PENELOPE-CTRL: Real Life Lipid Management Compared to Protocolized Implementation of the Current Dutch- and ESC-guidelines in Very High-risk CV-patients
Conditions: Atherosclerotic Cardiovascular Disease, STEMI, Non STEMI
Sponsor: Clinical Operations WCN B.V.

 
 
 
 
PENELOPE-CTRL: 
Real life lipid management compared to protocolized implementation of the 
current Dutch- and ESC-guidelines in very high-risk CV-patients 
 
 
 

Study protocol PENELOPE CRTL control group PENELOPE study 
Version number: 3.2, date January 25, 2023 
 CONFIDENTIAL 
2 of 16 
PROTOCOL TITLE Real life lipid management compared to protocolized implementation of the 
current Dutch- and ESC-guidelines in very high-risk CV-patients 
 
Protocol ID 
Sanofi ID nr: DCV-2017-11843 
Short title 
Comparison of two lipid management strategies in very 
high risk patients 
EudraCT number  
not applicable 
Version 
3.2 
Date 
25/JAN/2023 
Principal investigator / project leader 
 
 
 
 
Co-principal investigator 
 
 
FMAC Martens, MD, PhD, FESC 
Deventer Hospital, department of Cardiology, Nico 
Bolkesteinlaan 75, 7416 SE Deventer, the Netherlands 
on behalf of 
M. Alings, MD, PhD, FESC 
Amphia Hospital, department of Cardiology, Molengracht 
21, 4818 CK Breda, the Netherlands 
malings@amphia.nl 
 
T. van Trier, MD 
Amsterdam UMC, department of Cardiology 
Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands 
t.j.vantrier@amsterdamumc.nl  
 
Study centres 
Aim: 13 sites 
 
 
Sponsor  
Clinical Operations WCN (COW) 
 
 
Subsidising party 
Sanofi-Aventis Netherlands B.V.  
 
 

Study protocol PENELOPE CRTL control group PENELOPE study 
Version number: 3.2, date January 25, 2023 
 CONFIDENTIAL 
3 of 16 
PROTOCOL SIGN-OFF SHEET 
 
Name 
Signature 
Date 
Sponsor or legal representative: 
Clinical Operations WCN (WCN: Dutch 
Network for Cardiovascular Research) 
 
Drs. A. Schut (Board Member) 
Moreelsepark 1 
3511 EP Utrecht 
 
 
 
25JAN2023 
Coordinating Investigator/Project Principal 
Investigator: 
FMAC Martens, MD, PhD, FESC 
Deventer Hospital, department of Cardiology, 
Nico Bolkesteinlaan 75, 7416 SE Deventer, the 
Netherlands 
on behalf of 
M. Alings, MD, PhD  (investigator) 
Amphia Hospital, department of Cardiology, 
Molengracht 21, 4818 CK Breda,  
the Netherlands 
Malings@amphia.nl 
Co-principal Investigator:  
T. van Trier, MD  (co-investigator) 
Amsterdam UMC, department of Cardiology, 
Meibergdreef 9, 1105 AZ Amsterdam, the 
Netherlands   t.j.vantrier@amsterdamumc.nl  
 
 
 
 
 
 
 
 
 
 
  
25JAN2023 
 
 
 
 
 
 
25JAN2023 
 
 
 
25JAN2023 
 
 

Study protocol PENELOPE CRTL control group PENELOPE study 
Version number: 3.2, date January 25, 2023 
 CONFIDENTIAL 
4 of 16 
TABLE OF CONTENTS 
 
