PlAnt Vs Animal Based Oral Nutritional Supplements: Patients' Opinions and Nutritional Outcomes: A Multicenter Pilot Feasibility Study
Phase: NA
Conditions: Risk of Malnutrition
Sponsor: Radboud University Medical Center

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TEMPLATE RESEARCH PROTOCOL 
(November 2024) 
 
- 
May 2015: adaptation section 11.5: text in accordance to old and new Measure 
regarding Compulsory Insurance for Clinical Research in Humans  
- 
Sept 2015: adaptation section 9.1, 9.2 and 12.5: text in accordance to WMO 
amendment on reporting SAE and temporary halt (section 10 of WMO) 
- 
Oct 2015: adaptation section 4.4 – comment [CCMO15], 8.2 and 10.1 with respect to 
methodology/statistics 
- 
Sept 2018: adaptation section 12.1 and comment [CCMO46] due to applicability 
GDPR as of May, 2018 
- 
April 2024: link to template protocol to be used for CTR studies added and additional 
explanation and comments in section 9 Safety reporting 
- 
Nov 2024: removal of information related to studies with a medicinal product and 
replacing ToetsingOnline with Research Portal that will be launched on February 3, 
2025. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PROTOCOL TITLE: PlAnt Vs animal based Oral nutritional Supplements: Patients’ opinions 
and Nutritional outcomes: A multicenter pilot feasibility study (PAVOS) 
Protocol ID 
 
Short title 
Plant-based vs animal-based oral nutritional 
supplements 
Version 
4.0 
Date 
05-12-2025 
Coordinating investigator/project 
leader 
 
Dr. Manon van den Berg 
Radboud university medical center 
Geert Grooteplein Zuid 10 
6525 GA Nijmegen 
Phone: (+31) 24-36 35129 
Manon.vandenberg@radboudumc.nl 
Principal investigator(s) (in 
Dutch: hoofdonderzoeker/ 
uitvoerder) 
<Multicenter research: per site> 
 
M.A. Reintjes, MSc 
Radboud university medical center  
PhD Candidate of Gastroenterology and Hepatology 
- Dietetics 
Geert Grooteplein Zuid 10 
6525 GA Nijmegen 
Phone: (+31) 6 214 78 603 
Maud.reintjes@radboudumc.nl 
Principal investigator in both Radboudumc and 
Maastricht UMC+.  
 
 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
Radboud university medical center 
 
 
Subsidising party 
 
 
 
 
 
Fresenius Kabi Deutschland GmbH 
Annalena Neumann 
Else-Kroener-Strasse 1  
61352 Bad Homburg  
Germany 

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annalena.neumann@fresenius-kabi.com 
Independent expert(s) 
Dr. Geert Wanten  
Radboud university medical center 
Geert Grooteplein Zuid 10 
6525 GA Nijmegen 
geert.wanten@radboudumc.nl 
 
 
Prof. Dr. Marieke van den Beuken 
Maastricht University Medical Center + 
P. Debyelaan 25 
6229 HX Maastricht 
m.vanden.beuken@mumc.nl 
 
 
Laboratory sites   
Not applicable 
 
 
Pharmacy  
Not applicable  
 
 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Head of Department: 
Dr. D.J. de Jong, Head of the 
Gastroenterology Department 
 
 
 
Coordinating Investigator/Project 
leader/Principal Investigator: 
Dr. M.G.A. van den Berg, Theme leader 
nutrition, clinical dietician/ researcher 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TABLE OF CONTENTS  

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1. 
INTRODUCTION AND RATIONALE .............................................................................11 
2. 
OBJECTIVES ................................................................................................................13 
3. 
STUDY DESIGN ...........................................................................................................14 
4. 
STUDY POPULATION ..................................................................................................15 
4.1 Population (base) ........................................................................................................15 
4.2 Inclusion criteria ..........................................................................................................15 
4.3 Exclusion criteria .........................................................................................................15 
4.4 Sample size calculation ...............................................................................................16 
5. 
TREATMENT OF RESEARCH PARTICIPANTS ...........................................................16 
5.1 Investigational product/treatment ................................................................................16 
5.2 Use of co-intervention (if applicable) ...........................................................................16 
5.3 Escape medication (if applicable) ................................................................................16 
6. 
INVESTIGATIONAL PRODUCT ....................................................................................16 
6.1 Name and description of investigational product(s) .....................................................16 
6.2 Summary of findings from non-clinical and studies ......................................................16 
6.3 Summary of findings from clinical studies ....................................................................17 
6.4 Summary of known and potential risks and benefits ....................................................17 
6.5 Description and justification of route of administration and dosage .............................17 
6.6 Dosages, dosage modifications and method of administration ....................................17 
7. 
NON-INVESTIGATIONAL PRODUCT ...........................................................................17 
7.1 Name and description of non-investigational product(s) ..............................................18 
7.2 Summary of findings from non-clinical studies .............................................................18 
7.3 Summary of findings from clinical studies ....................................................................18 
7.4 Summary of known and potential risks and benefits ....................................................18 
7.5 Description and justification of route of administration and dosage..............................18 
7.6 Dosages, dosage modifications and method of administration ....................................18 
7.7 Preparation and labelling of Non Investigational Medicinal Product .............................18 
7.8 Drug accountability ......................................................................................................18 
8. 
METHODS ....................................................................................................................18 
8.1 Study parameters/endpoints .......................................................................................18 
8.1.1 
Main study parameter/endpoint .......................................................................18 
8.1.2 
Secondary study parameters/endpoints (if applicable) ....................................18 
8.1.3 
Other study parameters (if applicable) .............................................................18 
8.2 Randomisation, blinding and treatment allocation .......................................................18 
8.3 Study procedures ........................................................................................................19 
8.4 Withdrawal of individual research participants .............................................................23 
8.4.1 
Specific criteria for withdrawal (if applicable) ...................................................23 
8.5 Replacement of individual research participants after withdrawal ................................23 
8.6 Follow-up of research participants withdrawn from treatment ......................................23 
8.7 Premature termination of the study..............................................................................23 
9. 
SAFETY REPORTING ..................................................................................................23 
9.1 Temporary halt for reasons of research participant safety ...........................................23 

