Empowering Patients to Improve Safety in Polymedication (EmPaSafe)
Phase: NA
Conditions: Polypharmacy
Sponsor: Leiden University Medical Center

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PROTOCOL TITLE ‘Empowering patients to Improve Safety in Polymedication’
Protocol ID 
NL87027.058.24 
Short title 
Empowering 
patients 
to 
Improve 
Safety 
in 
Polymedication (EmPaSafe) 
EudraCT number 
N/A 
Version 
6 
Date
January 22nd, 2025 
Coordinating investigator/project 
leader
Jesse J. Swen, PharmD, PhD 
Professor of Clinical Pharmacy & Pharmacogenetics 
Dept. Clinical Pharmacy & Toxicology 
Leiden University Medical Centre 
P.O. Box 9600 
NL 2300 RC Leiden 
The Netherlands 
Tel.: +31 (0)71 526 2790 
E-mail: J.J.Swen@lumc.nl
Principal investigator(s) (in 
Dutch: hoofdonderzoeker/ 
uitvoerder) 
Leiden University Medical Centre 
(LUMC): 
University of Patras (UPAT): 
University of Ljubljana (UL): 
RWTH Aachen (UKA): 
(See Appendix 1 for contact information) 
Prof. Jesse J. Swen, PharmD PhD 
Prof. George P. Patrinos PhD 
Prof. Vita Dolzan, MD PhD  
Prof. Julia Stingl, MD 
Sponsor 
(in 
Dutch: 
verrichter/opdrachtgever)
Leiden University Medical Centre 
Subsidising party 
European 
Union 
(EU), 
HORIZON-HLTH-2021-
CARE-05, 101057639 
Independent expert (s) 
Prof. Teun van Gelder, MD PhD 
Professor of Clinical Pharmacology 
Phone: (+31) 71 526 2790 
E-mail: t.van_gelder1@lumc.nl
Prof. Blanka Kores Plesničar, MD PhD 
Medical 
Director, 
University 
Psychiatry 
Clinic 
Ljubljana  
Phone: +386 1 5872 467 
E-mail: blanka.kores@psih-klinika.si
Prof. Nikos Stefanis 
Professor of Psychiatry 
Phone: +30-210-72 89 40 
E-mail: nistefan@med.uoa.gr

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Tim Krüger, MD PhD 
Phone: +49 241 80-89134 
E-mail: tikrueger@ukaachen.de  
 
Laboratory sites  
Leiden University Medical Centre, Department of 
Clinical Pharmacy and Toxicology, Albinusdreef 2, 
2333 ZA Leiden, The Netherlands 
Saarland University, Clinical Pharmacy, Campus, 
Building C2 2, 66123 Saarbrücken 
Faculty of Medicine, Vrazov trg 2, 1000 Ljubljana 
Universitätsklinikum Aachen, AöR, Pauwelsstraße 
30, D-52074 Aachen, Germany 
Patras University, Πανεπιστημιούπολη Πατρών 265 
04, Greece 
Pharmacy 
Not applicable 

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PROTOCOL SIGNATURE SHEET
Name
Signaturef
Date
Head of Department:
Henk-Jan Guchelaar, PharmD, PhD
Professor of Clinical pharmacy
Principal Investigator:
Jesse J. Swen, PharmD, PhD
Professor of Clinical Pharmacy &
Pharmacogenetics
w
Version number: 4, September 23'''’, 2024
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TABLE OF CONTENTS 
1. 
INTRODUCTION AND RATIONALE ............................................................................... 11 
2. 
OBJECTIVES .................................................................................................................. 12 
2.1 
Primary objective ..................................................................................................... 12 
2.2 
Secondary objective ................................................................................................. 12 
3. 
STUDY DESIGN ............................................................................................................. 13 
3.1 
Overall study design ................................................................................................ 13 
3.2 
Patient journey ......................................................................................................... 16 
3.3 
Data collection procedures ...................................................................................... 17 
4. 
STUDY POPULATION .................................................................................................... 19 
4.1 
Population (base) ..................................................................................................... 19 
4.2 
Inclusion criteria ....................................................................................................... 19 
4.3 
Exclusion criteria ...................................................................................................... 20 
4.4 
Sample size calculation ........................................................................................... 20 
5. 
TREATMENT OF SUBJECTS ........................................................................................ 21 
5.1 
Investigational strategy ............................................................................................ 21 
5.1.1 
The medication management centre ................................................................ 21 
5.1.2 
Questionnaires .................................................................................................. 22 
6. 
INVESTIGATIONAL PRODUCT ..................................................................................... 23 
6.1 
Name and description of investigational product(s) ................................................. 23 
6.2 
Summary of findings from non-clinical studies ......................................................... 23 
6.3 
Summary of findings from clinical studies ................................................................ 23 
6.4 
Summary of known and potential risks and benefits ................................................ 23 
6.5 
Description and justification of route of administration and dosage ......................... 23 
6.6 
Dosages, dosage modifications and method of administration ................................ 23 
6.7 
Preparation and labelling of Investigational Medicinal Product ................................ 23 
6.8 
Drug accountability .................................................................................................. 23 
7. 
NON-INVESTIGATIONAL PRODUCT ............................................................................ 24 
7.1 
Name and description of non-investigational product(s) .......................................... 24 
7.2 
Summary of findings from non-clinical studies ......................................................... 24 
7.3 
Summary of findings from clinical studies ................................................................ 24 

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7.4 
Summary of known and potential risks and benefits ................................................ 24 
7.5 
Description and justification of route of administration and dosage ......................... 24 
7.6 
Dosages, dosage modifications and method of administration ................................ 24 
7.7 
Preparation and labelling of Non-Investigational Medicinal Product ........................ 24 
7.8 
Drug accountability .................................................................................................. 24 
8. 
METHODS ...................................................................................................................... 25 
8.1 
Study parameters/endpoints .................................................................................... 25 
8.1.1 
Main study parameter/endpoint ........................................................................ 25 
8.1.2 
Secondary study parameters/endpoints (if applicable) ..................................... 27 
8.2 
Randomisation, blinding and treatment allocation ................................................... 27 
8.3 
Study procedures ..................................................................................................... 27 
8.4 
Withdrawal of individual subjects ............................................................................. 28 
8.4.1 
Specific criteria for withdrawal (if applicable) .................................................... 28 
8.5 
Replacement of individual subjects after withdrawal ............................................... 28 
8.6 
Follow-up of subjects withdrawn from treatment ...................................................... 28 
8.7 
Premature termination of the study .......................................................................... 28 
9. 
SAFETY REPORTING .................................................................................................... 30 
9.1 
Temporary halt for reasons of subject safety ........................................................... 30 
9.2 
AEs and SAEs ......................................................................................................... 30 
9.2.1 
Adverse events (AEs) ....................................................................................... 30 
9.2.2 
Serious adverse events (SAEs) ........................................................................ 30 
9.3 
Follow-up of adverse events .................................................................................... 31 
9.4 
Data Safety Monitoring Board (DSMB) / Safety Committee .................................... 31 
10. STATISTICAL ANALYSIS ............................................................................................... 32 
10.1 
Primary study parameter(s) ..................................................................................... 32 
10.2 
Secondary study parameter(s) ................................................................................. 32 
11. ETHICAL CONSIDERATIONS ........................................................................................ 33 
11.1 
Regulation statement ............................................................................................... 33 
11.2 
Recruitment and consent ......................................................................................... 33 
11.3 
Benefits and risks assessment, group relatedness .................................................. 33 

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11.4 
Compensation for injury ........................................................................................... 34 
11.5 
Incentives ................................................................................................................. 34 
12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION ............................. 35 
12.1 
Handling and storage of data and documents ......................................................... 35 
12.2 
Monitoring and Quality Assurance ........................................................................... 35 
12.3 
Amendments ............................................................................................................ 35 
12.4 
Annual progress report ............................................................................................ 36 
12.5 
Temporary halt and (prematurely) end of study report ............................................ 36 
12.6 
Public disclosure and publication policy ................................................................... 36 
12.7 
Funding statement ................................................................................................... 36 
13. STRUCTURED RISK ANALYSIS ................................................................................... 37 
13.1 
Potential issues of concern ...................................................................................... 37 
14. REFERENCES ................................................................................................................ 38 
15. Appendices ..................................................................................................................... 39 
15.1 
Appendix 1: Contact information .............................................................................. 39 
15.1 
Appendix 2: MDR/IVDR exemption .......................................................................... 40 
15.2 
Appendix 3: Gene and variant panel ........................................................................ 41 
15.3 
Appendix 4: Index drugs .......................................................................................... 43 
15.4 
Appendix 5: Scientific Advisory Board ..................................................................... 44 
 
 
 
