sending a site qualification questionnaire to be completed. These 
contacted sites are free to accept or refuse to participate in the NIS. A stepwise process for site 
selection will be performed to allow for representative regional distribution of sites and site 
specialties. Geographic representativeness within the country is maintained as sites are selected 
from each province and, where applicable, language region. 
 
The site must meet the following criteria in order to be selected for participation in this study: 
 To have access to patients on LMTs or suitable for LMTs 
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 To be able to document the data in the English language 
 To be able to complete the study in the EDC system  
 To be able to conduct the study adequately, with enough time and staff to identify 
eligible patients, conduct the patient consent process, participate in required trainings, 
enter study data, and follow-up with study related activities  
 To agree in following-up patients for a period of 1 year per patient according to 
clinical routine. 
 
Eligibility Criteria 
Very High Risk and High Risk dyslipidemic patients requiring LMT’s are eligible for enrolment. 
Further inclusion criteria  
 
 ≥ 18 years of age 
 not simultaneously participating in any interventional study 
 providing written informed consent for participation in the study (ICF) 
 life expectancy > 1 year   
 
Patients will be stratified for High and Very High Risk as well as for previously and newly 
treated patients. 
As this is a non-interventional study, no explicit exclusion criteria are defined. 
  
Patient Groups 
There are no formal patient groups planned. No comparator groups will be introduced.  
 
Schedule 
The total study period from FPI to LPO is 30 months. The individual start per country depends 
on the approval status of the protocol by the responsible Ethics Committee and Competent 
Authorities and will range approximately from Q3 2019 to Q4 2020. Per country, the patient 
recruitment period consists of 9 months, followed by a 12-month follow-up period per patient. 
It is expected that the last patient will complete the study in Q4/2021. The final study report is 
expected to be available in Q4/2022. 
Patients eligible for the study at the site will be documented in a screening log to allow for 
judgement on representativeness of patient inclusion. 
 
Patient data will be documented at two data collection points in time: 
 Baseline at enrolment,  
 FU1 approximately 12 +/- 2 months after baseline  (face-to-face meeting preferred) 
 
At baseline, the patients’ medical history will be documented as well as the currently applied 
therapy. At the annual follow-up data collection point, changes in therapy and disease status 
since the last data collection point will be documented. At the baseline and the follow up data 
collection point the patients will be asked to complete the patient reported outcome (PRO) 
questionnaire EQ-5D-5L and the PAM-13 questionnaire. 
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9.3 
Variables 
Parameters recorded during the observation period: 
 
To be documented at baseline (if available): 
 Eligibility 
 Demographic and sociodemographic variables  
 Vital signs 
 Medical history, including CVD risk status-related medical history: 
o CV risk assessment with or without utilization of risk score 
o history/diagnosis and current status of dyslipidemia 
o heterozygous familial hypercholesterolemia (HeFH) 
o documented ASCVD either clinical or unequivocal on imaging  
 Concomitant diseases  
 For diabetic patients 
o disease type and date of diagnosis 
o treatment 
o microvascular complications 
 Current concomitant medication for CVD 
 Previous / current dietary restrictions 
 
 Previous / current use of lipid-modifying treatment 
Previous / current use of lipid-modifying treatment including details of dose, dose 
modification, switching, combination therapy, drug intolerance, insufficient 
responsiveness, investigators and patients assessment on compliance  
o Statin(s)  
o Bile acid sequestrant(s) 
o Cholesterol absorption inhibitor (Ezetimibe) 
o PCSK9 inhibitor(s) 
o Nicotinic acid 
o Drug combinations 
o Bempedoic acid and/or bempedoic acid fixed dose combination with ezetimibe 
o Other 
 
 Laboratory parameters  
o Lipid variables 
- 
LDL-C 
- 
HDL-C, non-HDL-C, TC, apoB, TG, Lp(a) 
o Diabetes-related parameters 
- 
fasting glucose 
- 
HbA1c 
o Inflammatory status 
- 
hsCRP 
o Renal function parameters (GFR, serum creatinine, blood urea nitrogen (BUN)) 
o Other laboratory parameters (liver function, serum chemistry, hematology) 
 