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9.2 AEs, SAEs ..................................................................................................................23 
9.2.1 
Adverse events (AEs) ......................................................................................23 
9.2.2 
Serious adverse events (SAEs) .......................................................................24 
9.3 Follow-up of adverse events........................................................................................25 
9.4 Data Safety Monitoring Board (DSMB) / Safety Committee .........................................25 
10. 
STATISTICAL ANALYSIS ..........................................................................................25 
10.1 Primary study parameter(s) .......................................................................................25 
10.2 Secondary study parameter(s) ..................................................................................25 
10.3 Other study parameters .............................................................................................26 
10.4I nterim analysis (if applicable) ...................................................................................26 
11. 
ETHICAL CONSIDERATIONS ...................................................................................26 
11.1 Regulation statement ................................................................................................26 
11.2 Recruitment and consent ..........................................................................................26 
11.3 Objection by minors or incapacitated research participants (if applicable) .................27 
11.4 Benefits and risks assessment, group relatedness ....................................................27 
11.5 Compensation for injury ............................................................................................28 
11.6 Incentives (if applicable) ............................................................................................28 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .........................28 
12.1 Handling and storage of data and documents ...........................................................28 
12.2 Monitoring and Quality Assurance .............................................................................29 
12.3 Amendments .............................................................................................................29 
12.4 Annual progress report ..............................................................................................29 
12.5 Temporary halt and (prematurely) end of study report ...............................................29 
12.6 Public disclosure and publication policy.....................................................................29 
13. 
STRUCTURED RISK ANALYSIS...............................................................................30 
13.1 Potential issues of concern........................................................................................30 
13.2 Synthesis ..................................................................................................................31 
14. 
REFERENCES ..........................................................................................................32 
 
 
 
 
 
 
 
 
 
 
 
 
LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  

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AE 
BIA 
BMI 
Adverse Event 
Bioelectrical Impedance Analysis  
Body Mass Index 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: 
Centrale Commissie Mensgebonden Onderzoek 
DSMB 
EPR 
ESPEN 
FM 
FFM 
Data Safety Monitoring Board 
Electronic Patient Record 
European Society of Parenteral and Enteral Nutrition 
Fat Mass 
Fat-Free Mass 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation; in Dutch: Algemene Verordening 
Gegevensbescherming (AVG) 
IC 
Informed Consent 
METC 
 
MNA 
MUST  
ONS 
PG-SGA-
(SF) 
Medical research ethics committee (MREC); in Dutch: medisch-
ethische toetsingscommissie (METC) 
Mini Nutritional Assessment 
Malnutrition Universal Screening Tool 
Oral Nutritional Supplements 
Patient Generated Subjective Global Assessment (Short Form) 
Review 
Committee 
RCT 
RNIT 
Medical research ethics committee (MREC) or CCMO 
 
Randomized Controlled Trial 
Randomized Controlled Non-Inferiority Trial 
(S)AE 
SNAQ 
SPPB 
(Serious) Adverse Event 
Short Nutritional Assessment Questionnaire 
Short Physical Performance Battery 
Sponsor 
 
 
 
 
SQUASH 
TUG 
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. 
Short Questionnaire to Assess Health-enhancing physical activity 
Timed Up and Go 

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UAVG 
 
WHO 
Dutch Act on Implementation of the General Data Protection 
Regulation; in Dutch: Uitvoeringswet AVG 
World Health Organization  
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet 
Medisch-wetenschappelijk Onderzoek met Mensen 

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SUMMARY 
Rationale: Risk of malnutrition is a common condition in hospitalized patients, with a 
prevalence up to almost 40% depending on the specific patient population. As part of the 
dietary counseling, oral nutritional supplements (ONS) (i.e., energy and protein-rich drinks) 
are advised when habitual oral nutritional intake remains inadequate (75% of protein and 
energy requirements). ONS are effective in increasing total energy and protein intake, 
resulting in less complications and re-admissions, as well as improved body weight and 
physical functioning.  
Recently the Dutch Ministry of Health, Welfare and Sport and the Dutch Federation of 
University centers signed the Green Deal “Working together on sustainable care” in which 
they agreed on “Green and climate neutral care” by 2026. This also includes meeting criteria 
for purchasing medical and non-medical nutrition in hospitals for future tenders. 
The development of ONS transitioning towards more plant-based proteins already receives 
much attention, which is deemed relevant in terms of overall sustainability. However, so far 
no studies have investigated the effectiveness of long-term use of plant-based ONS on an 
adequacy of protein and energy intake, nutritional status, muscle status, as well as physical 
and clinical outcomes. Hence, further research is needed to address the knowledge gaps on 
effectiveness of plant-based ONS. Yet, before conducting a randomized controlled trial 
(RCT), it is essential to first assess the feasibility of such a study in terms of patient 
recruitment, drop-out rates, adherence, and feasibility of study measurements. The current 
protocol describes this pilot feasibility, the results of which will provide essential insights to 
subsequently setup a study protocol for a full scale RCT to address effectiveness of plant-
based ONS vs (traditional) animal-based ONS. Thus, this pilot feasibility study aims to 
assess the feasibility of a multicenter randomized controlled non-inferiority trial (RNIT) to 
compare plant-based ONS versus animal-based ONS.  
Objective: The primary objective of this study is to investigate the feasibility (patient 
recruitment, drop-out rate, adherence, and study measurements) of a multicenter RNIT 
comparing plant-based versus animal-based ONS. The secondary objective of this study is 
to evaluate the energy and protein intake versus requirements, nutritional status, muscle 
status, physical and clinical outcomes, and patient's satisfaction with long-term 
supplementation. 
Study design: A multicenter pilot randomized feasibility study 
Study population: Patients from the medical oncology, lung diseases, cardiology, 
cardiothoracic surgery, and orthopaedic departments at risk for inadequate nutritional intake 
treated at Maastricht UMC+ and Radboudumc.  

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Intervention (if applicable): the intervention group receives plant-based ONS 
(Fresubin® Plant-based Drink vanilla) and the control group receives animal based ONS 
(Fresubin® Yodrink raspberry) during hospital admission/treatment and up to 3 months after.  
Main study parameters/endpoints:  The primary endpoint of the study is the feasibility of  
the RNIT with respect to the recruitment, drop-out, adherence, and study measurements.  
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: This study will not cause much additional burden on the patients in 
addition to their normal treatment as measurements are carried out during their hospital 
admission, or when possible, they are already present in the hospital for another 
appointment at the outpatient clinic. There will be two moments where measurements will be 
performed. The additional time needed to performing the measurements of this study will be 
approximately 90 minutes, both at the start and at the end of the intervention period. After 
one and after two months, a short ‘check-in’ will be done (phone call or at the hospital if 
patient has appointment there), this takes approximately 10 minutes. 
The participants are asked to perform 3 physical tests and complete questionnaires, which 
could be experienced as exhausting/ a burden. There are no further risks associated with this 
research. Patients will not perceive direct benefits from participation in this study. It is 
expected that the use of ONS will increase energy and protein intake of the participants, 
which in turn could improve their nutritional status.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. INTRODUCTION AND RATIONALE 
 