 
 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ABR 
General Assessment and Registration form (ABR form), the application form 
that is required for submission to the accredited Ethics Committee; in Dutch: 
Algemeen Beoordelings- en Registratieformulier (ABR-formulier) 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AI 
Artificial Intelligence 
CCMO 
Central Committee on Research Involving Human Subjects, in Dutch: 
Centrale Commissie Mensgebonden Onderzoek 
CV 
Curriculum Vitae 
DDGI 
Drug-drug-gene interaction 
DDI 
Drug-Drug Interactions 
DNA 
Deoxyribonucleic Acid 
DPWG 
Dutch Pharmacogenomics Working Group 
eCRF 
Electronic Case Report Form 
EU 
European Union 
FAIR 
Findable, Accessible, Interoperable, Reusable 
GDPR 
General Data Protection Regulation; in Dutch: Algemene Verordening 
Gegevensbescherming (AVG) 
HC 
Healthcare 
ICH-GCP 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Guideline for Good Clinical Practice 
(GCP)  
LUMC 
Leiden University Medical Centre 
MAF 
Minor Allele Frequency 
METC LDD 
Medical Research ethics committee (MREC); in Dutch: Medisch-Ethische 
Toetsingscommissie (METC). LDD: Leiden, Den Haag, Delft 
MMC 
Medication Management Centre 
MP 
Data Management Plan 
PGx 
Pharmacogenomics 
PoC 
Proof Of Concept 
PRO-CTCAE 
Patient-Reported Outcomes version of the Common Terminology Criteria for 
Adverse Events 
PROMs 
Patient-Reported Outcome Measures 
SAE 
Serious Adverse Event 
SNP 
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SOP 
Standard Operating Procedure 
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. 
UAVG 
Dutch Act on Implementation of the General Data Protection Regulation; in 
Dutch: Uitvoeringswet AVG 
UKA 
University Hospital Aachen 
UL 
University of Ljubljana 
UPAT 
University of Patras 
U-PGx 
Ubiquitous Pharmacogenomics 
UUID 
Universal Unique Identifier 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 
 
 

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SUMMARY 
Rationale: In current clinical practice, polypharmacy and patient empowerment are critical yet 
often overlooked. Polypharmacy, the chronic use of five or more drugs, poses risks such as 
adverse drug reactions and decreased medication adherence, especially in elderly and multi-
morbid patients. Despite the interconnected nature of drug-drug and drug-gene pro interac-
tions, they are considered separately. Ignoring these interactions can be hazardous, yet clinical 
trials to investigate them are infeasible due to fast-growing complexity, variability among pa-
tients, high costs associated with large-scale studies, and ethical and logistical challenges. 
Consequently, there is a substantial knowledge gap in managing complex medication regi-
mens in real-life scenarios and providing guidelines to enhance patient empowerment and drug 
safety. The SafePolyMed project aims to develop a patient-centred framework to define, as-
sess and manage drug-drug, drug-gene and drug-drug-gene interactions. This framework, a 
web-based medication management centre, will support patients in managing their therapy-
related health data, enhancing education and empowerment, and improving patient safety.  
 
Objective: To assess the impact of the developed medication management centre on patient 
empowerment in polypharmacy patients, thereby improving drug safety. Secondary objectives 
are to explore if the tool is able to identify patients at risk for a drug-drug-gene interaction and 
lower the adverse drug event rate.  
 
Study design: The study is a proof of concept study conducted at four institutes located in 
Germany, Greece, Slovenia and The Netherlands. Polypharmacy patients will use the medi-
cation management centre (MMC), which provides curated, patient-specific information about 
drug interactions and PGx. To assess patient empowerment, patients will receive question-
naires during a 12 week follow-up period.  
 
Study population: 120 subjects with polypharmacy (defined as the chronic use of 5 or more 
drugs) of at least 18 years of age, with a first prescription for one of 10 index drugs. The study 
will be performed at 4 different sites (Leiden (NL), Patras (GR), Ljubljana (SL), Aachen (DE)) 
to represent different clinical settings across Europe. Each site will recruit 30 patients. 
 
 

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Intervention: The MMC that provides patient centred information on drug-drug interactions 
and pharmacogenetics affecting personal polytherapy. The MMC will show a selection of high 
quality publicly available information such as details on different types of medications, including 
their uses, side effects and instructions for use, in the language of the patient. This information 
is targeted at an individual patient’s medication profile to inform patients to better understand 
and deal with their personal health information, with regard to drug therapy. Patients in the 
Netherlands, Slovenia and Greece also will receive their PGx profile to further personalise the 
MMC experience. 
 
Main study parameters/endpoints: The primary outcome is the sense of empowerment and 
health literacy for participants before and after use of the MMC. Secondary outcomes include 
an evaluation of the drug-drug-gene interactions and adverse drug events in the study popu-
lations compared to matched historical controls. 
 
Nature and extent of the burden and risks associated with participation, benefit, and 
group relatedness: Patients are exposed to the regular treatment. In addition, patients will 
receive questionnaires at baseline, two, and twelve weeks regarding the use and experience 
of the medication management centre, and a close-out interview at week twelve. In addition, 
10ml of blood will be collected during a venipuncture for pharmacogenetic analyses. 
 
Benefits include having access to the medication management centre for the duration of the 
study. Additionally, patients will receive their PGx profile. This can be used to individualize drug 
treatment, based on the Dutch Pharmacogenetics Working Group (DPWG) guidelines.  
 
Overall, minimal risks are expected for subjects as they will receive normal clinical care. Infor-
mation from the MMC will be a curation of existing publicly available data. Any information 
regarding DDIs and DGIs will be supplemented with a disclaimer that the patient should not 
adjust their treatment without talking to a healthcare provider.  
 
 

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1. INTRODUCTION AND RATIONALE 
Adverse drug reactions (ADRs) are a major burden to our healthcare (HC) and economic sys-
tems. In the European Union (EU) alone, approximately 197,000 deaths annually are attributed 
to ADRs.(1) Polypharmacy, multimorbidity and genetic heterogeneity can affect drug efficacy, 
raise the risk for ADRs and consequently increase healthcare costs. This issue is exacerbated 
by the growing prevalence of polypharmacy (the chronic use of five or more medications con-
comitantly) which affects 26 to 40% of elderly European citizens.(2) 
Public education on drug intake, polypharmacy, and individual medication risks remains insuf-
ficient. This contributes to weakened patient security, poor medical adherence, and suboptimal 
therapy outcomes.(3; 4) Elderly individuals, polymedicated patients, and those with multiple 
chronic conditions often face challenges in managing their health, potentially leading to in-
creased healthcare needs. Systematic documentation of health status using patient-reported 
outcome measures (PROMs) is crucial for early identification of ADR-related issues and en-
hancing communication between patients and healthcare providers. A comprehensive ap-
proach involving patient education and active participation in documenting therapy-related 
health status can empower patients, improve treatment outcomes, and reduce ADRs.(5; 6) 
The SafePolyMed project aims to develop a patient-oriented framework for defining, as-
sessing, and managing drug-gene product interactions (DGIs) and drug-drug interactions 
(DDIs). This framework will support patients in managing their therapy-related health data, 
improving education, patient empowerment, and patient safety. Tools for PROM management, 
DDI information, and DGI information will be integrated into a web-based Medication Manage-
ment Centre (MMC). This tool will help patients manage and monitor their therapies, educate 
them about their therapy, thereby empowering the patients by creating a sense of participation 
in the decision process when it comes to the management of their diseases. The information 
in this tool is curated publicly available information. Moreover, novel tools that uses machine 
learning and mechanistic modelling techniques using relevant real-world datasets to assess 
patients at risk for ADRs have been developed but are not yet clinically validated. These tools 
can be integrated into the MMC to show interconnectability but are not yet validated and there-
fore not reported to patients or used for drug management, this is a separate part of the over-
arching SafePolyMed consortium. Additionally, the MMC will be used to collect patient-re-
ported outcomes. 
 
To assess the impact of the developed medication management centre on patient empower-
ment in polypharmacy patients to improve drug safety, we will execute a transnational proof-
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2. OBJECTIVES 
2.1 Primary objective 
The primary objective is to assess the impact of the developed medication management centre 
on the patient empowerment of polypharmacy patients, thereby improving drug safety. 
 
2.2 Secondary objective 
To investigate if the medication management centre is able to identify patients at risk for a 
drug-drug-gene interaction. Moreover, it will be investigated whether integrating the MMC into 
healthcare will lower the adverse drug event rate compared with matched historical control.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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3. STUDY DESIGN 
3.1 Overall study design 
This study is a multi-centre, open-label study to assess the impact of the developed MMC in 
combination with the developed risk score algorithms, patient-reported outcome tool, and 
model-based precision dosing tool on patient empowerment of polypharmacy patients, thereby 
improving drug safety. In the study, a total of 120 patients will be enrolled in The Netherlands, 
Greece, Slovenia, and Germany (30 patients per country). The study subjects will be followed 
for 12 weeks. At set time intervals (2 and 12 weeks) the subjects will be asked to complete a 
validated questionnaire through the eClinical Data Management Platform Castor (table 1), for 
which the patients receive an email and a reminder through the MMC. These questionnaires 
collect information on the experience with the MMC, clinical monitoring, clinical outcome, and 
adverse events.  
Table 1. Overview of the questionnaires during the 12-week follow-up. The baseline questionnaire com-
prises of 97 questions, the 2-week questionnaire of 133 questions and the 12-week questionnaire of 
206 questions. All questionnaires are adaptive. 
 
