Prospective Clinical Validation of the Eleveld Pharmacokinetic and Pharmacodynamic Model of Propofol for Procedural Sedation in Adults.
Conditions: Deep Sedation
Sponsor: University Medical Center Groningen

Template non-WMO Study Protocol, version 7; Page 1 of 12 
 
 
Prospective clinical validation of the Eleveld 
pharmacokinetic and pharmacodynamic model 
of propofol for procedural sedation in adults. 
< Research Register number …..> 
(non-WMO study protocol) 
 
 
Date of document: 
<23-11-2023> 
Version number: 
<1.0> 
CONTENT 
 
1. STUDY ORGANIZATION ................................................................................................................ 2 
2. PROTOCOL SIGNATURE SHEET ................................................................................................... 3 
3. ABSTRACT ........................................................................................................................................ 3 
4. BACKGROUND ................................................................................................................................. 4 
5. METHOD ............................................................................................................................................ 4 
5.1 Description study design ............................................................................................................... 4 
5.2 Design ............................................................................................................................................ 5 
5.3 Population ...................................................................................................................................... 6 
5.4 Recruitment and informed consent/objection ................................................................................ 6 
5.5 Research Data Management Plan (RDMP) ................................................................................... 7 
5.6 Management of biomaterials ....................................................................................................... 10 
5.7 Burden, Risks & Benefits (Prospective studies only) ................................................................. 11 
5.8 Incidental findings ....................................................................................................................... 11 
5.9 Data analysis................................................................................................................................ 11 
5.10 Participant information after the study ...................................................................................... 11 
5.11 Research revenue ....................................................................................................................... 11 
6. REFERENCES .................................................................................................................................. 12 
 
 
 

Template non-WMO Study Protocol, version 7; Page 2 of 12 
 
1. STUDY ORGANIZATION 
 
Study title 
Prospective clinical validation of the Eleveld pharmacokinetic 
and pharmacodynamic model of propofol for procedural 
sedation in adults.  
Planned start date 
<01-01-2024> 
Estimated completion date 
<01-01-2025> 
Project leader 
(UMCG or external) 
 
(Principal) investigator UMCG 
 
Researcher(s) UMCG 
• 
 
Corresponding researcher UMCG 
 
(Principal) investigator other 
centers 
NA 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
UMCG 
Financial support/subsidising 
party 
• 
NA 
Collaboration with non-profit 
Laboratory / research sites (in- 
and outside UMCG) 
• 
NA 
Collaboration with commercial 
parties / companies (in- and 
outside UMCG) 
NA or  
 
Name bio- or databank and 
bankmanager 
NA 
Name previous study ('FAIR data') 
and (principal) investigator 
NA 
 
 

Template non-WMO Study Protocol, version 7; Page 3 of 12 
 
2. PROTOCOL SIGNATURE SHEET 
 
The undersigned (Principal) investigator and head of department UMCG confirm that the study and 
its procedures will comply with the present study protocol and the nWMO Kaderreglement UMCG. 
Without ethical approval the data/biomaterials will not be used for other (research) purposes (e.g. 
'FAIR data'). 
 
Name 
Signature 
Date 
(Principal) investigator UMCG: 
 
 
 
 
2-11-2023 
 
Head of the department 
UMCG: 
 
 
 
2-11-2023 
 
 
 