Risk of malnutrition is highly prevalent in hospitals, with prevalence rates up to almost 40% 
on hospital admission, depending on the specific patient population (1-3). Especially in 
oncological, surgical and elderly patients, malnutrition is very common with reported 
prevalence ranging from 21% of severe risk on malnutrition up to even 40% in specific 
cancer types such as head and neck, gastrointestinal, lung, ovarian and urological cancer 
(4,5) and up to 66% in older patients in acute care and rehabilitation (6). Malnutrition is 
associated with poor physical functioning, impaired wound healing, complications, prolonged 
duration of hospitalization, lower quality of life and increased mortality (7-9). In the 
Netherlands, the additional health care costs associated with malnutrition are estimated at an 
annual € 1.8 billion (10). Given its prevalence and the associated negative health 
consequences, the Dutch Inspectorate of Health and Youth has included ‘Malnutrition’ in the 
“Basic set of medical specialist care” as a target for improvement for 2023 and beyond. The 
objective for improvement described in this Basic set is to diagnose and treat malnutrition in 
an early phase before, during and/or after hospitalization, while also giving special attention 
to continuation of treatment after discharge, in the home situation (11). In all Dutch hospitals, 
patients should be screened for malnutrition upon hospitalization (MUST ≥2/SNAQ≥3/PG-
SGA-SF ≥9). 
Throughout hospitalization, food intake of patients is often inadequate, due to reduced 
appetite and disease impact symptoms, such as pain, nausea, decreased taste and smell 
(12). Adding further complexity to this problem, nutritional requirements are increased due to 
illness, treatment and the healing process. As such, it can be challenging to adequately meet 
the nutritional requirements during the course of hospitalization and rehabilitation. Patients at 
risk of malnutrition will receive individual counseling by a dietitian, aimed at reaching 
adequate protein and energy intake. As part of this nutritional counseling, oral nutritional 
supplements (ONS) (i.e., energy and protein-rich drinks) are advised when habitual oral 
nutrition remains inadequate (75% of protein and energy requirements) (13). ONS are 
effective in increasing total energy and protein intake, resulting in less complications and re-
admissions, as well as improved body weight and physical functioning (14). Currently 
available ONS mostly contain animal-based proteins, usually in the form of dairy proteins, 
ensuring high-quality proteins with regard to digestibility, amino acid composition, and 
bioavailability.  
Recently the Dutch Ministry of Health, Welfare and Sport and the Dutch Federation of 
University centers signed the Green Deal “Working together on sustainable care” in which 
they agreed on “Green and climate neutral care” by 2026. One of the five goals is to 
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meeting criteria for purchasing medical and non-medical nutrition in hospitals for future 
tenders. 
Already much attention is given to replacing part of the animal-based protein in hospital diets 
with plant-based protein sources, which is deemed relevant in terms of overall sustainability 
as well as enabling to feed the ever-growing world’s population (16). Although in general, 
plant-based proteins are assumed to be of less nutritional value (e.g., less complete amino 
acid profile, lower digestibility), more and more options are being developed to improve the 
bioavailability and nutritional value of more sustainable, plant-based proteins, thereby 
supporting their use to meet specific protein and amino acid requirements. For example, 
various legumes such as soy, lentils, and pea, and/or (combinations of) wheats and nuts, 
and even insect proteins have been suggested as alternative protein sources. The first 
studies in young, healthy adults even confirm that ingestion of an ample amount of 
(combinations of) such plant-based proteins can induce a similar anabolic response as 
compared to high-quality milk protein (17). One of the important factors that drives the 
anabolic response to protein ingestion is the essential amino acid content of the protein with 
leucine being of particular importance (18). In this respect, soy protein is traditionally viewed 
as a relevant plant-based protein source due to its excellent digestibility as well as its 
relatively high essential amino acid content (27%) and leucine content (19). Although soy 
protein supplementation has been suggested as a promising strategy for maintaining muscle 
mass and function in older people, the more long-term effects in both healthy and more 
compromised (clinical) populations remain to be established (20). 
The transition towards more plant-based ONS already receives much attention. However, it 
is unknown whether patient satisfaction (e.g., taste, smell, satiety, opinion) of plant-based 
ONS is similar compared to regular animal-based products. Moreover, so far the 
effectiveness of plant-based ONS to support adequate protein and energy intake, nutritional 
status, muscle status, as well as physical and clinical outcomes with long-term 
supplementation has not been investigated. Hence, further research is needed to address 
these knowledge gaps. However, before conducting a randomized controlled trial (RCT), it is 
essential to first assess the feasibility of such a study in terms of patient recruitment, drop-out 
rates, adherence, and feasibility of study measurements. The current protocol describes this 
pilot feasibility study, the results of which will be used to setup the study protocol for full scale 
RCT. This pilot feasibility study aims to assess the feasibility of a (subsequent) multicenter 
randomized controlled non-inferiority trial (RNIT) to evaluate energy and protein intake 
versus requirements in patients with cancer and lung diseases, cardiology patients, patients 
with cardiothoracic surgery, and orthopaedic patients  at risk for inadequate nutritional intake 
when using plant-based or animal-based ONS.  
 

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2. OBJECTIVES 
 
Primary Objective:  
The primary objective of this study is to investigate the feasibility (patient recruitment, drop-
out rates, adherence, and study measurements) of a multicenter RNIT comparing plant-
based versus animal-based ONS in patients with cancer and lung diseases, cardiology 
patients, patients with cardiothoracic surgery, and orthopaedic patients at risk for inadequate 
nutritional intake.  
 
Primary research question: 
What is the feasibility of a multicenter RNIT comparing plant-based ONS versus animal-
based ONS in patients with cancer and lung diseases, cardiology patients, patients with 
cardiothoracic surgery, and orthopaedic patients at risk for inadequate nutritional intake with 
respect to the patient recruitment, drop-out rates, adherence, and study measurements?  
 
Sub-questions: 
Recruitment: 
• 
What is the recruitment rate?  
• 
What are characteristics of included and excluded patients (per patient group)? 
 
Drop-out: 
• 
What is the drop-out rate (percentage of patients that dropped out)?  
• 
At what time points in the study (week number after inclusion) do patients drop out? 
• 
What are reasons for dropping out? 
 
Adherence: 
• 
What is the percentage of ONS consumed versus advised? 
• 
What are the reasons of not filling out questionnaires? 
 
Study measurements:  
• 
What is the percentage of successfully performed measurements? 
• 
What are reasons for unsuccessful measurements? 
 