 
Baseline 
questionnaire 
Adaptive questionnaire in the MMC at 
time point: 
2 weeks 
12 weeks 
Experience 
Usability 
 
x 
x 
Health literacy 
x 
 
x 
Clinical monitoring 
Comorbidities and allergies 
x 
 
 
Concurrent medication and herbal 
remedies (through patient diary) 
x 
x 
x 
Clinical outcome 
Drug adherence 
x 
x 
x 
Quality of Life 
x 
 
x 
Adverse events 
Patient reported ADR 
 
x 
x 
Assessment of ADR severity 
 
x 
x 
Pharmacogenomics 
 
 
 
DNA sample collection 
x 
 
 
 
 

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The baseline questionnaire will additionally comprise questions covering in- and exclusion cri-
teria, demographics, recruitment information, previous PGx test results, comorbidities and al-
lergies, and the level of health literacy before use of the MMC. In total, the baseline question-
naire consists of 97 questions. The questionnaire offered two weeks after inclusion in the study 
consists of 133 questions. The last questionnaire, offered 12 weeks after inclusion in the study, 
consist of 206 questions. All questionnaires are adaptive meaning that the length and duration 
of the questionnaire depends on the answers of the participants. 
Effectiveness in the prevention of ADRs and the ability to identify drug-drug-gene interactions 
will be explored as a secondary endpoint by comparing results of the pilot study with those 
obtained from matched historical controls obtained from the control arm of the U-PGx project. 
This control arm is suitable as historical control group for the EmPaSafe study because of its 
alignment in key aspects, allowing for meaningful comparisons: 
- Genotyped but not empowered with PGx Data: Participants in the U-PGx control arm were 
genotyped retrospectively, meaning their PGx information was available but not actively 
utilized in their care. This setup provides a unique baseline to assess the effectiveness of 
the MMC and the empowerment of EmPaSafe patients with PGx data, as we can analyse 
whether access to their genetic information and medication adjustments reduces ADRs and 
improves drug efficacy. 
- Comparable Follow-up and Monitoring Protocols: The U-PGx control arm and the EmPaS-
afe study share similar follow-up methods, including regular monitoring for ADRs and the 
use of similar questionnaires. This similarity minimizes variation in data collection pro-
cesses, allowing us to more directly compare ADR prevalence and other outcomes between 
the two groups. 
- Matching for Key Variables: The control group will be matched to EmPaSafe participants 
based on age, sex, and type and number of medications, controlling for these variables in 
the analysis. This matching enhances the comparability of the two cohorts and strengthens 
the reliability of conclusions drawn about the impact of empowering patients with PGx data 
through the MMC. 
Using the U-PGx control arm as a historical comparison thus allows EmPaSafe to evaluate the 
added value of PGx-informed care without needing a concurrent control group, streamlining 
the study while leveraging pre-existing data to explore the MMC’s role in improving medication 
safety and personalization.  
 
 

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The EmPaSafe study design is depicted in figure 1.  
Figure 1. Design of the EmPaSafe study. 
 
 
Of note: UKA does not have the ability to genotype and will also not be able to report PGx 
results in a clinical setting and act upon it due to the German regulations. Due to the Arzneimit-
telgesetz, which consists of strict regulations for clinical research that deal with drug effects 
(e.g., safety, efficacy, and pharmacokinetics), and the Gendiagnostikgesetz, which are regu-
lations concerning pharmacogenetic diagnostics, it is not allowed to study actionable variants 
that are not in use in German clinical practice. However, the inclusion of data from the German 
site offers critical insights that enhance the robustness and applicability of the EmPaSafe study 
results. Although regulatory restrictions in Germany limit the use of PGx results to cases with 
specific medical indications, the observations gathered from the German cohort remain highly 
valuable for the study, contributing to broader objectives beyond PGx data alone. Below are 
three primary ways in which including the German population will provide valuable information 
to the EmPaSafe study: 
- 
Comparability with the Target Population: The German cohort primarily consists of elderly, 
polymedicated patients—a group closely resembling the primary target population of the 
EmPaSafe study. These patients typically have complex medication regimens and could 
greatly benefit from improved medication safety and personalized care. By including data 
from this population, we enhance the comparability of findings across the study’s interna-
tional sites, including those in the Netherlands, Slovenia, and Greece, allowing us to eval-
uate the consistency of our results across diverse patient populations and contexts. 
- 
Insights into Patient Empowerment and Health Literacy: The purpose of the MMC within 
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empowerment and health literacy in medication management. Although PGx data usage 
is limited in Germany, the MMC still enables us to gather valuable information on how the 
tool impacts patients’ understanding of, and engagement with, their medication. This is 
particularly useful to assess the broader functionality of the MMC as a patient-support 
resource, providing insights into its effectiveness in enhancing patient empowerment and 
health literacy independent of PGx information. 
- 
Enhanced Generalizability of Findings: By collecting data from Germany, a region with 
distinct legal, healthcare, and cultural contexts, we improve the generalizability of our 
study’s results. This allows us to analyse whether the MMC’s effectiveness in promoting 
patient empowerment and health literacy is consistent across different healthcare systems 
and regulatory frameworks. Such insights are essential for evaluating the potential ap-
plicability of the MMC in other European countries, especially those with similar regulatory 
constraints on PGx data usage. 
In summary, the German site provides valuable data that extends beyond PGx-specific analy-
sis. The inclusion of this site enables a comprehensive evaluation of the MMC’s impact on 
patient empowerment, health literacy, and the general functionality of the tool across different 
European healthcare settings. This international perspective is essential for understanding the 
potential for broader implementation of EmPaSafe within Europe. 
3.2 Patient journey 
The patient journey starts when the patient receives a first prescription for one of the index 
drugs (see table 3). Upon enrolment, patients get access to the MMC. The day of the first 
prescription is considered T=0. 
• 
Medication Management Centre 
The MMC will offer patients curated, personalised information regarding DDIs and DDGIs and 
a patient diary to manage and monitor their drug therapy. Additionally, the MMC will remind 
the patients by email to complete a questionnaire through the eClinical Data Management 
Platform Castor These questionnaires collect information on the experience with the MMC, 
clinical monitoring, clinical outcome, and adverse events, according to the schedule in table 2. 
Patients can report ADRs in the medication management centre through patient reported out-
come measures (PROMs) in the patient diary. More information regarding the MMC can be 
found in section 5.1.1. 
• 
PGx profile 
Additionally, the patients in The Netherlands, Greece and Slovenia will donate DNA by a blood 
sample by a venipuncture or through saliva, and will be genotyped within two weeks for our 
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will be communicated through the MMC. Patients will be stimulated to share these results with 
their healthcare providers. This approach is used due to the patient centred nature of our study 
and MMC approach. Physicians will not receive any specific additional results other than what 
the patients share with them.  
At the end of the 12-week study period, patients will have a semi-structured close out interview 
with the research nurses regarding the experience of the medication management centre. 
• 
Gene and variant selection 
The genes that will be tested are CYP2C19, CYP2C9, CYP2D6 and SLCO1B1 (see also Ap-
pendix 3). These all have actionable recommendations in the DPWG guidelines and are re-
lated to drugs frequently used in outpatients with polypharmacy. The selection of the genes is 
based on the drugs that were selected to be index drugs. Additionally, testing these genes is 
technically feasible and readily implemented in Leiden, Patras and Ljubljana. Updates in the 
guidelines of the DPWG will be taken into account during the project. 
The variants chosen to study align with those studied by the Ubiquitous Pharmacogenomics 
(U-PGx) consortium. See Appendix 3 for the full pharmacogene and variant panel. 
• 
Genotyping 
The method used to genotype the variants is up to the recruiting sites themselves. They must 
meet the following criteria: 1) test for the updated variant panel and 2) participate in proficiency 
testing programme to ensure quality of genotyping.  
3.3 Data collection procedures 
T=0 is defined as the day the patient initiates the index drug (table 3). During the 12-week 
follow-up period, the patients will receive surveys at baseline, 2 weeks and 12 weeks and a 
semi-structured close-out interview at week 12. Patients are requested to complete the surveys 
within a week. In case a patient discontinues the index drug within the 12-week follow-up pe-
riod, the follow-up will continue as initially anticipated. The questionnaires will be provided to 
the patients through the medication management centre.  
The data collected by the surveys is summarized in table 2. The MMC will collect: 1) Data 
entered by patients: demographic information, medical information, symptom diary, 2) Data 
created by the MMC and its tools: medication plan assessed with its safety risks (DDIs, DGIs, 
risk score, dosing information) and 3) statistical information collected by the system about the 
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All data will be entered into an electronic Case Report Form (eCRF), which guarantees con-
sistency of data collection procedures. Data will be used exclusively in a pseudonymous fash-
ion and data protection will be guaranteed according to international regulations. Local, inde-
pendent internal monitors will guarantee data integrity and data homogeneity across all four 
implementation countries by risk-based monitoring of a random sample of the collected data. 
The research team will collect and store patient contact information (e-mail address, telephone 
number, name, and study-ID number) in a separate, local file (national subject identification 
code list). 
 