 HEOR parameters 
o Hospital admissions  
o Length of hospital stay  
o Number of days in ICU  
o Interventions  
o Other HEOR parameters  
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o Adherence to former and current treatment  
o Patient reported outcomes (EQ-5D-5L, PAM-13) 
  
To be documented at 1-year follow-up (if available): 
 Vital signs 
 CVD risk status: 
o CV risk assessment with or without utilization of risk score 
o history/diagnosis and current status of dyslipidemia 
o heterozygous familial hypercholesterolemia (HeFH) 
o documented ASCVD either clinical or unequivocal on imaging  
 Concomitant diseases  
 For diabetic patients 
o disease type and date of diagnosis 
o treatment 
o microvascular complications 
 Current concomitant medication for CVD 
 Previous / current dietary restrictions 
 
 Previous / current use of lipid-modifying treatment 
Previous / current use of lipid-modifying treatment including details of dose, dose 
modification, switching, combination therapy, drug intolerance, insufficient 
responsiveness, investigators and patients assessment on compliance  
o Statin(s)  
o Bile acid sequestrant(s) 
o Cholesterol absorption inhibitor (Ezetimibe) 
o PCSK9 inhibitor(s) 
o Nicotinic acid 
o Drug combinations 
o Bempedoic acid and/or bempedoic acid fixed dose combination with ezetimibe 
o Other 
 
 Clinical events associated with the lipid modifying treatment modalities: 
o Insufficient lipid lowering efficacy 
o Muscle-associated symptoms 
o New-onset diabetes mellitus 
o Reduced kidney function 
o Drug-drug interaction 
o Noncompliance 
o Neurocognitive impairment 
o Laboratory abnormalities 
o Other 
 
 Adverse drug reactions associated with the use of bempedoic acid and/or bempedoic 
acid fixed dose combination with ezetimibe 
 
 Laboratory parameters  
o Lipid variables 
- 
LDL-C 
- 
HDL-C, non-HDL-C, TC, apoB, TG, Lp(a) 
o Diabetes-related parameters 
- 
fasting glucose 
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- 
HbA1c 
o Inflammatory status 
- 
hsCRP 
o Renal function parameters (GFR, serum creatinine, blood urea nitrogen (BUN)) 
o Other laboratory parameters (liver function, serum chemistry, hematology) 
 
 HEOR parameters 
o Hospital admissions  
o Length of hospital stay  
o Number of days in ICU  
o Interventions  
o Other HEOR parameters (e.g. insurance status , employment status, education) 
o Adherence to former and current treatment  
o Patient reported outcomes (EQ-5D-5L, PAM-13)* 
 
*For documenting PRO (Patient Reported Outcomes) two validated questionnaires/assessments 
will be used as explained below.  
 
EQ-5D-5L.  The EuroQol (EQ-5D-5L), developed by the EuroQoL group, is a generic utility 
measure rating the current overall health states.  It consists of five domains (mobility, self-care, 
usual activities, pain or discomfort, and anxiety or depression) and a visual analogue scale 
(VAS). The scores range from 0 to 100 based on the level of health for each domain given by 
participants. A score of 100 indicates that the current health is equivalent to full health; a score 
of 0 indicates that the current health is equivalent to death. According to the scores of the five 
domains, a sum utility score is calculated ranging from 0 to 1. A score of 1 represents a perfect 
state. In addition, patients have to rate their current health on a 20-centimeter vertical visual 
analogue scale scored from 0 to 100 reflecting the continuum from a best imaginable to the 
worst imaginable health state. The EQ-5D is proved to be a reliable, valid, self-reported 
measure. It is used most widely for general healthcare evaluation, including cost-utility 
evaluation. 
 