3. ABSTRACT 
 
• 
Background 
Propofol is the preferred drug of choice for procedural moderate to deep sedation. This can be 
titrated by using pharmacokinetic (PK) and pharmacodynamic (PB) models programmed in 
infusion pumps for target controlled infusion (TCI). In 2021 Vellinga et al published a study on the 
validation of the Eleveld model in patients undergoing general anesthesia. (Vellinga et al. 386-
394) So far, the Eleveld model has not been externally validated for the use of procedural 
sedation in adult patients.  
• 
Main research question 
The primary objective is to identify effect-site target concentrations of propofol for the Eleveld 
model that is associated with procedural sedation; a modified observer’s assessment of alertness 
and sedation (MOAAS) score  5-1 and the associated depth- of- anesthesia monitor parameter 
levels in adult patients. The secondary outcome is the time to reach MOASS 5 representing fully 
awake after having stopped propofol infusion using the Eleveld model. 
• 
Design (including population, confounders/outcomes) 
Prospective observational study of adult patients undergoing procedures under sedation by using 
the Eleveld model for propofol. Descriptive statistics in SPSS.  
Expected results 
To have identified effect site concentrations (CET) of propofol using the Eleveld model for 
different levels of procedural sedation. 
 
 

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4. BACKGROUND 
 
• 
Introduction and rationale  
 
- 
Since the Dutch guideline on procedural sedation outside of the operating room in 20121  has 
been published, procedural sedation practices in Dutch hospitals has taken a huge flight. 
Propofol is the preferred drug of choice for moderate to deep sedation. This can be titrated 
by using pharmacokinetic (PK) and pharmacodynamic (PB) models programmed in infusion 
pumps for target controlled infusion (TCI). Several PKPD models for TCI propofol are 
available. While most TCI systems incorporate PK or PKPD models for specific patient groups 
such as adults, children or older patients, the Eleveld model has been developed for TCI of 
propofol for general anesthesia and sedation in a broad range of patients.2 In 2021 Vellinga 
et al published a study on the validation of the Eleveld model in patients undergoing general 
anesthesia.3 So far, the Eleveld model has not been externally validated for the use of 
procedural sedation in adult patients. The aim of this study is to identify effect-site target 
concentrations of propofol for the Eleveld model that are associated with moderate to deep 
sedation levels, MOAAS 5-1 and the associated BIS levels in adult patients.4 The secondary 
outcomes are: time to introduction of the endoscope and the time to reach MOAAS 5 after 
having stopped TCI propofol. The use of vasopressors such as ephedrine, phenylephrine or 
norepinephrine. The need for airway maneuvers such as chin lift, jaw thrust or 
nasopharyngeal airway. 
 
• 
Research question 
 
Primary outcome 
To identify CET propofol using the Eleveld model for different levels of procedural sedation as 
measured by MOAAS and EEG monitoring. 
 
Secondary outcomes 
 
- 
Relevant clinical endpoints i.e. time to introduction of the endoscope, the time to reach 
MOAAS 5 after having stopped TCI propofol. 
- 
The use of vasopressors such as ephedrine, phenylephrine or norepinephrine. 
- 
The need for airway maneuvers such as chin lift, jaw thrust or nasopharyngeal airway. 
 
 
5. METHOD 
 
5.1 Description study design 
 
This is a prospective observational study. Adult patients undergoing sedation for endoscopic 
procedures in the UMCG between 01-01-2024 and 01-01-2025 will be included. Written informed 
consent will be obtained prior to the procedure. Exclusion criteria are: age <18 years, the use of 
esketamine during the procedure, the use of benzodiazepines prior or during the procedure, hearing 
disability and a BIS quality index < 50. 
 
 

Template non-WMO Study Protocol, version 7; Page 5 of 12 
 
Monitoring 
All patients will be monitored according to the departmental protocol5 
(https://umcg.zenya.work/portal/#/document/217c7341-ad32-4655-b2e7-6e49665e8869) with a 
Philips IntelliVue MP30 monitor (Philips Medizin Systeme Boeblingen GmbH, Boeblingen). This 
consists of continuous 3-lead electrocardiogram (ECG), peripheral hemoglobin oxygen saturation 
(SpO2), respiration rate, end-tidal carbon dioxide concentration (etCO2) using a Medtronic 
MicrostreamTM Advance Adult Oral-Nasal CO2 Filter Line, noninvasive blood pressure (NIBP) with a 
measurement interval of 5 minutes.  
 