Secondary Objective(s):  
To assess the energy and protein intake, nutritional status, muscle status, physical and 
clinical outcomes, and patient’s satisfaction of long-term use of ONS.  

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Secondary research questions: 
 
1. What is the energy and protein intake in patients receiving plant-based ONS with 
patients receiving animal-based ONS?  
 
2. How do nutritional status, muscle mass status, physical and clinical outcomes differ 
between patients using plant-based ONS compared to patients using animal-based 
ONS?  
 
3. How are the plant-based ONS and animal-based ONS evaluated regarding patients’ 
satisfaction (taste, smell, satiety), their wishes and needs, and their opinion about 
sustainable nutrition? 
 
 
3. STUDY DESIGN 
This study is a pilot randomized feasibility study in patients with cancer and lung diseases, 
cardiology patients, patients with cardiothoracic surgery, and orthopaedic patients at risk for 
inadequate nutritional intake to evaluate feasibility and patient satisfaction necessary to 
determine a suitable patient population and calculate the sample size for a larger RNIT (i.e. 
study 2). In study 2, a large RNIT will be conducted to establish the long-term efficacy of 
plant-based vs animal-based ONS. During this pilot study, patients who are advised ONS 
according to usual care and signed informed consent (IC) will be randomized to receive 
either plant-based ONS or animal-based ONS. Several measurements will be performed at 0 
and 3 months. A total of 60 patients will be included. The main aim is to establish the 
feasibility in terms of recruitment, drop-out rate, adherence, and study measurements of the 
different subpopulations, reflecting feasibility for performing study 2. Furthermore, we will 
collect data on protein and energy intake, which will be used for the sample size calculation 
of study 2. Apart from the quantitative measurements, study 1 will also be setup as a 
qualitative study to determine patients’ satisfaction, wishes and needs towards the ONS. 
Data on patients’ satisfaction will only be used as observational data, no comparison 
between the two types of products will be made.  
Measurements will be performed during hospital admission, or before/after an already 
scheduled appointment at the hospital outpatient clinic (baseline T0), and three months after 
baseline (T3). Within these 3 months, patients will be contacted by the researcher 1 month 
after the start (T1) and 2 months after the start (T2) for a ‘check-in’ conversation. For this 
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hospital if the patient is already there for another appointment. The researcher will ask about 
any changes in body weight, discuss changes in the nutritional advice provided by the 
dietitian, ensure the patient is still correctly filling out the logbook, and address any questions 
or concerns related to the study. The study will be conducted at Radboud university medical 
center (Radboudumc) in Nijmegen, the Netherlands, and Maastricht University Medical 
Center (Maastricht UMC+) in Maastricht, the Netherlands.  
 
 
4. STUDY POPULATION 
4.1 Population (base)  
The study population will consist of patients with cancer and lung diseases, cardiology 
patients, patients with cardiothoracic surgery, and orthopaedic patients at risk for inadequate 
nutritional intake treated at Radboudumc or Maastricht UMC+. 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a participant must meet all of the 
following criteria: 
• 
Clinical patients with cancer and lung diseases, cardiology patients, patients with 
cardiothoracic surgery, and orthopaedic patients age ≥18 years, and treated at 
Radboudumc or Maastricht UMC+.  
• 
Patients who have been advised at least 2 bottles of ONS daily based on their 
nutritional requirements.  
• 
Written informed consent (IC) 
 
4.3 Exclusion criteria 
A potential participant who meets any of the following criteria will be excluded from 
participation in this study: 
• 
Patients who are or become dependent on tube or parenteral nutrition 
• 
Patients where life-extending therapy is no longer possible  
• 
Unable to follow up study instructions  
• 
Lactose intolerance 
• 
Soy allergy/intolerance 
• 
Vegan diet 
• 
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4.4 Sample size calculation 
We aim to enrol a convenience sample of 60 patients in this feasibility study, with n=30 per 
study group (i.e. plant-based vs animal-based ONS) which is deemed sufficient to answer 
the primary research question (21, 22).  
If the results of this study show that the intervention can be considered feasible, future 
research with a fully powered sample size shall be performed to investigate the effect of the 
intervention on all parameters.  
 
5. TREATMENT OF RESEARCH PARTICIPANTS 
5.1 Investigational product/treatment 
Intervention product: plant-based ONS, Fresubin® Plant-based Drink vanilla. This will be 
compared to regular ONS, Fresubin® Yodrink raspberry with a similar nutritional content, 
i.e.  200ml, 300 kcal, 15 gram protein. 
If the patient approves to participate in this study and signed the written IC then the 
patient will be randomised to one of the 2 groups: plant-based ONS or animal-based 
ONS.  
 
5.2 Use of co-intervention (if applicable) 
Not applicable  
5.3 Escape medication (if applicable) 
Not applicable  
 
6. INVESTIGATIONAL PRODUCT  
6.1 Name and description of investigational product(s) 
 
     6.1.1. Plant-based 
Investigational product is Fresubin® Plant-based Drink vanilla.  
 
6.1.2. Animal-based 
Control products is Fresubin® Yodrink raspberry. 
Both types of ONS have the same nutritional content, i.e. 200ml, 300 kcal, 15 gram protein 
 
6.2 Summary of findings from non-clinical and studies 
Not applicable, there are no previous studies done with this plant-based ONS that is related 
to this research.  

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6.3 Summary of findings from clinical studies 
Not applicable, no previous studies with this plant-based ONS have been performed before.   
6.4 Summary of known and potential risks and benefits 
There are no potential risks associated with this research. Patients will receive ONS as 
part of their regular treatment, however, with participating in this study they will be 
randomized to receive either the plant-based or animal-based ONS. Both types of ONS 
are already available and used in hospitals. Participating in this study has no specific 
additional benefit. Generally, the use of ONS is expected to increase the energy and 
protein intake for patients at risk for malnutrition, which in turn improves nutritional status. 
6.5 Description and justification of route of administration and dosage 
The dietitian or nurse will decide the number of bottles the patient needs per day, fully in 
accordance with usual care. The advice of the dietitian or nurse needs to be at least 2 
bottles ONS a day for patients to be eligible to participate in this study. This is based on 
their nutritional intake observed by the nurse or the dietitian will base this advice on their 
nutritional requirement at the start of their treatment. 2 bottles of ONS is equal to 600 kcal 
and 30g protein. This means that there need to be a gap between their intake and 
requirements of ≥600 kcal and ≥30 g protein, in order to advice the ONS. Nutritional 
requirements will be estimated for protein intake as 1.5-1.9 g/kg fat-free mass (FFM)/d 
and energy intake WHO formula + surcharge up to 50% according to the Dutch guidelines 
of malnutrition and the ESPEN guidelines Clinical nutrition in surgery, cancer, and 
geriatrics (6, 13, 23, 24).   
If the patient approves to participate in this study and signed the written IC then the 
patient will be randomised to one of the 2 groups: plant-based ONS or animal-based 
ONS.  
 