PAM-13. PAM assesses patient knowledge, skills, and confidence for self-management based 
on 13 items. 
It segments individuals into one of four activation levels along an empirically derived 100-point 
scale. 
Each level provides insight into an extensive array of health-related characteristics, including 
attitudes, motivators, and behaviors. Individuals in the lowest activation level do not yet 
understand the importance of their role in managing their own health, and have significant 
knowledge gaps and limited self-management skills. Individuals in the highest activation level 
are proactive with their health, have developed strong self-management skills, and are resilient 
in times of stress or change. 
 
9.4 
Data Sources 
As this is a non-interventional study, only data on clinical routine practice will be documented. 
To facilitate accurate recording of data, patients can optionally fill in a memory aid (patient 
diary) to note important details. 
 
For this disease registry, safety reporting for drugs will be covered outside the scope of this 
study through the local processes of spontaneous reporting.  
Scheduled assessments for the study are presented in the Data Collection Flow Chart provided 
below (Table 1). All data elements will be collected from information routinely recorded in the 
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9.6 
Data Management 
The CRO’s EDC system will be used for data capture. Data will be collected in standardized 
English eCRFs.  
A data management plan will be created in the study start phase and will describe all functions, 
processes, and specifications for data collection, cleaning and validation. The eCRFs will 
include automated plausibility checks (e.g. range checks, conditional checks, etc.) at data entry 
to obtain immediate feedback if data are missing, out of range, illogical or potentially erroneous 
and allow for correction or confirmation by the site. Concurrent manual data review will be 
performed based on parameters defined in the data management plan. If necessary, queries will 
be manually generated within the EDC system and followed up for resolution.  
Critical data variables will be defined that need to be filled in by the site to be able to complete 
and sign the eCRF module.  
Data from the project specific EDC database will be exported into SAS data sets (as per CDISC 
SDTM definition) for further validation and analysis. 
  
Data Entry/Electronic Data Capture 
All data will be collected and entered directly into the CRO EDC system. Each participating 
site will have access to its enrolled patient data only. All sites will be fully trained on using the 
on-line data capture system, and on the eCRF completion guidelines and other help files. Sites 
will be responsible for entering patient data into the secure internet-based EDC database via the 
eCRF. Investigators and site personnel will be able to access their account with a unique 
personalized username and password. All eCRFs should be completed by designated, trained 
personnel as appropriate. Each eCRF is to be reviewed, electronically signed, and dated by the 
investigator. All changes or corrections to eCRFs will be documented in an audit trail and an 
adequate explanation is required.  
 
Source Documents 
In most cases, the source documents are contained in the patients’ medical record and data 
collected on the eCRFs must be traceable to these source documents in the patients’ medical 
records. In some cases, the eCRF, or part of the eCRF, may also serve as source documents. In 
these cases, a document should be available at the investigator’s site and clearly identify those 
data that will be recorded directly in the eCRF, and for which the eCRF will be regarded as the 
source document. All original source documentation is expected to be stored at the site for the 
longest possible time required by local applicable regulations. The site will be instructed to 
notify the sponsor before any destruction of medical records of study participants. 
 
File Retention and Archiving 
To enable evaluations and/or audits from regulatory authorities or the sponsor, the investigator 
agrees to keep records, including the identity of all participating patients, all original signed 
informed consent forms and source documents. The records should be retained by the 
investigator according to local regulations, or as specified in the study contract, whichever is 
longer. 
 
Each site will receive a study site file at study initiation which contains all documents necessary 
for the conduct of the study and is updated throughout the study. This file must be available for 
review in the event the site is selected for monitoring, audits, or inspections and must be safely 
archived for at least 10 years or according to local legislation respectively after completing the 
participation in the study. Documents to be archived include the patient screening log, copy of 
eCRF burned on a CD and the signed informed consent forms (ICF). 
 
 
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9.7 
Data Analysis 
This section describes the most relevant parts of the statistical analyses planned for a 
NIS/registry. All statistical methodology will be described in detail in the Statistical Analysis 
Plan (SAP) which will be finalized at the latest prior to database lock. All variables collected 
in the CRFs and/or other recordings (if applicable) and all derived parameters will be used in 
the statistical analysis. 
A report including descriptive statistics of all documented parameters will be generated also if 
required for each participating country. Details on the selection criteria used will be given in 
the SAP and in the statistical section of the report. 
Referring to the primary objective, the statistical analysis will be performed in a purely 
explorative descriptive way according to DSE SOP R-440. 
 