 
Dose-response relationship will be determined with a depth-of-anesthesia-monitor as per the 
department’s standard protocol for sedation. Depth of sedation will be monitored using non-invasive 
monitoring ( BIS® monitor (BIS Vista, Medtronic, Boulder, CO, USA and Masimo Root with Sedline 
Masimo Irvine, CA). The Modified Observer’s Assessment of Alertness and Sedation score (MOAAS 
score) will be noted every 10 minutes and is used to record the depth of sedation. All data from the 
vital signs monitor and infusion pumps will be automatically stored in an electronic medical record 
system (Epic Systems corporation, 1979 Milky Way, Verona, WI).  
Sedation protocol 
Sedation will be administered using Target-Controlled Infusions (TCI) of propofol (administered by 
effect-site TCI using the Eleveld model) and remifentanil (administered by effect site TCI using the 
Eleveld model). Target controlled infusion of propofol and remifentanil is according the departmental 
protocol (https://umcg.zenya.work/portal/#/document/217c7341-ad32-4655-b2e7-6e49665e8869).  
TCI propofol will be administered by stepwise increasing effect-site targets until the desired depth of 
sedation has been reached as per clinical practice. 
 
 
5.2 Design 
5.2.1 Mono- or multicenter study 
Mono-center study 
yes 
Multicenter study 
 
<text> 
5.2.2 Retrospective study (available data/ 
biomaterials only) or prospective study (data/ 
biomaterials from [some] participants will be 
collected in the future). 
Retrospective study 
No 
skip 
Sections 5.4.2/5.5.6 
Prospective study 
Yes 
skip 
Sections 5.4.1 
<text> 
5.2.3 Cross-sectional or follow-up study 
Cross-sectional study 
yes 
Follow-up study 
 
<text> 
 
 
5.2.4 Quantitative or qualitative study (click both 
if mixed-method) 
Quantitative study 
yes 
Qualitative study 
 
<text> 
5.2.4 Pilot study 
No 
<text> 
 
 
 

Template non-WMO Study Protocol, version 7; Page 6 of 12 
 
 
5.3 Population 
5.3.1 Inclusion and exclusion criteria 
• 
Inclusion criteria: Adult patients for procedural sedation in the UMCG between 01-01-2024 and 
01-01-2025. 
• 
Exclusion criteria: age <18 years; use of esketamine during the procedure, use of benzodiazepines 
prior or during the procedure, hearing disability, BIS quality index < 50 
5.3.2 Number of participants 
• 
Target total number of participants: 75 sample size based on previous literature Vellinga et al. 
• 
Target number of UMCG participants: three groups of 25 patients; patients age ≥ 18- <65,  
patients age ≥ 65 and over, patients BMI ≥ 30. 
5.3.3 Study subjects (tick all that apply) 
• 
Healthy volunteers 
• 
Patients 
no 
yes 
<text> 
 
5.3.4 Subject classification (tick all that apply) 
 
• 
Participants ≥ 16 years 
• 
Children between 12 and 16 years (if applicable, written informed consent will 
be obtained from child and both parents - if both have authority, or guardian [or 
parents/guardian only if incapacitated child]) 
• 
Children < 12 years (if applicable, written informed consent will be obtained 
from both parents - if both have authority, or guardian) 
yes 
no 
 
 
no 
<text> 
 
5.3.5 Incapacitated adults 
 
Participants are incapacitated/ decisionally incompetent adults (if applicable, 
written informed consent will be obtained from legal representative) 
no 
<text> 
5.4 Recruitment and informed consent/objection 
5.4.1 Retrospective study (tick all that apply) 
☒ Not applicable (see section 5.2.2) 
☐ Data will be copied from (electronic) patient records (e.g. ‘EPD UMCG’) 
• 
Informed consent is not feasible for this number of patient records. 
o Total number of participants who will not be asked informed consent for 
screening: 50000 
o Total number of UMCG participants who will not be asked informed consent 
for screening: 50000 
• 
Informed consent is not feasible for this number of patient records. 
o Total number of participants who will not be asked informed consent: 50000 
o Total number of UMCG participants who will not be asked informed consent: 
50000 
☐ Data/biomaterials will be obtained from an already existing internal or external 
(UMCG/non-UMCG) bio- or databank (see Section 1. Study organization).  
<text> 
☐ Data/biomaterials will be obtained from a previous study ('FAIR data' - 
internal/external; see Section 1. Study organization).  
<text> 
5.4.2 Prospective study 
☐ Not applicable (see section 5.2.2) 