6.6 Dosages, dosage modifications and method of administration 
Dosage depends on advise of the dietitian or a nurse. This could be 2 bottles or more. 
Throughout the 3 months of the study, the advised amount of ONS may be adjusted to 
more or less bottles a day. This depends on their energy and protein intake and their 
requirements. Patients will record this advice in their logbook to ensure clarity to the 
researcher. The researcher will check this logbook with the patient.  
 
 
7. NON-INVESTIGATIONAL PRODUCT 
Not applicable  

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7.1 Name and description of non-investigational product(s) 
7.2 Summary of findings from non-clinical studies 
7.3 Summary of findings from clinical studies 
7.4 Summary of known and potential risks and benefits 
7.5 Description and justification of route of administration and dosage 
7.6 Dosages, dosage modifications and method of administration 
7.7 Preparation and labelling of Non Investigational Medicinal Product 
7.8 Drug accountability 
 
 
8. METHODS 
8.1 Study parameters/endpoints 
8.1.1 Main study parameter/endpoint 
The primary endpoint of the study is the feasibility (patient recruitment, drop-out rates, 
adherence, and study measurements) of a multicenter RNIT comparing plant-based 
and animal-based ONS in patients with cancer and lung diseases, cardiology 
patients, patients with cardiothoracic surgery, and orthopaedic patients at risk for an 
inadequate nutritional intake.  
8.1.2 Secondary study parameters/endpoints (if applicable) 
The secondary endpoints of this study is the energy and protein intake, nutritional 
status, muscle status, physical and clinical outcomes, and patient's satisfaction with 
long-term supplementation. 
8.1.3 Other study parameters (if applicable) 
Not applicable  
8.2 Randomisation, blinding and treatment allocation 
Patients will be randomized to either the plant-based ONS or animal-based ONS. 
Randomisation will be done by Castor EDC database. This system will generate the 
randomisation performed by stratification for 3 different patient populations: (1) oncology, 
(2) pulmonary diseases (3) other (including cardiology, cardiothoracic surgery, 
orthopaedic patients) and for the study location (Radboudumc and Maastricht UMC+). In 
this way, it will be done independently. Patients can not be blinded in this study since it is 

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not feasible to cover every bottle the patients drink in those 3 months (i.e. patients will 
receive already existing products with standard packaging and labelling). Nevertheless, 
the analyses will be carried out in a blinded manner.  
8.3 Study procedures 
 
Measurements during this study will be combined as best as possible during appointments 
planned within routine care at the hospital. Baseline measurements will take place at the 
start of the ONS treatment (T0) during hospital admission or during an appointment at the 
outpatient clinic. 1 month after the start (T1) and 2 months after the start (T2) the researcher 
will have a brief ‘check-in’ via a phone call or a conversation at the hospital if the patient is 
there for another appointment. 3 months after initiation (T3) the same measurements will be 
performed as at baseline (T0). In addition, at T3, the researcher will conduct an interview 
about patients’ satisfaction about the ONS (Table 1).  
 
 
Table 1: Overview of the study measurements for each time point. 
Measurements 
Treatment 
initiation  
(T0) 
1 month after 
initiation (T1) 
2 months after 
initiation (T2) 
3 months after 
initiation (T3) 
Body height, body 
weight, usual 
body weight, BMI  
X 
X 
X 
X 
Nutritional intake 
(protein and 
energy)  
X  
 
 
X 
Compliance ONS  X 
X  
X 
X 
Check-in 
conversation 
 
X 
X 
 
Nutritional status 
(PG-SGA, fat  
mass and fat-free  
mass, and 
muscle  
thickness) 
 
X 
 
 
X 

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Hand grip 
strength 
X 
 
 
X 
Physical Activity 
(SQUASH) 
X 
 
 
X 
Physical 
performance 
(TUG, SPPB) 
X 
 
 
X 
Quality of life 
(EORTC-QoL-
C30) and 
Clinical outcome 
measures (length 
of hospital stay, 
complications, 
readmission and 
mortality) 
 
X 
 
 
X 
Patient's 
satisfaction about 
the Oral 
nutritional 
supplements 
 
 
 
X 
 
Body height, body weight, BMI are measured on a calibrated scale and stadiometer. Usual 
body weight will be asked. During the check-in process, patients are required to weigh 
themselves either at home or at the hospital, if they have another appointment scheduled 
there. 
 
Nutritional intake and compliance of oral nutritional supplements used during hospital 
admittance will be measured by food registration in the Electronic Patient Record (EPR) 
registered by the nutritional assistant with a cross-check of a nutritional researcher. 
Additionally, the researcher will also ask if there are any variations in their food intake on bad 
versus good days and whether there have been any changes in eating habits compared to a 
month ago. Patients who are not admitted to hospital but come to the hospital on an 
outpatient basis, are being asked to fill out a 3-day food diary (2 week days and 1 weekend 
day). After 3 months the all patients will all fill out a 3-day food diary. During the 3 months, 

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participants will keep a logbook which they must record how much ONS was consumed daily 
for the total study period.  
Individual protein requirement will be set at 1.5-1.9 g/kg FFM and energy requirements at 
WHO formula + surcharge up to 50% according to the Dutch guidelines of malnutrition and 
the ESPEN guidelines Clinical nutrition in surgery and cancer (6, 13, 23, 24).   
 
For the check-in conversations the researcher will either make a phone call or have brief 
conversation at the hospital if the patient is already there for another appointment. The 
researcher will ask about any changes in body weight, discuss changes in the nutritional 
advice provided by the dietitian, their satisfaction about the ONS, ensure the patient is still 
correctly filling out the logbook, and address any questions or concerns related to the study. 
 
Nutritional status will be measured by the Scored Patient-Generated Subjective Global 
Assessment (PG-SGA). The full PG-SGA has been validated among different patient groups 
and reported to be a simple instrument to use. Since the PG-SGA consists of a patient-
reported part, the Dutch version of the PG-SGA will be used. This version is already 
available and considered comprehensible and easy to complete by patients, and 
comprehensible and relevant by professionals (20). One part is completed by the patient and 
another part by a specialist. 
 