 
 

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4. STUDY POPULATION 
4.1 Population (base) 
Polypharmacy patients of any ethnicity, which are over 18 years of age and within routine care 
receiving a first prescription for one of the index drugs (see table 3), are eligible to participate 
in the study. The participating centres will focus on, but are not limited to, recruiting within a 
specific therapeutic area that cover both in- and outpatient settings (see table 2). This diverse 
population is a reflection of the general polypharmacy population which allows us to assess 
the use of the MMC in this diverse and heterogenous group of patients.  
Table 2. Centres participating to the study, with corresponding recruitment of patients. The centres are 
not limited to recruiting patients within these specific therapeutic areas and can also include patients 
outside them. 
Site 
Therapeutic focus for treatment 
Number of patients in-
cluded in total 
Country/  
Language 
LUMC 
Leiden University Medical Centre will in-
volve community pharmacies in Leiden to 
recruit patients. 
30 
The Netherlands/ 
Dutch 
UPAT 
Psychiatric patients will be recruited from 
the psychiatric clinic of the General Uni-
versity Hospital of Patras. 
30 
Greece/ 
Greek 
UL 
Primary care patients will be recruited 
from three primary health care centres 
(Community Health Centre Ljubljana, 
Family Medicine Clinic KUS and Health 
Institute Zdravje) 
30 
Slovenia/ 
Slovenian 
UKA 
Polypharmacy patients from different 
fields of medicine, above 60 years of age 
will be recruited in UKA’s outpatient unit 
for clinical pharmacology. 
30 
Germany/ 
German 
Total for study 
 
120 
 
  
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following criteria:  
• 
Polypharmacy defined as the use of 5 or more drugs 
• 
Start usage of at least one index drug according to the list in table 3. See Appendix 4. 
• 
Subject must be ≥ 18 years old 
• 
Subject is able and willing to take part and be followed-up for at least 12 weeks 
• 
Subject is able to donate blood or saliva 
• 
Subject has signed informed consent 
 

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Table 3. List of index drugs eligible for inclusion, based on their presence in the U-PGx cohort. For all 
these drug-gene combinations, an actionable DPWG guideline is available. See also Appendix 4. 
Drug name 
Gene 
Amitriptyline 
CYP2D6 
Atorvastatin 
SLCO1B1 
Citalopram 
CYP2C19 
Codeine 
CYP2D6 
Escitalopram 
CYP2C19 
Paroxetine 
CYP2C9 
Sertraline 
CYP2C19 
Simvastatin 
SLCO1B1 
Tramadol 
CYP2D6 
Venlafaxine 
CYP2D6 
 
4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from participation 
in this study: 
• 
Pregnancy or lactating  
• 
Life expectancy estimated to be less than three months by treating clinical team  
• 
Unable to consent to the study 
• 
Unwilling to take part 
• 
Subject has no fixed address 
• 
Subject has previously been genotyped for PGx genes 
• 
Subject has no current general practitioner  
• 
Subject is, in the opinion of the Investigator, not suitable to participate in the study 
• 
Estimated glomerular filtration rate (MDRD) of less than 15 ml/min per 1,73m2  
• 
Patients with advanced liver failure (stage Child-Pugh C)  
 
4.4 Sample size calculation 
As this is a proof-of-concept (PoC) pilot study, the sample size is aimed at showing the impact 
of the use of the MMC on patient empowerment and exploring associations, rather than statis-
tically significant relations. Therefore, no formal sample size and power calculation is done. A 
number of 30 participants per site is the number of subjects that we estimate to be sufficient 
to investigate the impact of using the medication management centre and associated tools.  
To explore potential effectiveness of the tool, results will be compared with those of matched 
historical controls obtained from the control arm of the U-PGx project. While the study is not 
aimed at or powered for statistical comparisons, we are in the unique position to have a access 
to a substantial cohort of comparable patients. Controls will be matched for age, sex and type 
and number of mediations. These results will help to design a larger study to perform a formal 
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5. TREATMENT OF SUBJECTS 
5.1 Investigational strategy 
In this study, participants will be granted access to the MMC. This tool provides personalised 
patient-centred information on drug-drug interactions (DDIs) and PGx affecting polytherapy.  
 
5.1.1 The medication management centre 
All patients participating in the EmPaSafe study will gain access to the Medication Manage-
ment Center (MMC), a digital platform developed to empower patients with information and 
enhance medication safety, particularly in cases of polymedication. The MMC’s primary pur-
pose is to serve as an educational resource that provides tailored, patient-specific insights into 
drug-drug interactions (DDIs) and drug-drug-gene interactions (DDGIs) based on individual 
pharmacogenomic (PGx) profiles. These insights aim to support adherence to therapy, im-
prove patient outcomes, and mitigate risks associated with complex medication regimens. 
The MMC annotates each patient’s medication plan with curated safety information sourced 
from validated guidelines, including those from the Dutch Pharmacogenetics Working Group 
(DPWG), and trusted public databases such as the ABDA-Database. By offering personalized, 
high-quality content, the MMC helps patients understand their therapies and the potential risks 
associated with their medications. It also provides tools for reporting health concerns, such as 
adverse drug reactions (ADRs), through integrated patient-reported outcome measures 
(PROMs). 
A core feature of the MMC is its emphasis on patient engagement. The platform equips users 
with the knowledge to have meaningful discussions with healthcare providers, thereby foster-
ing collaborative decision-making. However, the MMC strictly serves an informational purpose; 
it neither facilitates self-adjustment of medication nor replaces professional medical advice. 
This distinction ensures compliance with regulatory requirements and underscores its role as 
an educational rather than a diagnostic tool. 
The MMC also includes advanced functionalities that may shape the future of personalized 
medicine. These include exploratory tools, such as machine learning models and mechanistic 
risk assessments, designed to analyse real-world data for predicting adverse drug reactions 
(ADRs). While these tools are not yet clinically validated, they represent the innovative poten-
tial of integrating cutting-edge technologies into medication management. 
By enabling patients to record their experiences in health diaries and providing access to cu-
rated, reliable information, the MMC empowers individuals to actively participate in their 
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with the broader goals of the SafePolyMed project: enhancing the safety and effectiveness of 
polytherapy through patient-centred innovation. 
It's important to note that all information provided by the MMC is publicly available and curated 
by the experts working on the SafePolyMed project. While the MMC and its tools serve to 
empower patients, they are not medical devices and do not replace professional medical ad-
vice or therapy adjustments. See also Appendix 2. 
5.1.2 Questionnaires 
The baseline questionnaire will comprise questions regarding demographics, in- and exclusion 
criteria, and comorbidities. Additionally, standardized questionnaires will be offered to the pa-
tients at 2 and 12 weeks after initiation of the index drug to obtain information about health 
behaviour, drug use, ADRs (PRO-CTCAE), quality of life (SF-36), MMC experience and health 
literacy (HLS-EU-Q47). The questionnaires are adaptive meaning that based on the provided 
answers only relevant follow-up questions will be asked to minimize the burden. Lastly, a semi-
structured close-out interview will be held at week 12 to gather information on the experience 
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6. INVESTIGATIONAL PRODUCT  
Not applicable 
6.1 Name and description of investigational product(s) 
Not applicable 
6.2 Summary of findings from non-clinical studies 
Not applicable 
6.3 Summary of findings from clinical studies 
Not applicable 
6.4 Summary of known and potential risks and benefits 
Not applicable 
6.5 Description and justification of route of administration and dosage 
Not applicable 
6.6 Dosages, dosage modifications and method of administration 
Not applicable 
6.7 Preparation and labelling of Investigational Medicinal Product 
Not applicable  
6.8 Drug accountability 
Not applicable 
 
 
 
 
 
 
 
 
 
 
 
 

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7. NON-INVESTIGATIONAL PRODUCT 
7.1 Name and description of non-investigational product(s) 
Not applicable. 
7.2 Summary of findings from non-clinical studies 
Not applicable.  
7.3 Summary of findings from clinical studies 
Not applicable.   
7.4 Summary of known and potential risks and benefits 
Not applicable.   
7.5 Description and justification of route of administration and dosage 
Not applicable.   
7.6 Dosages, dosage modifications and method of administration 
Not applicable.  
7.7 Preparation and labelling of Non-Investigational Medicinal Product 
Not applicable.  
7.8 Drug accountability 
Not applicable.   
 