Data will be collected at the following data collection points  
 baseline ,  
 1-year prospective follow-up   
 
Following analysis sets will be used for analysis 
 The All-Documented Patient Set (APS) consists of all patients with any eCRF 
documentation.  
 The Baseline Analysis Set (BAS) consists of all eligible patients of the APS who 
provide adequate baseline information. 
 The Full Analysis Set (FAS) consists of all patients from the BAS with available 1-
year follow-up data. 
 The Safety Set (SAF) includes all patients who received at least one dose of 
bempedoic acid and/or bempedoic acid fixed dose combination according to their 
documentation in the eCRF. 
 
No primary endpoint was defined in this study. No formal statistical tests will be performed 
within the statistical analysis. 
All statistical analyses will be performed in a purely exploratory descriptive way.  
 
Binary, categorical, and ordinal parameters will be summarized by means of absolute and 
percentage numbers within the various categories (including ‘missing data’ as valid category at 
baseline). 
 
Numerical data will be summarised by means of standard statistics (i.e. number of available 
data, number of missing data, mean, standard deviation, minimum, median, maximum, lower 
and upper quartile). In addition, adequate graphs (e.g. bar charts, box-whisker plots) may be 
presented to summarize the results for some parameters. Analysis of changes in numerical 
parameters (as the differences in Score risk between baseline and 1-year follow up) will be done 
by paired Wilcoxon signed rank test and paired t-test if assumptions of parametric tests will be 
met. Comparison of these 1-year changes between subgroups will be done by Kruskal-Wallis 
test and ANOVA test if assumptions of parametric tests will be met. Also adjusted analyses for 
age, sex and country effects will be done.  Time-to-event variables will be analyzed via a Cox 
proportional hazard regression model presenting hazard ratios and the corresponding 95% 
confidence intervals. Additionally, adjusted Cox model for age, sex and country effects will be 
presented.  In addition, Kaplan-Meier curves will be presented for time-to-event variables. 
Two-sided 95% confidence intervals will be presented for important parameters, but should be 
interpreted in an exploratory descriptive way. 
Depending on the variable(s) of interest, additional selection criteria for patients (e.g. subgroup 
analyses) considered in specific analyses may be used, if considered useful during the statistical 
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analysis. Details on the selection criteria used will be given in the Statitical Analysis Plan (SAP) 
and in the statistical section of the report. 
 
The statistical analysis will be performed using SAS version 9.4 or higher  
 
9.8 
Quality Control/Monitoring 
Data quality checks will be performed on an ongoing regular basis. Queries will be raised by 
the responsible CRO and shall be answered by the site in due course. The purpose is to ensure 
that the rights of the patients are protected, that the reported data are accurate and complete, 
and that the conduct of the study is in compliance with the observational plan and applicable 
regulatory requirements. 
 
Particular attention will be paid during monitoring activities to the completeness and 
correctness of safety data. 
 
The physician will comply with the confidentiality policy as described in the site contract. The 
physician will comply with the observational plan and the requirements described in the 
contract. The physician is ultimately responsible for the conduct of all aspects of the NIS at the 
site and verifies by signature the integrity of all data transmitted to the sponsor.  
On-site monitoring will be performed in 20% randomly selected sites. During on-site 
monitoring the monitor will verify 100% of informed consent documentation and perform 
source data verification against the patients’ medical records in randomly selected patients (3 
per site).  
This study will be conducted according to the rules of ‘Good Pharmacoepidemiology Practice’ 
(GPP) and the ‘Guideline on Good Pharmacovigilance Practices’ (GVP). Related quality 
control mechanisms (e.g., data plausibility checks, monitoring of data) will be performed 
accordingly. 
 