Body composition Fat mass (FM) and fat-free mass (FFM) will be measured using 
bioelectrical impedance analysis (BIA). The BIA device measures resistance in the body to 
an alternating current at 50kHz. FFM is then calculated with a formula that includes 
resistance, height, weight, sex and age. BIA represents a simple, non-invasive measure that 
takes only 5-10 min to perform. 
Muscle thickness will be measured by muscle ultrasound with the Lumify (Philips) at the m. 
rectus femoris, vastus intermedius and m. biceps brachii. 
 
Handgrip strength will be measured with the JAMAR handheld dynamometer in a standardized 
manner. Participants are asked to sit in an upward position with their elbows in a 90-degree 
angle and the wrist in a neutral position (thumb side upwards) and squeeze as hard as possible. 
Both hands will be measured 3 times, the highest value is used. Handgrip strength is a valid 
non-invasive method to measure muscle functionality and serves as a predictor for the overall 
muscle strength and change in nutritional status of participants. 
 
Physical activity will be assessed using the questionnaire Short QUstionnaire to Assess 
Health-enhancing physical activity (SQUASH) at baseline and 3 months. 

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To measure Physical performance, the Short Physical Performance Battery (SPPB) and Timed 
Up and Go (TUG) will be used. The SPPB combines 3 separate tests, measuring gait speed, 
standing balance, and ability to rise from a chair. For the SPPB the scores of the 3 sub tests 
are all converted to a score range of 0-4, making the maximum score 12 points, indicating the 
best physical function (25). The TUG measures the time it takes for the patient to rise from a 
chair, walk comfortably 3 meters, turn around, walk back, and sit down. The patient may use 
their own walking aid and/or orthosis, but no physical assistance or encouragement should be 
given. This measurement is considered to be a reliable, cost-effective, safe, and time-efficient 
way to evaluate overall physical performance (26). The TUG and SPPB will be performed at 
baseline and 3 months. 
 
Quality of Life will be evaluated using the EORTC-QoL-C30, a validated questionnaire for 
measuring quality of life. Questionnaires will be scored according to the procedures specified 
by the EORTC-QoL-C30 scoring manual (27). 
 
Clinical outcome measures such as length of hospital stay, mortality and re-admissions within 
3 months after hospital discharge will be determined retrospectively by using information from 
the EPR and confirmed by questionnaire with the participant since admissions from hospitals 
outside this study are not registered in an EPR. Complications within 3 months after hospital 
discharge will be determined by using information from the EPR. A complication is defined in 
line with the Dutch Association of Medical Specialists (FMS) as an unintended and undesirable 
event or condition during or following medical specialist intervention, which is so harmful to the 
health of the participant that change in medical treatment is necessary or that there is 
irreversible damage. Complications will be obtained from patients’ medical records during 
hospital stay up to 3 months after baseline and coded as infectious, decubitus, surgical (non-
infectious) complications and other (e.g., cardiopulmonary). 
 
Qualitative interviews at T3 
All participants of the pilot feasibility study will be approached by the researcher for an in-
depth interview. Patients will be interviewed using a topic list. The topic list is based on the 
subscale ‘Quality’ of the validated ‘measure of food access in hospitals’ questionnaire (28), 
adapted to the use of ONS, and complemented with additional questions about sustainability. 
These interviews will be conducted using purposeful sampling based on sex, age, and 
patient group. We will continue these interviews till data saturation (no new information 
emerges) is reached. The estimated time for this interview will be set at 45 minutes. 
 

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8.4 Withdrawal of individual research participants 
Participants can leave the study at any time for any reason without any 
consequences if they wish to do so. The investigator can decide to withdraw a 
participant from the study for urgent medical reasons. 
8.4.1 Specific criteria for withdrawal (if applicable) 
 
 
Not applicable 
8.5 Replacement of individual research participants after withdrawal 
In this pilot feasibility study, participants will not be replaced after withdrawal, as both 
recruitment and drop-out rates are key measurements of feasibility.  
8.6 Follow-up of research participants withdrawn from treatment 
 
Not applicable  
8.7 Premature termination of the study 
In case the study is terminated prematurely, the investigators will notify the CCMO 
 and the local ethical committee within 15 days, including the reasons for premature 
 termination. Premature termination of the study is possible if the sponsor (i.e. 
 Radboudumc), the government or the judging medical ethical committee (METC 
Radboudumc) decides to end the study. This could be decided when the study has 
led to unsafe or unethical situations. 
 
 
9. SAFETY REPORTING 
9.1 Temporary halt for reasons of research participant safety 
 
In accordance to 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 
 
participant health or safety. The sponsor will notify the review committee 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 review committee. The 
 
investigator will take care that all participants are kept informed.  
9.2 AEs, SAEs  
9.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a participant 
during the study, whether or not considered related to oral nutritional supplements 
intervention or study procedures. All adverse events reported spontaneously by the 
participant or observed by the investigator or his staff will be recorded. 

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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 hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- 
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 will not be considered as a serious adverse event. 
 
The illness in this study population, consisting of cancer and lung diseases, 
cardiology-, cardiothoracic surgery- and orthopaedic conditions often progresses to a 
life-threatening stage due to the advanced nature of their disease. Similarly, 
prolonged hospitalizations are frequent among cancer patients due to the need for 
ongoing treatment, as well as among lung and cardiology/cardiothoracic surgery 
patients who may experience complications related to their disease and treatment  
conditions with no relation to the study interventions. Additionally, congenital 
anomalies or birth defects are not relevant to this study population, these conditions 
are not typically seen.   
Therefore, the investigator will report all SAEs to the sponsor without undue delay 
after obtaining knowledge of the events, except for the following SAEs:   
- 
is life threatening (at the time of the event); 
- 
requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- 
is a congenital anomaly or birth defect 
 
The sponsor will report the SAEs through the web portal Research Portal to the 
review committee that approved the protocol, within 7 days of first knowledge for 
SAEs that result in death or are life threatening followed by a period of maximum 8 
days to complete 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 indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the 
protocol.  
 
9.4 Data Safety Monitoring Board (DSMB) / Safety Committee 
Not applicable  
 
 
10. STATISTICAL ANALYSIS 
The Statistical Package for the Social Sciences for Windows (version 29.0; IBM, SPSS  
Inc., Chicago, IL, USA) will be used for statistical analysis. Descriptive statistics will be  
used to explore the data and will be presented in tables and figures. Normally distributed 
data will be expressed as mean and standard deviation or as median, interquartile range, 
and minimum and maximum. Categorical data will be summarized by frequency or 
percentage.  
10.1 Primary study parameter(s) 
The primary analysis will explore the feasibility of a multicenter RNIT comparing plant-
based and animal-based ONS in patients at risk of malnutrition with respect to the patient 
recruitment, drop-out rate, adherence, and the feasibility of study measurements.  
 