 
 
 

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8. METHODS 
8.1 Study parameters/endpoints 
8.1.1 Main study parameter/endpoint 
Proof of principle-study focused on assessing the impact of the developed MMC on patient 
empowerment in polypharmacy patients in order to improve drug safety. The primary endpoint 
is the sense of empowerment and health literacy for participants before and after use of the 
MMC. The endpoint consists of: 
• 
Patient capacities, beliefs or resources including self-efficacy, sense of meaning and co-
herence about their condition, health literacy, perceived control and feeling respected by 
their healthcare providers. 
• 
Activities or behaviours (things patient do) e.g., participate in shared decision-making by 
taking an active role and making informed decisions about their health and healthcare, 
self-manage and monitor their condition by choosing meaningful and realistic goals and 
taking steps to achieve those goals, participate in collective activities such as patient sup-
port or advocacy groups, and search for information about their health condition e.g., on 
the internet.  
Literature shows that effective patient-provider communication, access to health information, 
a supportive healthcare environment and educational interventions can be listed as the main 
drivers for patient empowerment.(7-10) The health literacy questionnaire (HLS-EU-Q47) in-
cludes questions regarding these main drivers, but also the mentioned capacities, beliefs and 
resources, as well as activities or behaviour regarding patient empowerment. Health literacy 
can therefore be used as a proxy for patient empowerment.(11; 12) The questionnaire is vali-
dated in all four local languages (Dutch, German, Greek and Slovenian). The questionnaire is 
divided into three domains: health care (16 questions), disease prevention (15 questions) and 
health promotion (16 questions). These domains are subdivided into 4 categories: Accessing 
information, Understanding information, Appraising information and Applying information. To-
gether, these domains cover 47 questions. The scores for the domains will be calculated using 
the instrument’s scoring rules. For the questions incorporated in the questionnaire. Each ques-
tion will have 5 responses: 1 = Cannot do or always difficult, 2 = Usually difficult, 3 = Sometimes 
difficult, 4 = Usually easy and 5 = Always easy.(11) A cut off of ≥3 was determined to quantify 
empowerment because scores of 1 to 3 on each item indicate a level of difficulty (‘cannot do 
or always difficult’, ‘usually difficult’ or ‘sometimes difficult’). Descriptive statistics will be per-
formed to analyse the results. An average score of ≥3 is defined as ‘empowered’ and serves 
as endpoint. Secondary, the growth in empowerment will be quantified, specifying the change 
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achieved, and the analysis will take into account both proportions and the magnitude of growth 
in empowerment. 
A semi-structured close-out interview to obtain information on the patient experience of the 
medication management centre will be held. This interview can be divided into six sections: 
General experience with the MMC, Usability of the MMC, Patient empowerment, Impact, App 
features and functionality and Suggestions for improvement. All sections contain two to three 
questions each. This semi-structured close-out interview should be performable within an hour.  
The interviews will be performed on a random sampling basis, until the saturation point is 
reached. This method allows for the collection of sufficient, diverse insights while minimizing 
redundancy.(13; 14) The interviews will be recorded using voice recorders and transcribed 
using ATLAS.ti to be able to analyse the responses.  
The responses will then be categorized using a framework-analysis to capture higher-order 
concepts (e.g. “more involved in decisions” and “understood medication better” may form the 
category ‘Empowerment’ while “easy to navigate” and “intuitive layout” may form the category 
‘Usability Strengths’). After that, we will develop overarching themes based on these catego-
ries (e.g. “The MMC improves patient empowerment through enhanced medication under-
standing”). The analysis will be performed according to AMEE-guide No. 164. The analysis will 
start deductively, using the existing framework, while allowing space for inductive insights to 
emerge, such as new themes or patterns that arise from the data.(15) Analysis of the re-
sponses will be performed within ATLAS.ti, To ensure accurate and consistent coding, we will 
implement agreement sessions where team members will collaboratively review and align their 
coding approaches. The findings from these interviews will be compared to questionnaire re-
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8.1.2 Secondary study parameters/endpoints (if applicable) 
Secondary analyses are aimed at defining the ability of the MMC to accurately identify patients 
at risk for a drug-drug-gene interaction. The effect of integrating the MMC into healthcare on 
the incidence of adverse drug events compared to matched historical controls from the U-PGx 
cohort will also be assessed.  
Baseline demographics and clinical monitoring: 
• 
Demographic measurements 
• 
Current and past medical history 
• 
Comorbidities 
• 
Global Health Score 
• 
Co-medication 
• 
Renal function 
• 
Liver function 
 
Secondary clinical outcome: 
• 
Total number of ADEs (related to index and subsequent drugs) 
• 
Dose adjustments to index drug 
• 
Drug cessation (and reason for discontinuation) 
• 
Additional drugs that are prescribed during follow-up 
• 
Routine drug levels (only those that are collected routinely) as a proxy for exposure 
• 
Patient-reported drug adherence 
 
8.2 Randomisation, blinding and treatment allocation 
No randomization will be applied. The Dutch, Slovenian and Greek patients will receive the 
MMC with PGx testing. The German patients will get access to the MMC, but will not receive 
any PGx testing. We will test the user experience.  
8.3 Study procedures 
See also Section 3. Patients matching inclusion criteria as described in Section 3 will be invited 
to participate. If a patient agrees and provides IC, they are asked to complete a baseline ques-
tionnaire (table 1). All patients will be provided access to the MMC. In The Netherlands, Greece 
and Slovenia, 10 ml blood will be collected during a venipuncture or with saliva using saliva 
collection kits designed for DNA purification. The participants will then be genotyped for 
CYP2C9, CYP2C19, CYP2D6, and SLCO1B1. All participants will gain access to the MMC, 
where participants that are genotyped will receive the PGx results. Questionnaires collecting 
data on the patient experience, clinical monitoring, clinical outcome, and adverse events will 
be collected at 2 and 12 weeks through the eClinical Data Management Platform Castor, for 
which the patients receive an email. The questionnaire and genetic information will be used for 
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8.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for urgent 
medical reasons. 
8.4.1 Specific criteria for withdrawal (if applicable) 
Not applicable, there are no specific criteria for withdrawal. The national principal investigator 
can decide to withdraw a subject from the study for urgent medical reasons. 
The eCRF will have a specific page that enables the type of withdrawal to be classified pre-
cisely, and where possible the individual reason to be documented. Types of withdrawal from 
which can be selected: 
• 
Complete withdrawal (none of the patient’s data can be used, e.g., because the subject 
wants to fully withdrawal/wrong initial drug etc.) 
• 
Withdrawal from remaining follow-up only (patient consents for the study to use their 
data which has already been collected, but they decline to continue to be followed-up 
OR patient did not use index drug for at least 7 consecutive days) 
• 
Lost to follow-up (the subject does not specify that they decline further follow-up, they 
are unable to be contacted) 
• 
Partial withdrawal (e.g., withdraw from ever using the patient-reported online monitor-
ing system, but happy to be contacted by research team) 
• 
Death 
 
8.5 Replacement of individual subjects after withdrawal 
Individual subjects will not be replaced after withdrawal, unless the participant is loss-to-follow-
up before the first questionnaire. 
8.6 Follow-up of subjects withdrawn from treatment 
If a patient does not reply to attempts of contact, every effort will be made to contact the patient. 
If a patient wishes to withdraw, the reason for discontinuation will be noted, if the patient 
agrees. The date and reason (if disclosed) will be noted in the eCRF. How missing data is 
handled in the analyses will be described in the statistical analysis plan. 
Participants will be given two options: 1) complete withdrawal, 2) withdrawal from follow-up 
only. Additionally, we can offer the patients the choice whether or not to report the PGx results 
back to them. 
8.7 Premature termination of the study 
The study will be terminated prematurely when the safety of participants cannot be guaranteed. 
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defined for premature termination of the study. When terminated prematurely the participants 
will be informed and the PGx results will be shared with the Dutch, Greek and Slovenian par-
ticipants. 
 
 
 
 
 

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9. SAFETY REPORTING 
9.1 Temporary halt for reasons of subject safety 
In accordance with section 10, subsection 4 of the WMO, the sponsor will suspend the study 
if there is sufficient ground that continuation of the study will jeopardise subject health or safety. 
The sponsor will notify the accredited METC without undue delay of a temporary halt including 
the reason for such an action. The study will be suspended pending a further positive decision 
by the accredited METC. The investigator will take care that all subjects are kept informed.  
 