Template non-WMO Study Protocol, version 7; Page 7 of 12 
 
<text> 
 
5.4.3 Objection (Registry)  
in case one or more participants will not be asked informed consent, the 
objection registry will be checked for these participants and the data from those 
who objected will be excluded from the analyses. 
yes 
 
 
<if no, give reasons> 
5.4.4 Informed consent (IC): access to identifiable participant data 
 
in case one or more study team members will have access to direct/indirect 
identifiable participant data, informed consent will be/has been obtained for this 
access. 
 
 
yes 
<if no, explain> 
5.4.5 IC: Collaboration with commercial parties 
 
In case of collaboration with commercial/profit organizations, informed consent 
will be/has been obtained for this type of collaboration 
NA 
<if no, explain> 
5.4.6 IC: Linking with other registries 
 
In case the data will be linked with other registries, informed consent will be/has 
been obtained for this linkage(s) 
NA 
<if no, explain> 
5.4.7 IC: Incidental findings 
 
In case there is a risk of incidental findings, informed consent will be/has been 
obtained to return findings to the participant 
NA 
<text> 
5.4.8 IC: FAIR Data 
 
In case data collected for the present study will be shared for future studies, 
informed consent will be obtained for this 
yes 
<if no, please explain> 
5.4.9 IC: other aspects  
NA or <other relevant aspects of the study for which informed consent will be/has been obtained> 
5.4.10 Withdrawal 
• 
Can participants withdraw informed consent before publication and will all 
data/ biomaterials of that participant be destroyed 
• 
Does the participant information letter contain information on how to 
withdraw 
yes 
 
yes 
<if no, please explain> 
 
5.5 Research Data Management Plan (RDMP) 
In this study the data will be collected, processed, and archived in accordance with the General Data 
Protection Regulation (GDPR) and the FAIR (Findable, Accessible, Interoperable, Reusable) principles 
under the responsibility of the Principal Investigator. A research data management plan (RDMP) <has 
been/will be> drawn up to describe the further operational details and procedures. <For details on 
the RDMP please find the RDMP enclosed in the Appendix> 
The RDMP section below is completed 
 
5.5.1 Data collection 
• 
Only essential baseline characteristics and data required to answer the research 
question(s) will be collected. 
yes 
Primary outcome: 
 

Template non-WMO Study Protocol, version 7; Page 8 of 12 
 
• 
Tooling (eg. software and procedures) used for collecting, processing, analysing, 
and storing data will be compliant with the UMCG policy and Standard 
Operating Procedures in the UMCG Research Toolbox. 
yes 
<if no, explain> 
5.5.2 Anonymization and pseudonymization 
• 
Data will be anonymised during data collection (i.e. data 
cannot be linked back to the participant) 
 