3. 
INTRODUCTION AND RATIONALE .........................................................................................8 
4. 
OBJECTIVES .......................................................................................................................9 
5. 
STUDY DESIGN ...................................................................................................................9 
6. 
STUDY POPULATION ...........................................................................................................9 
a. 
POPULATION................................................................................................................9 
b. 
INCLUSION CRITERIA .....................................................................................................9 
c. 
EXCLUSION CRITERIA ..................................................................................................10 
d. 
PATIENT SELECTION ....................................................................................................10 
7. 
DATA COLLECTION ...........................................................................................................11 
8. 
STUDY OUTCOMES ...........................................................................................................11 
a. 
PRIMARY STUDY OUTCOME .........................................................................................11 
b. 
SECONDARY STUDY OUTCOMES ...................................................................................11 
c. 
STUDY PROCEDURES ...................................................................................................12 
d. 
Randomisation, blinding and treatment allocation .........................................................12 
e. 
Withdrawal of individual subjects .................................................................................12 
f. 
Premature termination of the study .............................................................................12 
9. 
DATA SAFETY MONITORING BOARD ...................................................................................13 
10. STATISTICAL ANALYSIS ......................................................................................................13 
11. SAFETY REPORTING ..........................................................................................................13 
12. ETHICAL CONSIDERATIONS ................................................................................................13 
a. 
Regulation statement ..................................................................................................13 
b. 
Recruitment and consent ............................................................................................14 
c. 
Benefits and risks assessment, group relatedness...........................................................14 
d. 
Compensation for injury ..............................................................................................14 
13. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION ...............................................14 
e. 
Handling and storage of data and documents ................................................................14 
f. 
Monitoring and Quality Assurance ................................................................................14 
g. 
Amendments .............................................................................................................15 
h. 
Annual Progress Report ...............................................................................................15 
i. 
Temporary halt and (prematurely) End of Study Report ..................................................15 
j. 
Public disclosure and publication policy ........................................................................15 
14. REFERENCES ....................................................................................................................16 

Study protocol PENELOPE CRTL control group PENELOPE study 
Version number: 3.2, date January 25, 2023 
 CONFIDENTIAL 
5 of 16 
1. LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ACS 
Acute coronary syndrome 
ASCVD 
Atherosclerotic cardiovascular disease 
CFS 
Clinical Frailty Score 
CVE 
Cardiovascular event 
CVRM 
Cardiovascular Risk Management 
ESC 
European Society of Cardiology 
LDL-C 
Low density lipoprotein cholesterol 
LLT 
Lipid Lowering Therapy 
NSTEMI 
Non-ST-Elevation Myocardial Infarction 
PCSK9-i 
Proprotein convertase subtilisin/kexin type 9 inhibitors 
Sponsor The sponsor is the party that commissions the organisation or performance of the 
research, for example a pharmaceutical company, academic hospital, scientific 
organisation or investigator. A party that provides funding for a study but does not 
commission it is not regarded as the sponsor, but referred to as a subsidising party. 
STEMI 
ST-Elevation Myocardial Infarction 
T2DM 
Type 2 Diabetes Mellitus 
WCN 
WMO 
Werkgroep Cardiologische centra Nederland 
Medical Research Involving Human Subjects Act (in Dutch, Wet Medisch-
wetenschappelijk Onderzoek met mensen) 
 
 
 
 
 
 
 
 
 
 
 
 
 

Study protocol PENELOPE CRTL control group PENELOPE study 
Version number: 3.2, date January 25, 2023 
 CONFIDENTIAL 
6 of 16 
2. ABSTRACT 
Rationale: Guideline recommended evidence-based clinical care correlates with improved patient 
outcomes. In real life care, however, adherence to guideline recommendations remains suboptimal. 
In real life, patients may receive suboptimal treatment and as a result treatment targets are not 
always met. To support and improve secondary prevention for cardiovascular disease, PENELOPE and 
PENELOPE-CTRL are designed to support guideline implementation on lipid management and provide 
valuable feedback to care-givers on real world data. 
The recent PENELOPE study was designed to determine the effect of a protocolized, Dutch-, and 
European Society of Cardiology (ESC) guidelines based strategy of stepwise intensified lipid 
management in patients at very high risk for Acute coronary syndrome (ACS). In PENELOPE 22 Dutch 
non-academic hospitals, members of the WCN investigator network, implemented a protocol guided 
guideline approach in a consecutive cohort of very high-risk patients admitted for ACS over the 
period 01-01-2019 to 31-08-2020. Lipid values and medication strategy are collected at baseline 
(index ACS), and after three months and one year post ACS, in order to establish the percentage of 
patients on target Low density lipoprotein cholesterol (LDL-C). 
The current PENELOPE-CTRL study on the other hand, is designed to serve as a contemporary control 
cohort for PENELOPE. PENELOPE-CTRL is a retrospective observational study, creating a 
contemporary snapshot of real-life lipid management for secondary prevention in very high-risk 
patients. PENELOPE-CTRL will collect data in similar hospitals who did not participate in the 
PENELOPE trial. 
To allow comparison of these two strategies, protocol guided versus real life implementation of the 
cholesterol treatment guidelines, both cohorts include similar patients, and similar data will be 
collected (e.g., lipid lowering drugs, lipid panels) . Analysis will be done at similar time points. 
Comparing the real-life data from PENELOPE-CTRL with the data from the PENELOPE study will 
quantify the effect of a strategy of protocolized guideline-based lipid management with regards to 
the incidence of target LDL-C levels in very high-risk patients, 3 months and one year after 
hospitalisation with a myocardial infarction. 
 