9.2 AEs and SAEs  
9.2.1 Adverse events (AEs) 
AEs reported by the patient will be followed up until they have abated, or until a stable situation 
has been reached, as done within the realm of routine clinical care. AEs will be monitored via 
patient reporting through the medication management centre. 
9.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
• 
results in death; 
• 
is life threatening (at the time of the event); 
• 
requires hospitalization or prolongation of existing inpatients’ hospitalization; 
• 
results in persistent or significant disability or incapacity; 
• 
is a congenital anomaly or birth defect; or 
• 
any other important medical event that did not result in any of the outcomes listed above 
due to medical or surgical intervention but could have been based upon appropriate 
judgement by the investigator. 
An elective hospital admission or prolongation of hospitalization will not be considered as a 
serious adverse event. 
All national principal investigators have the responsibility for safety within their own country. 
The local investigators will report SAEs to the national principal investigators, who in turn will 
report it to their national spontaneous reporting system within 7 days of first knowledge SAEs 
that result in death or are life threatening followed by a period of maximum of 8 days to com-
plete the initial preliminary report. All other SAEs will be reported within a period of maximum 
15 days after the sponsor has first knowledge of the serious adverse events. 
 

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9.3 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been reached. 
Depending on the event, follow up may require additional tests or medical procedures as indi-
cated, and/or referral to the general physician or a medical specialist. SAEs need to be re-
ported till end of study, as defined in the protocol. 
9.4 Data Safety Monitoring Board (DSMB) / Safety Committee 
The MMC is not designed for the patients to adjust their treatment on their own. Rather, it is a 
collection of curated, publicly available information tailored to their personal polytherapy. Ad-
ditionally, it is up to the healthcare providers to follow the DPWG guidelines and incorporate 
PGx testing results into their prescriptions. Therefore, no additional safety issues are expected. 
 
 
 
 
 
 

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10. STATISTICAL ANALYSIS 
10.1 Primary study parameter(s) 
Descriptive statistics will be used to describe the primary outcome.  
10.2 Secondary study parameter(s)  
Descriptive statistics will be used to describe the secondary outcomes. 
 
 
 
 
 

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11. ETHICAL CONSIDERATIONS 
11.1 Regulation statement 
The EmPaSafe study will be conducted according to the study protocol, applicable regulatory 
requirements, the ethical principles of the Declaration of Helsinki (2013, see for the most recent 
version: www.wma.net) and in accordance with the Medical Research Involving Human Sub-
jects Act (WMO), and in accordance with national law and legislation. 
11.2 Recruitment and consent 
It is the responsibility of the national Principal Investigators to obtain ethical approval or favour-
able opinion in writing of the study protocol and protocol amendments, the patient information 
leaflet, and the informed consent form from the before enrolment of any subject into the study. 
Recruitment will differ per site. In the Netherlands, recruitment will involve the LANA pharma-
cies as well as the outpatient pharmacy of the Leiden University Medical Center (LUMC). All 
participating pharmacies will receive information about the study during a site initiation visit. 
Pharmacies will identify eligible polypharmacy patients and pharmacies will identify eligible 
polypharmacy patients and verbally inform eligible patients about the EmPaSafe study. If pa-
tients are interested to participate, the pharmacy will provide the patient information leaflet. 
Within 2 work days, a researcher from the LUMC will call the patient to provide further infor-
mation about the study and answer questions. Upon agreement by the patient, an ICF will be 
provided. The patient inclusion will be managed by the LUMC research team. The study team 
is also available for any questions both during recruitment and throughout the study. 
11.3 Benefits and risks assessment, group relatedness 
Subjects undergo a small, extra burden. Firstly, 10 ml additional blood will be collected during 
a venipuncture. Secondly, subjects have to complete questionnaires at T=0, T=2 and T=12 (T 
in weeks). Lastly, the subjects will be contacted at T=12 for a close-out interview. No extra 
visits to the clinic are necessary. 
 
Benefits to subjects in the study include having access to the medication management centre 
for the duration of the study. Additionally, Dutch, Greek and Slovenian participants will receive 
their PGx profile. This can be used to individualize drug treatment, based on the DPWG guide-
lines.  
 
Overall, minimal risks are expected for subjects as they will receive normal treatment.  
 
 

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11.4 Compensation for injury 
The investigator has a liability insurance which is in accordance with article 7 of the WMO. The 
sponsor (also) has an insurance which is in accordance with the legal requirements in the 
Netherlands (Article 7 WMO). This insurance provides cover for damage to research subjects 
through injury or death caused by the study. The insurance applies to the damage that be-
comes apparent during the study or within 4 years after the end of the study. The METC LDD 
did provide liberation of the subject insurance. 
11.5 Incentives  
No financial compensation will be offered; the only things that can be considered as incentive 
are the access to the medication management centre for the duration of the study, and the 
PGx profile that will be obtained for all participating subjects. 
 
 
 

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12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 Handling and storage of data and documents 
The members of the SafePolyMed consortium are committed to open access and open sci-
ence. To achieve this, data stewardship according to the FAIR principles (https://www.go-
fair.org/fair-principles/) is crucial. Therefore, we developed a data management plan (DMP) 
using the Horizon Europe DMP Template, in compliance with regulation 2016/679. The DMP 
includes details on: (i) handling of research data during and after the project; (ii) types of data 
to be collected; (iii) application of data methodology and standards; (iv) methods for sharing 
and accessing data; and (v) data curation and preservation strategies. The plan will outline the 
project's organizational and technical procedures for data collection, reuse, storage, retention, 
destruction, privacy, and confidentiality. The DMP, confirmations, and related support docu-
ments were submitted to the EU as a deliverable. 
 
Clinical data and associated metadata will be stored in a structured, searchable format in a 
publicly accessible database. Individual entries will be identifiable by a generated unique iden-
tifier (UUID) and a standardized version number using semantic versioning (major, minor, and 
patch version numbering). Changes to existing entries will receive a new UUID, and version 
updates will follow standard semantic versioning conventions. The database will be searchable 
by keywords and critical endpoints. Metadata will include information about study design, co-
hort, administration protocol, and data origin. The acquired patient materials such as blood or 
saliva, as well as the obtained clinical data will be stored for 15 years, in accordance with the 
ICH-GCP and EU-directives. 
 
12.2 Monitoring and Quality Assurance  
Local, internal monitors will perform the monitoring of the EmPaSafe study, according to the 
monitoring plan which will be written before initiation of the study. Monitoring will occur at reg-
ular intervals to oversee the progress of the study, ensure the wellbeing of study subjects, 
ensure accuracy and completeness of study data, and monitor compliance with the study pro-
tocol, SOPs, ICH-GCP and the Declaration of Helsinki, EU directives and applicable regulatory 
requirements.  
12.3 Amendments  
All amendments will be notified to the METC that approved the protocol. All substantial amend-
ments will be notified to the METC and to the competent authority. Non-substantial amend-
ments will not be notified to the accredited METC and the competent authority but will be rec-
orded and filed by the sponsor.  
 

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12.4 Annual progress report 
The investigator will submit a summary of the progress of the trial to the accredited METC once 
a year. Information will be provided on the date of inclusion of the first subject, numbers of 
subjects included and numbers of subjects that have completed the trial, serious adverse 
events, other problems, and amendments.  
12.5 Temporary halt and (prematurely) end of study report 
The investigator/sponsor will notify the accredited METC of the end of the study within a period 
of 8 weeks. The end of the study is defined as the last patient’s last questionnaire. The sponsor 
will notify the METC immediately of a temporary halt of the study, including the reason of such 
an action. In case the study is ended prematurely, the sponsor will notify the accredited METC 
within 15 days, including the reasons for the premature termination. Within one year after the 
end of the study, the investigator/sponsor will submit a final study report with the results of the 
study, including any publications/abstracts of the study, to the accredited METC.  
12.6 Public disclosure and publication policy 
The clinical study report will form of manuscripts intended for publication in a medical or sci-
entific journal. Publications will be conform the ‘CCMO-notitie Publicatiebeleid.’ 
12.7 Funding statement 
The SafePolyMed project receives funding from the European Union’s Horizon Europe Re-
search and Innovation Programme under Grant Agreement No. 101057639.  
 
 
 
 
 

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13. STRUCTURED RISK ANALYSIS  
13.1 Potential issues of concern 
Medication management centre 
A potential issue of concern is for patients to adjust their therapy without consulting a health 
care provider, basing the adjustments on notifications of interactions. To overcome this con-
cern, we will repeatedly inform the patients not to act upon notified interactions themselves, 
and to always consult a health care provider before adjusting the therapy. 
 
Collection of clinical data 
To mitigate the threat of poor collection of clinical data, we will implement a central web-based 
database including eCRFs. 
 