9.9 
Limitations of the Research Methods 
Although sites will be selected to guarantee representativeness for the respective country or 
region as much as possible, sites also need to have sufficient capabilities, interest and capacities 
to participate in the NIS. This may influence the sites’ representativeness in some smaller 
regions. 
 
Eligible patients not giving their informed consent to participate in the NIS cannot be enrolled. 
Therefore this may impact the consecutive enrolment at a site. To be able to assess the 
consecutiveness of enrolment, eligible patients will be listed in the patient screening log. 
Patients participating in competing interventional trials are not eligible and will not be entered 
in the screening list. 
 
At the annual documentation time point all relevant changes/events since the last 
documentation time point need to be entered. Due to the long time between Baseline and the 
Follow-up data collection point an underreporting of data might occur that are not considered 
essential or that are difficult to remember. The patient memory aid and the patients’ medical 
records at the site shall support the precise documentation of the time between two annual data 
documentation time points. The utility of both records is however influenced by the precision 
and accuracy with which the memory aid and the medical records have been completed in the 
meantime. It is expected that possible underreporting will not appear in case of severe events 
and hospitalizations and that this data is considered to be representative for the whole study 
population.  
 
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In addition to the above mentioned underreporting of events, the time between two 
documentation points might cause an incorrect documentation of treatment changes. This could 
lead to a misclassification with respect to the exposure. However, this risk is considered to be 
low as relevant treatment changes are usually documented in the medical records and can 
furthermore be entered into the eCRF at any time (log-file approach). In addition, the patient 
memory aid again supports a precise documentation. 
  
Also differences between the countries/regions might occur, especially when rating compliance. 
Therefore, especially for the compliance the analysis by country/region will be carefully looked 
at. In case that there will be mentionable differences, the interpretation has to be very careful 
and should consider regional differences. 
 
As the study is non-interventional, only data from the clinical routine treatment can be obtained. 
Therefore some information may be missing or unavailable. This needs to be taken into account 
when data are analyzed and reported. 
 
No explicit non-eligibility criteria are defined to avoid selection of patients and thus violation 
of the ‘real-life’ principle. 
 
10 
PROTECTION OF HUMAN SUBJECTS 
 
10.1 
Review by Ethics Committees/Competent Authorities 
Notification to or approval by independent Ethics Committees (IECs) and competent authorities 
(CAs) or other organizations will be performed as required by national regulations in the 
participating countries before commencement of enrolment at a study center. 
 
10.2 
Insurance and Liability 
All treatments of patients included in this NIS are local standard of care and occur as part of 
the clinical routine practice. The NIS is non-interventional and does not foresee any change of 
treatment nor additional examinations apart from the standard of care. Claims of the patient 
upon his/her physician resulting from an inappropriate use of the prescribed medication will 
not be covered by Daiichi Sankyo. A specific patient insurance for NIS is not necessary (if not 
in contradiction with specific legal requirements in the country of conduct). 
 
10.3 
Patient Information, Informed Consent (if applicable) 
Written Informed Consent (ICF) will be obtained from all patients. 
It is the responsibility of the investigator to inform the patient about his/her disease, possibilities 
for diagnostic and therapeutic measures, independent of a possible participation in any survey 
and therefore this information will not be part of the ICF.  
The written ICF will be provided to the sites in the local language(s) of the planned patient 
population. The ICF and any revision(s) will be approved by the Independent Ethics Committee 
(IEC) prior to being provided to potential patients, or submitted to IEC where no approval is 
required. 
The patients’ written informed consent will be documented in the patients’ medical records of 
the investigator. Two ICF forms should be signed and personally dated both by the patient and 
by the investigator who conducted the informed consent discussion. One original signed ICF 
should be retained at the study center (preferably in the patients’ medical records). The second 
original of the signed consent form should be provided to the patient. The date informed consent 
was given will also be recorded in the Case Record Forms (eCRF). 
 