Yes 
skip section 
5.5.2 
 
 
<if no, explain why it is not possible to anonymise the data during collection> 
• 
Data will be pseudonymized by use of <a code list/an encryption key> during 
data collection. 
yes/no 
<if no, explain> 
• 
Indirect and direct identifiable information collected will be minimized and only 
collected for the purpose of this study 
yes/no 
<if no, explain why you collect more information> 
• 
Direct identifiable information (e.g. contact details, code list/encryption 
key/subject identification log) will be stored separately from pseudonymized 
data <in the electronic patient files (EPD), in an electronic file, on paper in the 
study file, other> 
yes/no 
<if no, explain> 
5.5.3 Data access (during the study) 
• 
Direct identifiable information can only be accessed by the Principal Investigator 
and study delegates after authorization by the Principal Investigator. 
yes 
<if no, explain> 
• 
Pseudonymized/anonymized data can only be accessed by the Principal 
Investigator and study delegates after authorization by the Principal 
Investigator. 
yes 
<if no, explain> 
• 
Data roles, responsibilities, access and authorization - during the study and after 
study completion - will be managed and documented (e.g. in the RDMP, on 
study delegation log). 
yes 
<if no, explain> 
5.5.4 Data sharing (during and after study completion) 
 
In case data (and biomaterials) will leave or enter the UMCG, will you contact the 
loket Contract Research to arrange the proper contracts? 
(Loket_Contract_Research@umcg.nl) 
NA 
<if no, explain> 
 
5.5.5 Data storage (during and after study completion) 
• 
Digital data will be archived on the UMCG network complying with strict UMCG 
security and back-up policy. 
yes 
<if no, explain> 
• 
Paper source data and study files will be archived within the UMCG facilities. 
yes 
<if no, explain> 
• 
Source data, study files and digital data will be stored 15 years after the study is 
completed. 
yes 
<If no, explain and give number of years> 
5.5.6 Data re-use and access after completion of the present study (‘FAIR data’) 
 
 

Template non-WMO Study Protocol, version 7; Page 9 of 12 
 
• 
Data will become available and shared for re-use and participants will be asked 
informed consent for this ('FAIR data') 
 
FAIR data is the UMCG policy. If no is chosen, an explanation is required 
no 
 
specify and 
explain when 
no is chosen 
and then 
skip section 
5.5.6 
<if no, specify and explain>Not applicable 
• 
Data will be made findable by including the description of the study (and type of 
data (i.e. metadata) in the UMCG FAIR data catalogue and other discipline 
specific catalogue(s). 
no 
<if no, explain> Not applicable 
• 
Review procedure, conditions and agreements for re-use of data and access to 
data by other researchers will be drawn up. 
yes 
<if no, explain> 
• 
For this study a discipline specific metadata standard will be chosen (i.e. to 
increase interoperability and re-use). 
no 
<if no, explain> Not applicable 
 
 
 

Template non-WMO Study Protocol, version 7; Page 10 of 12 
 
5.6 Management of biomaterials 
Will biomaterials be collected, processed, analyzed and/or stored for the 
purpose of this study 
 
 
No 
skip  
section 
5.6 
<text> 
5.6.1 Retrospective study (see sections 1, 5.2.2, and 5.4.1) 
If biomaterials will be used from a secondary/further use biobank that has not been 
approved by the Board of Directors of the UMCG, how will be prohibited that 
biomaterials necessary for future diagnostic/treatment purposes will be used in the 
present study. 
NA 
☐ 
<text> 
5.6.2 Biomaterials collection 
• 
Only biomaterials required to answer the research question(s) will be collected 
yes/no 
• 
What biomaterials will be collected 
<text> 
• 
How will the biomaterials be collected and processed 
<text> 
5.6.3 Pseudonymization and access to biomaterials 
• 
Does the storage unit of the biomaterials comprise information that the 
participant (in)directly identifies, other than the participant's number and / or 
the sample number. 
yes/no 
<if yes, explain> 
• 
Biomaterials can only be accessed by the Principal Investigator and study 
delegates after authorization by the Principal Investigator 
yes/no 
<if no, explain> 
5.6.4 Sharing of biomaterials (during and after study completion) 
In case biomaterials (and data) will leave the UMCG, will you contact the loket 
Contract Research to arrange the proper contracts? 
(Loket_Contract_Research@umcg.nl) 
NA/yes/no 
<if no, explain> 
5.6.5 Biomaterials storage (during and after study completion) 
• 
Where and how will the biomaterials be stored 
<text> 
• 
Biomaterials will be stored 15 years after the study is completed 
yes/no 
<If no, explain and give number of years> 
• 
What will be done with the remaining biomaterials after study completion (eg. destroyed, 
returned to biobank/previous study, stored)  
<text> 
5.6.6 Biomaterials re-use and access after completion of the present study 
NA 
☒ 
skip section 
5.6.6 
• 
Biomaterials will become available and shared for re-use and participants will 
be asked informed consent for this ('FAIR data') 
yes/no 
<if no, specify and explain> 
• 
Biomaterials will be made findable by including the description of the study 
(and type of biomaterials in the UMCG FAIR data catalogue and other discipline 
specific catalogue(s). 
yes/no 