Ethics 
The risk that ethical aspects cannot be managed within the project is extremely low as we will 
be proactive and managing the ethical issues prospectively. As soon as a potential problem 
would appear, it will be managed by open discussion within the consortium and finding external 
advice. Therefore, a Scientific Advisory Board has been commissioned to advise on the devel-
opment of the protocol to ensure a scientifically sound method (see Appendix 5). 
 
Changes over time 
A potential threat is that during the project the panel of drugs and genetic variants will 
change. For example, new drugs for which genetic testing is recommended may be mar-
keted, drugs may be removed from the market, or a genetic test may become mandatory. In 
addition, new genetic variants may be identified that are not in the current panel. At this mo-
ment it is difficult to judge if and how fast these developments will proceed. The discovery of 
novel genetic variants can easily be addressed by incorporating them in the genotyping plat-
form which is open and flexible by design. Moreover, the project is planned to span a period 
of 7 months so no major changes are expected. 
 
 
 

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14. REFERENCES 
1. 
2008. Strengthening pharmacovigilance to reduce adverse effects of medicines. 
https://ec.europa.eu/commission/presscorner/detail/en/MEMO_08_782 
2. 
Midao L, Giardini A, Menditto E, Kardas P, Costa E. 2018. Polypharmacy prevalence 
among older adults based on the survey of health, ageing and retirement in Europe. 
Arch Gerontol Geriatr 78:213-20 
3. 
Awwad O, Akour A, Al-Muhaissen S, Morisky D. 2015. The influence of patients' 
knowledge on adherence to their chronic medications: a cross-sectional study in 
Jordan. Int J Clin Pharm 37:504-10 
4. 
Rognan SE, Kalvemark-Sporrong S, Bengtsson KR, Lie HB, Andersson Y, et al. 2021. 
Empowering the patient? Medication communication during hospital discharge: a 
qualitative study at an internal medicines ward in Norway. BMJ Open 11:e044850 
5. 
Nafradi L, Nakamoto K, Schulz PJ. 2017. Is patient empowerment the key to promote 
adherence? A systematic review of the relationship between self-efficacy, health locus 
of control and medication adherence. Plos One 12:e0186458 
6. 
Barbosa CD, Balp MM, Kulich K, Germain N, Rofail D. 2012. A literature review to 
explore the link between treatment satisfaction and adherence, compliance, and 
persistence. Patient Prefer Adherence 6:39-48 
7. 
Bhattad PB, Pacifico L. 2022. Empowering Patients: Promoting Patient Education and 
Health Literacy. Cureus 14:e27336 
8. 
van der Gaag M, Heijmans M, Spoiala C, Rademakers J. 2022. The importance of 
health literacy for self-management: A scoping review of reviews. Chronic Illn 18:234-
54 
9. 
Werbrouck A, Swinnen E, Kerckhofs E, Buyl R, Beckwee D, De Wit L. 2018. How to 
empower patients? A systematic review and meta-analysis. Transl Behav Med 8:660-
74 
10. 
Hickmann E, Richter P, Schlieter H. 2022. All together now - patient engagement, 
patient empowerment, and associated terms in personal healthcare. BMC Health Serv 
Res 22:1116 
11. 
Sorensen K, Van den Broucke S, Pelikan JM, Fullam J, Doyle G, et al. 2013. Measuring 
health literacy in populations: illuminating the design and development process of the 
European Health Literacy Survey Questionnaire (HLS-EU-Q). BMC Public Health 
13:948 
12. 
Bravo P, Edwards A, Barr PJ, Scholl I, Elwyn G, et al. 2015. Conceptualising patient 
empowerment: a mixed methods study. BMC Health Serv Res 15:252 
13. 
Guest G, Bunce A, Johnson L. 2006. How Many Interviews Are Enough?:An 
Experiment with Data Saturation and Variability. Field Methods 18:59-82 
14. 
Hennink MM, Kaiser BN, Marconi VC. 2017. Code Saturation Versus Meaning 
Saturation: How Many Interviews Are Enough? Qual Health Res 27:591-608 
15. 
Klingberg S, Stalmeijer RE, Varpio L. 2024. Using framework analysis methods for 
qualitative research: AMEE Guide No. 164. Med Teach 46:603-10 
 
 
 

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15. Appendices  
15.1 Appendix 1: Contact information 
LUMC: 
J.J. Swen, PharmD, PhD  
Professor of Clinical Pharmacy/Translational Pharmacogenetics 
Dept. Clinical Pharmacy & Toxicology 
Leiden University Medical Centre 
P.O. Box 9600 
NL 2300 RC Leiden 
The Netherlands 
E-mail: j.j.swen@lumc.nl 
 
UPAT: 
G. Patrinos 
Professor, Pharmacogenomics and Pharmaceutical Biotechnology 
Patras University,  
Πανεπιστημιούπολη Πατρών 265 04,  
Greece 
E-mail: gpatrinos@upatras.gr 
 
UL:  
Prof. Vita Dolzan, MD, PhD, spec. lab. med. gen. 
Head, Institute of Biochemistry and Molecular Genetics 
Faculty of Medicine, University of Ljubljana 
Vrazov trg 2, SI-1000 Ljubljana, Slovenia 
Head, Pharmacogenetics Laboratory  
Temporary address (till 2025): Zemljemerska ulica 12, 1000 Ljubljana 
E-mail: vita.dolzan@mf.uni-lj.si 
 
UKA: 
Univ.Prof.Dr.med. Julia Stingl 
Institute and Chair of Clinical Pharmacology 
Direktorin 
Building: MTI 2 
Wendlingweg 2 
52074 Aachen 
E-mail: jstingl@ukaachen.de 

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15.1 Appendix 2: MDR/IVDR exemption 
The Medication Management Centre (MMC) does not fall under the Medical Device Regulation 
(MDR) nor the In Vitro Diagnostic Regulation (IVDR) for several reasons.  
 
First, the primary role of the MMC is to serve as an educational and informational platform 
rather than a tool for diagnosis or treatment. The MMC presents curated, publicly available 
information regarding DDIs, DDGIs, and PGx, which patients are responsible for interpreting. 
Patients can use this information to discuss relevant results with their healthcare providers, but 
the MMC itself does not make any diagnostic or therapeutic decisions. Importantly, PGx test 
results are displayed on a separate screen within the same application, reinforcing the fact that 
the MMC does not function as a diagnostic tool or directly influence treatment. 
 
Additionally, the MMC does not impact clinical decision-making. It merely enhances patient 
knowledge by acting as a smart viewer that aggregates and merges data from different data-
bases. This data is presented in a user-friendly way for patient review and understanding, but 
it does not directly lead to medical interventions. Healthcare professionals remain responsible 
for all clinical decisions, ensuring that the MMC does not pose any undue risk to patients. Any 
mistakes in the presentation of information do not result in incorrect treatments, as the final 
responsibility rests with the healthcare provider. 
 
The MMC’s role as an informative platform also means it does not meet the MDR nor the IVDR 
definition of a medical device nor IVDR, which covers instruments or software intended for 
diagnostic or therapeutic purposes. The MMC provides educational support to polypharmacy 
patients without performing independent diagnostic or therapeutic functions. Although it allows 
patients to ADRs through patient-reported outcome measures (PROMs), it does not replace 
professional medical advice or facilitate therapy adjustments. In short, the MMC serves to em-
power patients by providing access to relevant information, but it remains separate from clinical 
decision-making processes, thus falling outside the scope of the MDR and IVDR. 
 
Moveover, the study will be submitted under the Dutch Medical Research Involving Human 
Subjects Act (WMO). This will ensure the safety and rights of the participants, addressing any 
potential risks. Thus, any concerns regarding patient safety are covered within this regulatory 
framework, independent of MDR or IVDR requirements. 
 
In summary, the MMC is primarily a viewer that compiles information for patient use and does 
not independently impact treatment or diagnostic decisions. Therefore, it does not fall under 
the scope of the MDR or IVDR. While the MMC does not currently meet the criteria for MDR 
or IVDR compliance, its regulatory status may need to be re-evaluated if future developments 
include direct clinical decision-making or therapeutic adjustments. 