Objective: To measure real life lipid lowering therapy (LLT) and resulting LDL-C levels in very high-risk 
patients. PENELOPE-CTRL will be used as a control cohort versus protocolized (PENELOPE study) 
implementation of the Dutch and ESC guidelines. 
 
Study design: Retrospective cohort study. 
 

Study protocol PENELOPE CRTL control group PENELOPE study 
Version number: 3.2, date January 25, 2023 
 CONFIDENTIAL 
7 of 16 
Study population: Patients with a history of Atherosclerotic cardiovascular disease (ASCVD) and/or 
type 2 diabetes (T2DM), admitted for a type I ST-elevation myocardial infarct (STEMI) or non-STEMI. 
Patients <18 years or >70 years of age will be excluded.  
In PENELOPE patients over 70 were included based on a frailty index. As this parameter cannot be 
determined retrospectively, patients over 70 will be excluded from the CTRL cohort, as well as from 
the comparative analysis for the two cohorts. 
 
Study parameters: Cardiovascular medical history and risk profile, baseline characteristics (including 
index event, lipid panels, baseline medication and LLT); and follow up data on LLT and lipid panels 
during the year post ACS  
 
Nature and extent of the burden and risks associated with participation, benefit and group 
relatedness:  None, retrospective data collection.  

Study protocol PENELOPE CRTL control group PENELOPE study 
Version number: 3.2, date January 25, 2023 
 CONFIDENTIAL 
8 of 16 
3. INTRODUCTION AND RATIONALE 
One of the main underlying causes of atherosclerotic cardiovascular disease is the retention of LDL-C 
and other cholesterol containing lipoproteins within the arterial wall. There is an approximately 
linear relationship between the absolute reduction in LDL-C and the proportional reductions in the 
incidence of coronary and major vascular events.[1] Clinical trials have clearly shown that the lower 
the achieved LDL-C values, the lower the risk of future cardiovascular events. Guidelines summarize 
and evaluate available evidence with the aim of assisting health professionals in proposing the best 
management strategies for an individual patient with a given condition.[2, 3] For secondary 
prevention in very-high-risk patients the 2016 ESC Guidelines for the management of dyslipidaemia 
recommended an LDL-C reduction to <1.8 mmol/l.[1] in the 2019 ESC Guidelines this was narrowed 
down even further to <50% from baseline and an LDL-C goal of <1.4 mmol/L.[4] If the LDL-C goal is 
not achieved 4 - 6 weeks after the cardiovascular event (CVE) despite maximal tolerated statin 
therapy, ezetimibe should be added first, followed by Proprotein convertase subtilisin/kexin type 9 
inhibitors (PCSK9-i). [3] The Dutch Cardiovascular Risk Management (CVRM) guideline (in the period 
PENELOPE was performed) recommends an LDL-C goal of at least <1.8 mmol/L for very high-risk CV-
patients. 
Adherence to treatment guidelines is a predictor of fewer CV hospitalizations. In real life care, 
however, compliance to guidelines for secondary prevention of cardiovascular disease, can be 
improved according to recent European and Swedish national studies. [5-8] A strategy of 
protocolized, Dutch- and ESC-guideline based stepwise approach in lipid lowering therapy (LLT) to 
reach target LDL-C in very high-risk patients was studied in the PENELOPE study. Protocolized LLT 
consisted of 3 steps, with LDL-C levels measured ≥4 weeks after each step: 
• 
Step 1: if at baseline LDL-C >1.8 mmol/L, then a high intensity statin (HIST), defined as 
atorvastatin ≥40 mg OD or rosuvastatin ≥20 mg OD, had to be initiated. 
• 
Step 2: if  ≥4 weeks after step (1) LDL-C >1.8 mmol/L, then ezetimibe 10 mg OD had to be 
initiated. 
• 
Step 3: if  ≥4 weeks after step (2) LDL-C >1.8 mmol/L alirocumab had to be initiated following 
pre-specified criteria: 
o if LDL-C 1.8-2.6 mmol/L, addition and dosing of alirocumab was left at the 
investigator’s discretion 
o if LDL-C 2.6-3.6 mmol/L, alirocumab 75 mg or 150 mg Q2W had to be initiated 
(dosing at the investigator’s discretion) 
o if LDL-C >3.6 mmol/L, alirocumab 150 mg Q2W had to be initiated. 
 

