Naltrexone/Bupropion With or Without Very Low Calorie Ketogenic Diet for Weight Regain After Bariatric Surgery
Phase: NA
Conditions: Weight Regain Post Bariatric Surgery, Obesity (Disorder)
Sponsor: Universitaire Ziekenhuizen KU Leuven

[Type here] 
[Type here] 
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PROTOCOL FOR A PROSPECTIVE STUDY 
 
Naltrexone/bupropion with or without very low calorie 
ketogenic diet for weight regain after bariatric surgery 
RELAY 
Version number: v 1.3   –  Date 19/11/2024 
 
Internal ref. nbr:  S68952 
Sponsor 
University Hospitals Leuven (UZ Leuven) 
Herestraat 49, B-3000 Leuven 
 
Coordinating Investigator  
Fien Van der Borght 
 
 
 
 

UZ/KU Leuven 
 
 
Protocol: RELAY 
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Version: 1.3_19Nov2024 
 
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LIST OF PARTICIPATING SITES 
List Of Participating Sites 
Principal Investigator 
UZ Leuven 
Herestraat 49, 3000 Leuven 
Prof. dr. R. Vangoitsenhoven 
AZ Sint-Jan Brugge 
Ruddershove 10, 8000 Brugge 
Dr. B. Dillemans 
 
 
Confidentiality Statement 
The information in this document is strictly confidential and is available for review to 
Investigators, potential Investigators and appropriate Ethics Committees, Institutional Review 
Boards or Competent Authorities.  No disclosure should take place without written 
authorization from the Sponsor 
 
 

UZ/KU Leuven 
 
 
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SIGNATURES 
Title:  Naltrexone/bupropion with or without very low calorie ketogenic diet for weight regain after 
bariatric surgery 
Protocol: RELAY 
 
The undersigned confirm that the above referenced protocol has been acknowledged and accepted, and 
agree to conduct the Study in compliance with the approved protocol, and will adhere to: the ICH 
guidelines, the most recent version of the Declaration of Helsinki, the Belgian law of May 7th 2004 regarding 
experiments on the human person (as amended), the EU General Data Protection Regulation 2016/679 
(GDPR), relevant Belgian laws implementing the GDPR, the Belgian Law of August 22nd 2002 on patient 
rights, and any other regulatory requirements and Standard Operating Procedures (SOPs), as applicable. 
The undersigned agree not to disclose the confidential information contained in this document for any 
purpose other than the evaluation or conduct of the Study, without prior written consent of the Sponsor. 
The undersigned also commit to make the findings of the Study publicly available through publication and/or 
other dissemination tools, in accordance with this protocol and applicable regulations, without any 
unnecessary delay and to provide an honest, accurate and transparent account of the Study; and to explain 
any discrepancies or deviations from the approved Study protocol.  
 
 
Coordinating Investigator 
 
Prof. dr. R. Vangoitsenhoven 
………………………… 
………………………… 
………………………… 
         Name & Title 
            Signature 
              Date 
 
Principal Investigator (UZ Leuven) 
` 
Prof. dr. R. Vangoitsenhoven 
………………………… 
………………………… 
………………………… 
         Name & Title 
Signature 
Date 
 
 
 

UZ/KU Leuven 
 
 
Protocol: RELAY 
Internal Ref.: S68952 
 
 
Version: 1.3_19Nov2024 
 
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SIGNATURES 
 
Title:  Naltrexone/bupropion with or without very low calorie ketogenic diet for weight regain after 
bariatric surgery 
Protocol: RELAY 
 
The undersigned confirm that the above referenced protocol has been acknowledged and accepted, and 
agree to conduct the Study in compliance with the approved protocol, and will adhere to: the ICH 
guidelines, the most recent version of the Declaration of Helsinki, the Belgian law of May 7th 2004 regarding 
experiments on the human person (as amended), the EU General Data Protection Regulation 2016/679 
(GDPR), relevant Belgian laws implementing the GDPR, the Belgian Law of August 22nd 2002 on patient 
rights, and any other regulatory requirements and Standard Operating Procedures (SOPs), as applicable. 
The undersigned agree not to disclose the confidential information contained in this document for any 
purpose other than the evaluation or conduct of the Study, without prior written consent of the Sponsor. 
The undersigned also commit to make the findings of the Study publicly available through publication and/or 
other dissemination tools, in accordance with this protocol and applicable regulations, without any 
unnecessary delay and to provide an honest, accurate and transparent account of the Study; and to explain 
any discrepancies or deviations from the approved Study protocol.  
 