Template non-WMO Study Protocol, version 7; Page 11 of 12 
 
<if no, explain> 
• 
Review procedure, conditions and agreements for re-use of biomaterials and 
access to biomaterials by other researchers will be drawn up. 
yes/no 
<if no, explain> 
 
 
5.7 Burden, Risks & Benefits (Prospective studies only) 
• 
If participants are patients: Can be deviated from the standard care / diagnostic 
procedures (e.g. can medical treatment be postponed or limited) 
NA 
<text> 
• 
Burden  
<text> 
 
• 
Will the participants risk any injuries and/or other 
discomfort when they participate in the proposed 
study 
Yes, minimal 
risk/burden 
 
☐ 
Yes, more than 
minimal 
risk/burden 
☐ 
No 
 
 
☒ 
<text> 
• 
Participant benefits/reward/incentives: 
<text> 
5.8 Incidental findings 
 
 
• 
Is there a risk of incidental findings?  
yes, minimal 
risk 
☐ 
yes, ≥ 
substantial risk 
☐ 
No 
 
☒ 
<text> 
If yes, 
o Procedure to assess if a finding should be returned to the participant, or not 
<text> 
o Procedure to inform the participant 
<text> 
5.9 Data analysis 
• 
Justification of sample size (e.g. power analysis) 
• 
Convenience sample size based on pre lit Vell 
• 
Statistical analysis: Describe in detail the statistical analysis used to test the research question.  
• 
Only descriptive statistics will be used 
5.10 Participant information after the study 
Will participants be informed about the study results 
no 
<text> 
5.11 Research revenue 
In case the study will result in revenues (e.g. as a result of the use of 
data/biomaterials or successful licensing of intellectual property or manufactured 
products), will you contact the loket Contract Research to arrange the proper 
contracts? 
NA 
<if no, explain> 
Describe what will be done with the revenues. 
<text> 

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6. REFERENCES 
 
1. Richtijn Sedatie en/of analgesie (PSA) op locaties buiten de operatiekamer. Deel I: bij volwassen 
en deel II: op intensive care. Kwaliteitsinstituut voor de Gezondheidzorg CBO 2009. 
 
2. Eleveld D J, Colin P, Absalom A R, Struys M M R F. Pharmacokinetic–pharmacodynamic model for 
propofol for broad application in anaesthesia and sedation. Br J Anaesth, 2018;120:942-59 
 
3. Vellinga R, Hannivoort L N,  Introna M, Touw, Daan J, Absalom A R; Eleveld D J,  Struys M M R F. 
Prospective clinical validation of the Eleveld propofol pharmacokinetic-pharmacodynamic model 
in general anaesthesia. British Journal of Anaesthesia, 2021; 126 (2): 386-394  
 
4. Xi C, Sun S, Pan C, Ji F, Cui X, Li. TDifferent effects of propofol and dexmedetomidine sedation on 
electroencephalogram patterns: Wakefulness, moderate sedation, deep sedation and recovery. . 
PLoS ONE 13(6): e0199120. https:// doi.org/10.1371/journal.pone.0199120 
 
5. Sedatie door physician assistant of sedatie praktijk specialist (versie 4). 
https://umcg.zenya.work/portal/#/document/217c7341-ad32-4655-b2e7-6e49665e8869