 
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10.4 
Data Protection 
The patients’ privacy will be kept according to the requirements of the Regulation (EU) 
2016/679 (General Data Protection Regulation). Data will be collected in a pseudonymous way. 
An identification number assigned to each patient will be used in lieu of the patient’s name to 
protect the patient’s identity when reporting study-related data.  
Only authorized personnel as hospital staff at the site has access to the identification list or 
original source documents (medical records). Representatives of the sponsor, the contract 
research organization (CRO) and authorities are allowed to get access in case of audit or 
inspection or for monitoring purposes. The patient will agree to this by signing a respective 
statement on the ICF.  
The database will be maintained under the CRO domain by the service provider with all safety 
instalments for a physically and logically secure computer system. The system is fully validated 
and in line with industry and regulatory standards. The system also meets the standards of the 
International Council on Harmonization (ICH) guideline E6R2 regarding electronic study data 
handling and is available for audit upon request. Patient confidentiality will be strictly 
maintained. 
 
10.5 
Numbering and Identification of Patients 
A unique identification number (patient ID) will be assigned to each patient when reporting 
data in the eCRF. 
At each study center a patient identification list will be kept linking the identification number 
to the patient’s identity.  
 
10.6 
Assessments (according to the study type) 
The investigators will be instructed about the correct documentation of the required variables 
for each patient in the eCRF. These data are available as part of the routine treatment. All 
examinations performed depend on the discretion and clinical routine of the physician. No 
diagnostic or monitoring procedures are applied to the patients in the study other than those 
performed as standard of care. 
 
11 
COLLECTION 
AND 
REPORTING 
OF 
ADVERSE 
DRUG 
REACTIONS/ADVERSE EVENTS (IF APPLICABLE) 
In this disease registry, the physician has to report any ADR in his/her routine ways as regular 
spontaneous reports in accordance with the Guideline on Good Pharmacovigilance Practices 
(GVP) as well as in accordance with local laws for all medication except bempedoic acid and/or 
bempedoic acid fixed dose combination with ezetimibe treatment. 
 
For patients treated with bempedoic acid and/or bempedoic acid fixed dose combination with 
ezetimibe treatment the following process needs to be followed in case of an Adverse Drug 
Reaction (ADR): 
 
11.1 Definitions  
Adverse Drug Reaction (ADR) 
A response to a medicinal product which is noxious and unintended and which occurs at doses 
normally used in man for the prophylaxis, diagnosis or therapy of disease or for the restoration, 
correction or modification of physiological function. 
Response in this context means that a causal relationship between a medicinal product and an 
adverse event is at least a reasonable possibility. 
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Adverse reaction also includes adverse clinical consequences associated with use of the product 
outside the terms of the Summary of Product Characteristics or other conditions laid down for 
the marketing and use of the product (including prescribed doses higher than those 
recommended, overdoses or abuse). 
Serious Adverse Drug Reaction (SADR) 
Serious adverse reaction means an adverse reaction which  
 Results in death,  
 Is life-threatening,  
 Requires inpatient hospitalization or prolongation of existing hospitalization,  
 Results in persistent or significant disability or incapacity, or  
 Is a congenital anomaly/birth defect. 
Life threatening in this context refers to a reaction in which the patient was at risk of death at 
the time of the reaction; it does not refer to a reaction that hypothetically might have caused 
death if more severe. 
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the patient 
or might require intervention to prevent one of the other outcomes listed above. Examples of 
such events are intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasia or convulsions that do not result in hospitalization or development of 
dependency or abuse. 
Note:  
Procedures are not ADRs or SADRs, but the reason for the procedure may be an ADR or SADR. 
Pre-planned (prior to signing the Informed Consent Form) procedures or treatments requiring 
hospitalizations for pre-existing conditions that do not worsen in severity are not ADRs. 
11.2 Reporting of Suspected ADRs by the Investigator 
All bempedoic acid or fixed dose combination related adverse drug reactions need to be 
reported within 24 hours, and will be documented by the site in the respective section of the 
eCRF as soon as the site becomes aware of it. The pharmacovigilance department of the sponsor 
(Daiichi Sankyo Europe GmbH, Clinical Safety & Pharmacovigilance Department, 
Zielstattstrasse 48, 81379 Munich, Germany) and the local safety officers (LSO) at the 
responsible Daiichi Sankyo affiliate will receive an automated notification email. All ADR 
details will be obtained from the eCRF and will be processed further in line with the 
requirements for spontaneous reporting and in accordance with the Guideline on Good 
Pharmacovigilance Practices (GVP). 
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If a patient completed the SANTORINI study, and an ADR occurs, the site will proceed 
further in line with spontaneous reporting as described above; if the outcome is not clear at 
the end of the SANTORINI study, then the site will fup until it is solved. 
 