Study protocol PENELOPE CRTL control group PENELOPE study 
Version number: 3.2, date January 25, 2023 
 CONFIDENTIAL 
9 of 16 
PENELOPE was designed to demonstrate feasibility and efficacy of guideline-based protocolized LLT 
in the Netherlands. 
PENELOPE-CTRL is designed to document real life LLT and resulting LDL-C target attainment in the 
Netherlands.  
Comparison of PENELOPE and PENELOPE-CTRL will demonstrate whether the strategy of protocolized 
guideline based LLT results in a higher incidence of target LDL-C levels in secondary prevention at set 
time points, and quantify this difference.  
 
4. OBJECTIVES 
Primary Objective:  
To compare real life LLT and reaching target LDL-C levels in very high-risk patients versus 
protocolized (PENELOPE study) implementation of the current Dutch and ESC guidelines.  
 
5. STUDY DESIGN 
PENELOPE-CTRL is designed as a retrospective cohort study with its enrolment-period coinciding with 
the inclusion period of PENELOPE, i.e. January 1st, 2019 until August 31st, 2020. 
 
6. STUDY POPULATION 
a. POPULATION 
All patients fulfilling the in- and exclusion criteria in the participating centres will be included in the 
PENELOPE-CTRL cohort (Registry). Participating sites are part of the WCN research network and have 
not participated in PENELOPE. These are all non-academic cardiovascular research centres, providing 
regional cardiovascular hospital care with a regional CVRM function. All sites are using the same 
standard operating procedures for clinical research.  
Inclusion criteria are identical to the Penelope trial, with the exception of the introduction of a 
maximum age of 70 years in PENELOPE-CTRL. (Table 1) In PENELOPE, patients >70 years of age were 
required to have a clinical frailty score (CFS) ≤3. As retrospective electronic medical records data do 
not allow for accurate determination of the CFS, all  patients >70 years will be excluded in PENELOPE-
CTRL. For the comparative analysis the CTRL population will be compared to the Penelope patients < 
70 years old (N=663).Furthermore, only patients who were alive at discharge will be registered.  
 
b. INCLUSION CRITERIA 
• 
Age >18 and ≤70 years 
• 
Alive at hospital discharge after admission for (N)STEMI between 1-1-2019 and 31-08-2020  

Study protocol PENELOPE CRTL control group PENELOPE study 
Version number: 3.2, date January 25, 2023 
 CONFIDENTIAL 
10 of 16 
• 
Planned for follow-up at a participating PENELOPE CTRL site 
• 
History of T2DM and/or history of ASCVD defined as either one of: 
o cerebrovascular disease/ event: transient ischemic attack, cerebral infarction, 
amaurosis fugax, retinal infarction 
o Coronary artery disease/ event: unstable angina pectoris, MI, ACS, coronary 
revascularization (coronary angioplasty or surgical procedure for coronary bypass) 
o Peripheral artery disease (symptomatic and documented obstruction of a distal 
extremity artery or surgical intervention (percutaneous transluminal angioplasty, 
bypass or amputation) 
 
Table 1. Inclusion criteria PENELOPE and PENELOPE CTRL, and PENELOPE analysis population 
 