10.2 Secondary study parameter(s)  
Secondary analysis will provide the mean difference in protein intake i.e., total protein 
intake in g/kg FFM/d (based on dietary history) divided by 1.5-1.9 g/kg FFM/d, times 
100%. In addition, the mean difference in energy intake i.e., total energy intake in kcal/d 
(based on dietary history) divided by WHO formula + surcharge up to 50%, times 100%. 
ANCOVA analysis will be used to estimate the effect of the group as independent factor 
on ‘mean difference in intake vs recommendation’ at T3 as dependent variable and T0 
measurement as covariate. This is only meant as exploratory analyses and to be used for 
sample size calculations for the subsequent full-scale RCT.  
The aim of the semi-structured interviews is to understand the experiences and 
perspectives of the patients using ONS regarding satisfaction (taste, smell, satiety), as 
well as their wishes and needs. Additionally, we are interested in their views of 

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sustainable nutrition. Therefore, these interviews will be approached from a 
phenomenological perspective. Qualitative analysis: all interviews will be audiotaped, and 
the records will be transcribed verbatim. Data will be analyzed using thematic analysis, 
starting with initial open coding to identify relevant data by minimal two independently 
working researchers. Codes will then be grouped into categories, the axial codes, and 
overarching themes will be identified. For this analysis, the software Atlas.ti will be used. 
 
10.3 Other study parameters 
Not applicable  
10.4 Interim analysis (if applicable) 
 
Not applicable  
 
11. ETHICAL CONSIDERATIONS 
11.1 Regulation statement 
The study will be conducted according to the principles of the Declaration of Helsinki  
in the current version of Helsinki, 2024 (29), guidelines for Good Clinical Practice (30),  
in accordance with the Medical Research Involving Human Subjects Act (Dutch: Wet  
medisch-wetenschappelijk onderzoek met mensen) (31), and in accordance with the  
General Data Protection Regulation (GDPR) (Dutch: Algemene Verordening  
Gegevensbescherming) (32). 
11.2 Recruitment and consent 
When during a consultation the dietitian decides that the patient needs at least 2 bottles of 
ONS and the patient is intended to use that amount of ONS, the dietitian checks eligibility for 
inclusion in the study based on the in- and exclusion criteria. When patients are eligible to 
participate in the study the dietitian will give the patient information about the study and ask 
permission to the patient whether they can be contacted by a researcher. If the patient 
agrees on being contacted by the researcher, the dietitian hands out the patient information 
letter, so they can read this in advance. The dietitian will inform the researcher which patients 
can be approached to participate in the study. Another way patients may receive ONS is 
through the nurse’s advice. In some cases, the nurse recommends that the patient take two 
bottles of ONS per day based on a MUST score of ≥2. The patient will continue using ONS 
during hospitalization and, upon discharge, will receive a referral letter to a dietitian in 
primary care. This ensures that patients continue to receive nutritional guidance at home. 
The researcher can check in the EPR which patients have an advice for ONS. If a patient is 
eligible to participate in the study, the researcher will contact the nurse, who will then 

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approach the patient to ask whether they are interested in receiving more information about 
the study from the researcher. The researcher will contact the patient as soon as possible. In 
this (phone) conversation the researcher further explains the study, and the patient can ask 
his/her questions. After this conversation the patient has 24 hours to decide if they want to 
participate or not. During this time, the patient will have the opportunity to consider their 
participation. If additional time is required for decision-making, this will be accommodated. 
Because the patient is at risk for inadequate nutritional intake, it is important that after the 
dietitian has advised the ONS, the patient also receives the drinks within a short period of 
time. That is why it is essential that we randomize the patient into one of the groups after 24 
hours. If the patient is willing to participate, an appointment is made for the IC procedure. 
The IC form will be provided by the researcher and will be signed in a private room, prior to 
study initiation. Confidential processing of data and anonymity are guaranteed. Participants 
will have the opportunity to withdraw from the study at any time without the need to provide a 
reason. 
11.3 Objection by minors or incapacitated research participants (if applicable) 
Not applicable  
11.4 Benefits and risks assessment, group relatedness 
Participating in this study has no specific additional benefit. Generally, the use of ONS is 
expected to increase the energy and protein intake for patients, which in turn improves 
nutritional status. There are no potential risks associated with this research. Patients will 
receive ONS as part of their regular treatment, however, with participating in this study 
they will be randomized to receive either the plant-based or animal-based ONS. Both 
types of ONS are already available and used in hospitals. This study will not cause much 
additional burden on the patients in addition to their normal treatment as measurements 
are carried out during their hospital admission, or when possible, they are already present 
in the hospital for another appointment at the outpatient clinic. There will be 2 moments 
where measurements will be performed. The additional time they need to be available for 
the measurements of this study will be approximately 90 minutes for the baseline 
measurement and the measurements after 3 months. Within these 3 months, patients will 
be contacted by the researcher 1 month after the start (T1) and 2 months after the start 
(T2) for a ‘check-in’ conversation. For this conversation the researcher will either make a 
phone call or have brief conversation at the hospital if the patient is already there for 
another appointment. This conversation takes approximately 10 minutes. The participants 
are asked to perform 2 physical tests and complete questionnaires, which could be 
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11.5 Compensation for injury 
The sponsor/investigator has a liability insurance which is in accordance with article 7 of 
the WMO.  
The study protocol was reviewed by the Medical Ethical Committee of MUMC+, the 
Netherlands (METC 2025-0268) and Medical Ethical Committee Oost-Nederland (METC 
2025-17931) and exempted from ethical review, according to the Dutch Medical 
Research Involving Human Subjects Act (WMO). Therefore, there is no insurance for the 
research participants.  
11.6 Incentives (if applicable) 
Patients will not receive any (financial) compensation for participation in this study.  
 