11.3 Pregnancy 
Daiichi Sankyo must be notified of those patients only who become pregnant while receiving 
or within 30 days of discontinuing bempedoic acid and/or fixed dose combination with 
ezetimibe. The patient should discontinue bempedoic acid and/or fixed dose combination with 
ezetimibe upon confirmation of pregnancy. 
Although pregnancy is technically not an adverse reaction, pregnancies for patients treated with 
Bempedoic acid and/ or fixed dose with ezetimibe must be followed to conclusion to determine 
their outcome.  This information is important for both drug safety and public health concerns.  
It is the responsibility of the Investigator, or designee, to report any pregnancy in a female 
patient using the Exposure In Utero (EIU) Reporting form.  
Please contact your study monitor to receive the EIU Reporting Form upon learning of a 
pregnancy.  The Investigator should make every effort to follow the patient until completion of 
the pregnancy and complete the EIU Reporting Form with complete pregnancy outcome 
information, including normal delivery and induced abortion.  
The adverse pregnancy outcome, either serious or non-serious, should be reported in accordance 
with study procedures.  If the outcome of the pregnancy meets any criteria for immediate 
classification as a SADR (e.g., post-partum complications, spontaneous or induced abortion, 
stillbirth, neonatal death, or congenital anomaly, including that in an aborted fetus), the 
Investigator should follow the procedures for reporting ADRs outlined in Section 11.2.  
 
 
12 
DOCUMENTATION AND ARCHIVING 
The sponsor is responsible for archiving study specific documentation (Observational plan, 
potential amendments, Final Report and Database) for at least ten years. Archived data may be 
held on electronic record, provided that a back-up exists and that hard copies can be obtained, 
if required. 
The investigator is responsible for archiving the patient identification list, all signed ICFs and 
his contract for at least ten years and in accordance with local legislation, if applicable. 
Physicians are obliged to keep patient files according to national requirements. 
 
13 
LEGAL REQUIREMENTS 
This NIS fulfils the requirements of the Directive 2001/83 EC, Guidelines on Good 
Pharmacovigilance Practices (GVP), Directive 95/46 EC, the Declaration of Helsinki and will 
be conducted in accordance with the respective SOPs of DSE. 
 
13.1 
Reimbursement 
Compensation according to local regulations and to the time spent to inform patients and to 
document patient data will be paid. This compensation also includes the honorarium for 
responding to queries and for monitoring if applicable. 
 
 
 
 
 
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13.2 
Registration 
This registry will be listed in a public registry which meets International Committee of Medical 
Journal Editors (ICJME) requirements, before the onset of patient enrolment. 
 
14 
FINAL REPORT  
A final NIS report will be presented latest one year after data base lock, if not required earlier 
by local legislation. 
 
15 
PUBLICATION 
In order to protect confidential information and/or the interests of DSE, all publications 
(manuscripts and congress presentations) or announcements originating from this research are 
governed jointly by the SC and the Sponsor.  
Aside from the main publication, participating investigators in the study can propose subgroup 
analysis and related second level publications to the SC and the Sponsor. Such publications 
may be produced by a dedicated team of authors other than the SC in common agreement with 
and governed jointly by the SC and the Sponsor.  
 
16 
PREMATURE TERMINATION OF THE NIS/REGISTRY 
The physician may withdraw his/her participation in this registry at any time. In the case of a 
premature termination of the entire NIS/registry by the sponsor, the project leader has to inform 
all participating sites, Ethics Committees, and authorities. 
 
 
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17 
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