PENELOPE 
PENELOPE (cohort 
compared to CTRL) 
PENELOPE CTRL 
Age 
≥18 years, ≤70 
years 
≥18 years, ≤70 years 
≥18 years, ≤70 years 
>70 years and 
CFR≤3 
- 
- 
history of ASCVD 
✓ 
✓ 
✓ 
T2DM 
✓ 
✓ 
✓ 
admission for 
(N)STEMI 
✓ 
✓ 
✓ 
 
c. EXCLUSION CRITERIA 
• 
Pregnant and lactating women  
Participation in lipid modifying drug trials up to two years after index CVE. 
d. PATIENT SELECTION 
 
All eligible patients  will be identified for data capture in the participating PENELOPE CTRL centers by 
the local team of the PI. Eligible patients will be pre-identified from local electronic health records 
using text-mining (CT-cue) on the in- and exclusion criteria. A local member of the study team will 
confirm eligibility based on the detailed structured and non-structured local electronic health record 
data. A feasibility query in participating centres shows a cohort of 700-1200 candidates.  
 

Study protocol PENELOPE CRTL control group PENELOPE study 
Version number: 3.2, date January 25, 2023 
 CONFIDENTIAL 
11 of 16 
7. DATA COLLECTION  
The following data will be collected from the local electronic health record starting at admission up 
to 18 months: 
• 
Baseline characteristics including at least age at admission, index event, medical history and 
cardiovascular risk factors  
• 
Lipid lowering medication, including start and stop dates, (perceived) cause of interruption or 
intolerance, and dosage  
• 
Lipid panels: all available total cholesterol, LDL, HDL, and TG values will be collected 
• 
Clinical course, including death, myocardial infarction, stroke and (urgent) revascularisation 
and co-medication  
 
8. STUDY OUTCOMES 
a. PRIMARY STUDY OUTCOME 
The primary outcome is defined as the cumulative incidence of patients reaching the LDL-C target 
level (≤ 1.8 mmol/L) after admission for a type I (N)STEMI with oral lipid lowering medication only, 
compared to the designated PENELOPE cohort.  
Further details on handling of missing or out of window values collected form regular care will be 
detailed in the endpoint charter, used for endpoint adjudication.  
After analysis of the PENELOPE CTRL data the CTRL cohort will be compared to the original PENELOPE 
cohort.  
b. SECONDARY STUDY OUTCOMES 
a) Mean time of reaching the primary outcome, compared to the designated PENELOPE cohort.  
b) Cumulative incidence of patients reaching the LDL-C target level (≤ 1.8 mmol/L) within 90 days 
after admission for a type I (N)STEMI with oral lipid lowering medication only. This outcome will 
be estimated with two analysis:  
▪ 
only including patients reaching (at least once) LDL-C target within 90 days (without using 
LDL-C measurements after this window) and  
▪ 
additionally including the first available LDL-C measurement (at least 14 days) after the 
last modification in oral lipid lowering therapy within 90 days after baseline (even if this 
measurement is after 90 days). This way CTRL mimics the original PENELOPE dataset, 
where LDL measurement 4-6 weeks after a drug regimen change was mandatory to 
establish the treatment effect, and this measurement also includes the effect of the last 
drug regimen change within 90 days. 

Study protocol PENELOPE CRTL control group PENELOPE study 
Version number: 3.2, date January 25, 2023 
 CONFIDENTIAL 
12 of 16 
c) Cumulative incidence of patients reaching other LDL-C target levels (e.g. ≤ 1.4 mmol/L 
and 50% LDL-C reduction compared to baseline) and mean LDL-C levels with only oral 
medication after admission for a type I (N)STEMI, compared to the designated PENELOPE 
cohort.  
d) Cumulative incidence of reaching LDL-C target levels (≤ 1.8 mmol/L, ≤ 1.4 mmol/L and 
50% LDL-C reduction) compared to baseline) and mean LDL-C levels with any lipid 
lowering drugs (so including the effects of PCSK9i), compared to the designated 
PENELOPE cohort.  
e) Cumulative incidence of patients reaching LDL-C target levels with only (i) high-intensive 
statin (compared to cum. effect after STEP 1 in PENELOPE) or (ii) high-intensive statin 
and/or ezetimibe (compared to cum. effect after STEP 2 in PENELOPE).  
 
c. STUDY PROCEDURES 
As PENELOPE-Control is a retrospective cohort registration there are no study procedures. 
d. Randomisation, blinding and treatment allocation 
Not applicable. 
e. Withdrawal of individual subjects 
Not applicable. 
f. Premature termination of the study 
Not applicable. 
 