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15.2 Appendix 3: Gene and variant panel 
Gene 
Name 
dbSNP 
Allele 
Functional 
status 
DPWG guide-
line 
References 
Note 
CYP2C9 
CYP2C9*2 
rs1799853 
*2 
Reduced 
Yes 
(1) 
  
CYP2C9*3 
rs1057910 
*3 
  
CYP2C9*5 
rs28371686 
*5 
  
CYP2C9*11 
rs28371685 
*11 
  
CYP2C19 
CYP2C19*17 
rs12248560 
*17 
Increased 
Yes 
(1; 2) 
  
CYP2C19*9 
rs17884712 
*9 
Reduced 
  
CYP2C19*4A/B 
rs28399504 
*4A/B 
  
CYP2C19*8 
rs41291556 
*8 
  
CYP2C19*2 
rs4244285 
*2 
Inactive 
  
CYP2C19*2 
rs4986893 
*3 
  
CYP2C19*5 
rs56337013 
*5 
Reduced 
  
CYP2C19*10 
rs6413438 
*10 
  
CYP2C19*6 
rs72552267 
*6 
  
CYP2D6 
CYP2D6*3 
rs35742686 
*3 
Inactive 
Yes 
(1-8) 
  
CYP2D6*3 
CYP2D6*5 
rs3892097; 
rs1065852 
*4 
  
  
*5 
Whole gene deletion 
CYP2D6*6 
rs5030655 
*6 
  
CYP2D6*8 
rs5030865 
*8 
  
CYP2D6*9 
rs5030656 
*9 
Reduced 
  
CYP2D6*10 
rs1065852 
*10 
  
CYP2D6*14 
rs5030865 
*14 
Previously known as 14A 
CYP2D6*17 
rs28371706 
*17 
  
CYP2D6*41 
rs28371725 
*41 
  
CYP2D6*114 
rs5030865; 
rs1065852 
*114 
Previously known as 14B 
SLCO1B1 
 VKORC1 
rs9934438 
1173C>T Reduced 
Yes 
(10) 
  
 

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1. 
Swen JJ, Nijenhuis M, de Boer A, Grandia L, Maitland-van der Zee AH, et al. 2011. Pharmacogenetics: from bench to byte--an update of 
guidelines. Clin Pharmacol Ther 89:662-73 
2. 
Brouwer J, Nijenhuis M, Soree B, Guchelaar HJ, Swen JJ, et al. 2022. Dutch Pharmacogenetics Working Group (DPWG) guideline for the 
gene-drug interaction between CYP2C19 and CYP2D6 and SSRIs. Eur J Hum Genet 30:1114-20 
3. 
Nijenhuis M, Soree B, Jama WOM, de Boer-Veger NJ, Buunk AM, et al. 2023. Dutch pharmacogenetics working group (DPWG) guideline 
for the gene-drug interaction of CYP2D6 and COMT with atomoxetine and methylphenidate. Eur J Hum Genet 31:1364-70 
4. 
Matic M, Nijenhuis M, Soree B, de Boer-Veger NJ, Buunk AM, et al. 2022. Correction: Dutch Pharmacogenetics Working Group (DPWG) 
guideline for the gene-drug interaction between CYP2D6 and opioids (codeine, tramadol and oxycodone). Eur J Hum Genet 30:1196 
5. 
Matic M, Nijenhuis M, Soree B, de Boer-Veger NJ, Buunk AM, et al. 2022. Dutch Pharmacogenetics Working Group (DPWG) guideline 
for the gene-drug interaction between CYP2D6 and opioids (codeine, tramadol and oxycodone). Eur J Hum Genet 30:1105-13 
6. 
Sistonen J, Sajantila A, Lao O, Corander J, Barbujani G, Fuselli S. 2007. CYP2D6 worldwide genetic variation shows high frequency of 
altered activity variants and no continental structure. Pharmacogenet Genomics 17:93-101 
7. 
Gaedigk A, Blum M, Gaedigk R, Eichelbaum M, Meyer UA. 1991. Deletion of the entire cytochrome P450 CYP2D6 gene as a cause of 
impaired drug metabolism in poor metabolizers of the debrisoquine/sparteine polymorphism. Am J Hum Genet 48:943-50 
8. 
Steen VM, Molven A, Aarskog NK, Gulbrandsen AK. 1995. Homologous unequal cross-over involving a 2.8 kb direct repeat as a mecha-
nism for the generation of allelic variants of human cytochrome P450 CYP2D6 gene. Hum Mol Genet 4:2251-7 
9. 
Beunk L, Nijenhuis M, Soree B, de Boer-Veger NJ, Buunk AM, et al. 2023. Dutch Pharmacogenetics Working Group (DPWG) guideline 
for the gene-drug interaction between CYP2D6, CYP3A4 and CYP1A2 and antipsychotics. Eur J Hum Genet  
10. 
2023. Algemene achtergrondtekst Farmacogenetica – Organisch Anion Transporter 1B1 (SLCO1B1, OATP1B1, OATP-C) https://kennis-
bank.knmp.nl/files/medisch_farmaceutische_beslisregels/pdf/SLCO1B1.pdf 

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15.3 Appendix 4: Index drugs 
To select the index drugs for EmPaSafe, we analysed the incidence of prescription of the 39 
index drugs within the PREPARE study. From this analysis, we selected the top 20 drugs 
prescribed at each centre (LUMC, UPAT, UL). In table 4 below. Coloured cells indicate the 
overlapping drugs.  
Table 4. Overview of the top 20 drugs prescribed at each centre in the PREPARE study. 
LUMC 
UL 
UPAT 
Name 
Occurrence 
Name 
Occurrence 
Name 
Occurrence 
Simvastatin 
252 Sertraline 
247 Sertraline 
241 
Metoprolol 
200 Escitalopram 
220 Escitalopram 
215 
Flucloxacillin 
146 Haloperidol 
213 Haloperidol 
212 
Atorvastatin 
145 Venlafaxine 
193 Aripiprazole 
189 
Clopidogrel 
130 Aripiprazole 
189 Venlafaxine 
189 
Tramadol 
84 Tramadol 
172 Tramadol 
172 
Citalopram 
80 Citalopram 
141 Citalopram 
141 
Codeine 
67 Tacrolimus 
112 Simvastatin 
66 
Amitriptyline 
60 Simvastatin 
66 Atorvastatin 
51 
Nortriptyline 
32 Atorvastatin 
52 Paroxetine 
48 
Tacrolimus 
28 Paroxetine 
48 Capecitabine 
43 
Sertraline 
27 Capecitabine 
46 Tamoxifen 
29 
Escitalopram 
25 Amitriptyline 
30 Amitriptyline 
26 
Fluorouracil 
24 Tamoxifen 
29 Zuclopenthixol 
25 
Venlafaxine 
22 Zuclopenthixol 
25 Clomipramine 
24 
Oxycodone 
15 Clomipramine 
24 Codeine 
7 
Tamoxifen 
15 Fluorouracil 
9 Flucloxacillin 
7 
Flecainide 
13 Codeine 
7 Carbamazepine 
4 
Paroxetine 
12 Flucloxacillin 
7 Pimozide 
3 
The 10 drugs that overlapped most, with the highest prevalence in the cohort, were selected 
as the index drugs for the EmPaSafe study. These are listed in table 5 below. 
Table 5. Overlapping drugs with highest prevalence in the PREPARE study. 
Drug  
 Related gene 
Incidence PRE-
PARE LUMC 
Incidence PRE-
PARE UL 
Incidence PRE-
PARE UPAT 
Amitriptyline 
CYP2D6 / 
CYP2C19 
60 
30 
26 
Atorvastatin 
SLCO1B1 
145 
52 
51 
Citalopram 
CYP2C19 
80 
141 
141 
Codeine 
CYP2D6 
67 
7 
7 
Escitalopram 
CYP2C19 
25 
220 
215 
Paroxetine 
CYP2C9 
12 
48 
48 
Sertraline 
CYP2C19 
27 
247 
241 
Simvastatin 
SLCO1B1 
252 
66 
66 
Tramadol 
CYP2D6 
84 
172 
172 
Venlafaxine 
CYP2D6 
22 
139 
189 

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15.4 Appendix 5: Scientific Advisory Board 
The EmPaSafe Scientific Advisory Board consists of experts from academia, industry, and 
patient advocacy. This board provides strategic guidance and expertise to ensure the study's 
scientific rigor and relevance.  
- 
Professor Munir Pirmohamed (University of Liverpool): An eminent pharmacologist 
with extensive research in drug safety, pharmacogenetics, and personalized medi-
cine. 
- 
Sabrina Grigolo (EUPATI): A leading figure in patient advocacy, representing the Eu-
ropean Patients' Academy on Therapeutic Innovation, with a strong focus on patient 
involvement in research and healthcare decision-making. 
- 
Dr. Valerie Nock (Boehringer Ingelheim): A senior researcher with profound experi-
ence in drug development and clinical research from a leading pharmaceutical com-
pany. 
- 
Dr. Uros Urleb (Novartis): A prominent scientist in the field of drug discovery and de-
velopment, contributing valuable insights from his extensive work in the pharmaceuti-
cal industry. 
- 
Professor Søren Brunak (University of Copenhagen): A pioneer in bioinformatics and 
systems biology, known for his innovative work in integrating biological data to ad-
vance personalized medicine. 
The collective expertise of this board ensures that the EmPaSafe study adheres to the highest 
standards of scientific excellence, patient-centred care, and innovative research methodolo-
gies. Their diverse backgrounds and comprehensive knowledge support the study's goal of 
improving medication safety and patient empowerment through advanced technological solu-
tions.