 
12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 Handling and storage of data and documents 
Research data (including screening and enrolment files) will be stored in databases 
(Castoredc, Microsoft Excel, SPSS). Databases and audio recordings of the semi-
structured interviews will be stored in protected workspace for researchers at the 
department of Gastroenterology and Hepatology and Dietetics at Radboudumc and the 
department of Dietetics of Maastricht UMC+. The coordinating researchers in this project 
group will have managing rights and receive access to the research data. Other project 
group members (dietitians or master/bachelor intern students collecting data) will have 
rights for data-entry. Audio recordings will be deleted after the transcript is written. All 
study documents will be stored in a file that is only accessible for the researchers who are 
directly involved in the study. Written data will be locked in a room, which is sealed by an 
entrance code or where a smartcard is needed. This written data will also be entered in 
the database Castor EDC. Within this data base every participant receives a study 
number. Both the subject identification list and the coded data will be stored separately on 
the password protected workspace. Only the study numbers will be used for study 
documentation, annual progress reports and research publications. The patients will be 
informed about the study number use of research data in the patient information folder. In 
the IC form, subjects will be asked permission to use their coded data. In addition, 
patients will be asked if data may be exchanged between Radboudumc and Maastricht 
UMC+ in the IC form. ICs will be stored in the EPR, separated from the other documents. 
Participants will also receive a copy from the IC, signed by themselves and one of the 
researchers. Both the written data and the entered data in Castor EDC will be stored for 
up to 15 years after the study. The data of this research may only be made public (open 

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access) in anonymized form. The handling of personal data follows the European Union 
General Data Protection Regulation, the Dutch Act on Implementation of the General 
Data Protection Regulation (UAVG), and the privacy regulations of the Radboudumc and 
Maastricht UMC+. 
12.2 Monitoring and Quality Assurance  
Because this study is a non-wmo study, there will be no monitoring. 
12.3 Amendments  
Amendments are changes made to the research after a favourable opinion by the funder 
has been given. All amendments will be notified to the funder that gave a favourable 
opinion.  
Non-substantial amendments will not be notified to the review committee, but will be 
recorded and filed by the sponsor.  
12.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the funder 
once a year. Information will be provided on the date of inclusion of the first participant, 
numbers of participants included and numbers of participants 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 review committee 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 visit.  
The sponsor will notify the review committee 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 review committee 
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 review committee.  
12.6 Public disclosure and publication policy 
After analyzing all data, the goal is to present the results on (inter)national conferences 
and to publish the results in an international journal, independently on positive or negative 
outcome of the study. Also, the participants will be given insight into the general results, in 
the form of a summary. Individual results of the study will only be send to the participant if 
they specifically ask for this. This will be agreed with the sponsor in a contract. 
 
 

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13. STRUCTURED RISK ANALYSIS  
13.1 Potential issues of concern 
a. Level of knowledge about mechanism of action 
ONS (i.e., energy and protein-rich drinks) are advised when habitual oral nutrition remains 
inadequate (75% of protein and energy requirements) (13). ONS have been proven 
effective in increasing total energy and protein intake, resulting in less complications and 
re-admissions, as well as improved body weight and physical functioning (14). 
 
 
b. Previous exposure of human beings with the test product(s) and/or products with a 
similar biological mechanism 
In previous studies, ONS have been proven effective in increasing total energy and 
protein intake(14). One previous study is done with another plant-based ONS, this study 
demonstrate that a ready-to-drink plant-based ONS is highly complied with, tolerated, 
acceptable and safe, and is effective at increasing total energy, protein and micronutrient 
intakes, body weight and BMI, and reducing malnutrition risk (33). Both ONS used for this 
study are available on the market and is already used in hospitals.  
 
c. Can the primary or secondary mechanism be induced in animals and/or in ex-vivo 
human cell material? 
Experiments in animals or using ex vivo human cell material will not answer the research 
question of this study. We will particularly investigate patients with cancer and lung 
diseases, cardiology patients, patients with cardiothoracic surgery, and orthopaedic 
patients to gain novel information that can be used for the development of nutritional 
strategies to reduce malnutrition risk. Thereby, an important part of this pilot feasibility 
study is the patients’ satisfaction about the ONS.  
 
d. Selectivity of the mechanism to target tissue in animals and/or human beings 
Dietary protein-derived amino acids appear into the circulation and will be used by the 
entire human body (muscles, organs, skin). Plant-based medical nutrition contains high-
quality proteins through the use of plant-based protein isolates. Plant-based protein 
isolate is purified protein that has been extracted from a plant-based food source. In this 
way, plant-based protein isolates can be absorbed by the body just as well as animal 
proteins. Furthermore, the calories in ONS will be used by the human body as energy fuel.  
 
e. Analysis of potential effect 

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     No potential adverse effects are known for the use of ONS.  
 
f. Pharmacokinetic considerations 
Not applicable  
 
g. Study population 
Patients from the oncology, lung diseases, cardiology, cardiothoracic surgery, and 
orthopaedic departments at risk for inadequate nutritional intake, age ≥ 18 years, treated 
at Maastricht UMC+ and Radboudumc.    
 
h. Interaction with other products 
No interactions have been reported. 
 
i. Predictability of effect 
High predictability of effect has been reported from earlier intervention studies mentioned 
above with regard to the use of ONS in patients at risk of malnutrition.  
 
j. Can effects be managed? 
Strict inclusion and exclusion criteria have been set for the inclusion of participants. The 
experimental trials will be performed at the nursing ward or in the clinical research unit, 
dependent on the mobility of the participant. During measurements, a researcher will 
always be present. The strict guidelines on how to respond in case of emergency within 
the nursing wards of the hospital will be followed.  
 
13.2 Synthesis 
The overall risk of participation in this study is negligible for patients. Consuming dairy 
products will form risks for people suffering from lactose intolerance, and consuming soy 
products will form risks for people suffering from soy allergy / intolerance. Therefore, these 
people will be excluded from participating in this study. Both types of ONS are medically 
available and are therefore safe for human consumption. All measuring procedures are 
completely safe and routinely being performed within the Radboudumc and Maastricht 
UMC+. 
 
 
 
 
 

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14. REFERENCES 
 
1. Kruizenga H., Keeken S.van, Weijs P., et al. Undernutrition screening survey in 564,063 
patients: patients with a positive undernutrition screening score stay in hospital 1.4 d 
longer. Am J Clin Nutr 2016; 103(4): 1026-1032.  
2. Nederlandse Prevalentiemeting Ondervoeding in Ziekenhuizen (NPOZ) factsheet-NPOZ-
2015.pdf (kenniscentrumondervoeding.nl) 
3. van Vliet IMY, Gomes-Neto AW, de Jong MFC, Jager-Wittenaar H, Navis GJ. High preva-
lence of malnutrition both on hospital admission and predischarge. Nutrition. 2020 
Sep;77:110814. Doi: 10.1016/j.nut.2020.110814. Epub 2020 Mar 19. PMID: 32442829 
4. Durán Poveda M, Suárez-de-la-Rica A, Cancer Minchot E, Ocón Bretón J, Sánchez Per-
naute A, Rodríguez Caravaca G; PREMAS Study Group. The Prevalence and Impact of 
Nutritional Risk and Malnutrition in Gastrointestinal Surgical Oncology Patients: A Pro-
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