 

Study protocol PENELOPE CRTL control group PENELOPE study 
Version number: 3.2, date January 25, 2023 
 CONFIDENTIAL 
13 of 16 
9.  DATA SAFETY MONITORING BOARD 
Not applicable. 
 
10. STATISTICAL ANALYSIS 
The primary analysis consists of a comparison of outcomes between de PENELOPE CTRL and the 
original PENELOPE intention to treat population. Baseline characteristics of the cohorts will be 
presented. To assess for potential remaining imbalances between the cohorts a t-test and Chi-
squared test will be used for continuous and dichotomous variables, respectively. 
In case of imbalance in patient characteristics between the cohorts, a step-wise approach will be 
used to correct for this.  
• 
First, a propensity score is derived to asses for membership of trial. Second, a propensity 
score is derived on the baseline criteria.  
• 
If the distribution of the propensity scores is dissimilar between PENELOPE CTRL and 
PENELOPE adjustment for differences in propensity function is done in two methods.  
o First, logistic regression analysis with propensity score as co-variate.  
o Second, stratified analysis with deciles of the propensity score.  
Percentages are converted to Odds Ratio to allow for multivariable analysis. Missing values are 
reported and appropriately imputed in the statistical models. 
Statistical analysis will be formalised in the SAP, as well as the statistical methods to be used for 
endpoint analysis. For comparison between the PENELOPE and PENELOPE CTRL cohort, the same 
additional exclusion criteria were applied: ‘known intolerance for alirocumab’ and ‘active PCSK9-I 
therapy at baseline’. Life expectancy <1 year was omitted as this could not be determined reliably 
from the medical records retrospectively. For the primary outcome and secondary outcomes b, c and 
e (investigating the effects of oral LLT), patients will be excluded as soon as they start using PCSK9i. 
 
11. SAFETY REPORTING 
PENELOPE CTRL is a retrospective Registry cohort, collecting data from routine clinical care. 
Therefore safety reporting to IRB or RA is not applicable, and is the responsibility of the caregiver as 
part of routine clinical care. 
 
12. ETHICAL CONSIDERATIONS 
a. Regulation statement 
In the Netherlands, there is no regulation for non-interventional studies like the Medical Research 
Involving Human Subjects Act (WMO) for interventional studies. In the absence of a regulation, a 

Study protocol PENELOPE CRTL control group PENELOPE study 
Version number: 3.2, date January 25, 2023 
 CONFIDENTIAL 
14 of 16 
framework of standards (Normenkader) has been put in place to ensure non-interventional studies 
are properly conducted. These standards aim to provide a framework for those who initiate the 
study, for those who assess the legitimacy of the study and those who conduct the study. PENELOPE-
CRTL will be conducted in accordance with these standards. PENELOPE- CTRL will be used as a control 
cohort for PENELOPE. PENELOPE is evaluated as a “WMO-obligated” protocol, requiring informed 
consent. PENELOPE-CTRL is submitted in the DCRF route as a pharma funded investigator initiated 
nWMO cohort, and evaluated by the MEC-U who also was the central ethic committee for 
PENELOPE. 
b. Recruitment and consent 
Retrospective data will be used in this analysis and therefore recruitment and consent are not 
applicable. Informed Consent has been waived by the MEC_U under the condition that all 
participating centres have a local opt-out for use of data on the website. This will be documented in 
the Green Light process before start of data collection. 
c. Benefits and risks assessment, group relatedness 
Not applicable. 
d. Compensation for injury 
Not applicable. 
 
13. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
e. Handling and storage of data and documents 
The principal investigator of a study centre is responsible for data capture in CASTOR (eCRF), in which 
they have access to data of their centre only through personalised accounts. All data are captured in 
a coded manner, using fake initials and only age at admission, to avoid identification. The key that 
links patient study ID to EMR records is kept within the hospital by the investigator and his team.  
After data base lock, the PI will receive a digital copy of the data entered for his site.  All details 
related to data recording, data handling and data review will be documented in a Data Management 
Plan. 
The principal investigator has the option to outsource the data entry to a centralised person assigned 
by WCN, if preferred. This professional is kept by professional secrecy and will receive a named 
account for restricted EMR access.   
Study documentation will be kept for 15 years after study closure. 
 

Study protocol PENELOPE CRTL control group PENELOPE study 
Version number: 3.2, date January 25, 2023 
 CONFIDENTIAL 
15 of 16 
f. Monitoring and Quality Assurance  
There will be no monitoring in this retrospective data analysis. 
All WCN sites are well trained, have a valid ICH-GCP certificate and use WCN site SOP’s. 
A Clinical Study Report (CSR) will be sent to all study centres within 10 months following the study’s 
final data transfer. 
 
g. Amendments  
Amendments are changes made to the research after a favourable advice from the nWMO advisory 
committee has been obtained.  All amendments to this protocol will be notified to the nWMO 
advisory committee.  
 
h. Annual Progress Report 
Not applicable. 
 
i. 
Temporary halt and (prematurely) End of Study Report 
Not applicable. 
 
j. 
Public disclosure and publication policy 
Results of this study will be published in a peer reviewed medical journal and can be used in future 
discussions with the Dutch Health Authorities and the Health Insurance Companies. 
 

Study protocol PENELOPE CRTL control group PENELOPE study 
Version number: 3.2, date January 25, 2023 
 CONFIDENTIAL 
16 of 16 
14. REFERENCES 
 
1. 
Baigent C, Keech A, Kearney P M, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, 
Collins R, Simes R, Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of 
cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants 
in 14 randomised trials of statins. Lancet. 2005;366:1267-1278. 
2. 
Piepoli, M.F., et al., 2016 European Guidelines on cardiovascular disease prevention in 
clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other 
Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by 
representatives of 10 societies and by invited experts)Developed with the special contribution 
of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur 
Heart J, 2016. 37(29): p. 2315-81. 
3. 
Landmesser, U., et al., 2017 Update of ESC/EAS Task Force on practical clinical guidance for 
proprotein convertase subtilisin/kexin type 9 inhibition in patients with atherosclerotic 
cardiovascular disease or in familial hypercholesterolaemia. Eur Heart J, 2018. 39(14): p. 
1131-1143. 
4. 
Mach, F., et al, 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid 
modification to reduce cardiovascular risk. Eur Heart J 2020;41:111-188 
5. 
J W Balder, S Scholtens, J K de Vries, L M van Schie, S M Boekholdt, G K Hovingh, 
https://pubmed.ncbi.nlm.nih.gov/?term=Kamphuisen+PW&cauthor_id=26314714 , J A 
Kuivenhoven. Adherence to guidelines to prevent cardiovascular diseases: The LifeLines 
cohort study. Neth J Med 2015;73(7):316-23 
6. 
De Backer G, et al. Management of dyslipidaemia in patients with coronary heart disease: 
Results from the ESC-EORP EUROASPIRE V survey in 27 countries. Atherosclerosis. 2019 
Jun;285:135-146 
7. 
Allahyari A, Jernberg T, Lautsch D, Lundman P, Hagstrom E, Schubert J, et al. LDL-cholesterol 
target attainment according to the 2011 and 2016 ESC/EAS dyslipidaemia guidelines in 
patients with a recent myocardial infarction—nationwide cohort study, 2013–2017. Eur 
Heart J Qual Care Clin Outcomes. 2020 doi: 10.1093/ehjqcco/qcaa016. 
8. 
KK Ray, et al. EU-Wide Cross-Sectional Observational Study of Lipid-Modifying Therapy Use in 
Secondary and Primary Care: the DA VINCI study. Eur J Prev Cardiol. 2021 Sep 
20;28(11):1279-1289. doi: 10.1093/eurjpc/zwaa047.