 
Coordinating Investigator 
 
Prof. dr. R. Vangoitsenhoven 
………………………… 
………………………… 
………………………… 
 
Name & Title 
Signature 
Date 
 
Principal Investigator (AZ Sint-Jan Brugge) 
 
Dr. B. Dillemans 
………………………… 
………………………… 
………………………… 
 
Name & Title 
Signature 
Date 
 
 
 
 
 
 
 
 

UZ/KU Leuven 
 
 
Protocol: RELAY 
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Version: 1.3_19Nov2024 
 
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TABLE OF CONTENTS 
PROTOCOL FOR A PROSPECTIVE STUDY ............................................................................................................. 1 
LIST OF PARTICIPATING SITES .................................................................................................................................... 2 
SIGNATURES ...................................................................................................................................................................... 3 
SIGNATURES ...................................................................................................................................................................... 4 
TABLE OF CONTENTS ................................................................................................................................................... 5 
LIST OF ABBREVIATIONS ............................................................................................................................................... 8 
FUNDING AND SUPPORT ............................................................................................................................................ 9 
ROLES AND RESPONSIBILITIES ................................................................................................................................. 10 
STUDY SYNOPSIS .......................................................................................................................................................... 11 
STUDY FLOWCHART .................................................................................................................................................. 13 
1 
Background and Rationale .................................................................................................................................... 16 
2 
Study Design and Objectives ................................................................................................................................ 17 
2.1 
Study objectives ............................................................................................................................................. 17 
2.2 
Primary Endpoints ......................................................................................................................................... 17 
2.3 
Secondary Endpoints .................................................................................................................................... 17 
2.4 
Study design .................................................................................................................................................... 17 
2.5 
Expected duration of the Study ................................................................................................................. 17 
3 
Study Population / Eligibility Criteria .................................................................................................................. 18 
3.1 
Inclusion criteria ............................................................................................................................................ 18 
3.2 
Exclusion criteria ........................................................................................................................................... 18 
4 
Study Procedures .................................................................................................................................................... 19 
4.1 
Participant consent and withdrawal of consent ..................................................................................... 19 
4.2 
Selection of Participants / Recruitment ................................................................................................... 19 
4.3 
Randomization Procedure .......................................................................................................................... 19 
4.4 
Premature discontinuation .......................................................................................................................... 19 
4.5 
By visit ............................................................................................................................................................. 20 
4.6 
Very Low Calorie Ketogenic Diet (VLCKD) ......................................................................................... 20 
4.7 
Naltrexone/bupropion ................................................................................................................................. 20 
4.7.1 Concomitant / Prohibited Medication / Treatment .............................................................................. 20 
4.8 
Lifestyle ............................................................................................................................................................ 21 
5 
Assessment of Safety .............................................................................................................................................. 21 
5.1 
Adverse Event Reporting ............................................................................................................................ 21 
5.1.1 
Definitions .................................................................................................................................................. 21 
5.1.1.1 Adverse Event (AE) ................................................................................................................................. 21 
5.1.1.2 Adverse Reaction (AR) ........................................................................................................................... 22 
5.1.1.3 Serious Adverse Event (SAE) ................................................................................................................ 22 

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5.1.2 
Adverse Events that do not require reporting ...................................................................................... 22 
5.1.3 
Recording and reporting of Adverse Events ........................................................................................... 22 
5.1.3.1 Assessment ................................................................................................................................................ 23 
5.1.3.2 Timelines for reporting ........................................................................................................................... 23 
5.1.3.3 Follow-up ................................................................................................................................................... 24 
5.1.3.4 Pregnancy ................................................................................................................................................... 24 
5.1.3.5 Death .......................................................................................................................................................... 24 
5.1.4 
Reporting requirements to Ethics Committee’s (EC’s) ....................................................................... 24 
5.1.4.1 Annual reporting ...................................................................................................................................... 24 
5.1.4.2 Overview reporting requirements ....................................................................................................... 25 
5.1.5 
Pharmacovigilance ......................................................................................................................................... 25 
6 
Statistics and Data Analysis .................................................................................................................................. 25 
6.1 
Sample Size Determination ......................................................................................................................... 25 
6.2 
Statistical Analysis ......................................................................................................................................... 25 
6.2.1 
Efficacy Analysis ........................................................................................................................................ 26 
6.3 
Other Analysis ............................................................................................................................................... 26 
7 
Data handling ........................................................................................................................................................... 26 
7.1 
Data Collection Tools and Source Document Identification ............................................................. 26 
7.1.1 
Operational aspects ................................................................................................................................. 26 
7.1.2 
Legal requirements .................................................................................................................................. 27 
7.2 
Audits and Inspections ................................................................................................................................. 28 
7.3 
Monitoring ...................................................................................................................................................... 28 
7.4 
Archiving ......................................................................................................................................................... 28 
8 
Ethical and Regulatory Considerations .............................................................................................................. 29 
7.5 
Ethics Committee (EC) review & reports ............................................................................................... 29 
8.3 
Regulatory Compliance ............................................................................................................................... 29 
8.4 
Protocol / GCP compliance ........................................................................................................................ 29 
8.5 
Data protection and participant confidentiality ..................................................................................... 30 
8.6 
Insurance ......................................................................................................................................................... 30 
8.7 
Amendments .................................................................................................................................................. 30 
9 
Human Body Material ............................................................................................................................................ 30 
10 Research Registration, Dissemination of Results and   Publication Policy ................................................ 31 
11 Intellectual Property ............................................................................................................................................... 31 
12 References ................................................................................................................................................................ 32 
APPENDICES .................................................................................................................................................................... 33 
Appendix 1: Data Processing Annex (DPA) .............................................................................................................. 33 
Appendix 2: [Pro Well VLCKD protocol] ................................................................................................................. 36 
Appendix 3: [Pro Well Lifestyle protocol] ................................................................................................................. 37 

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UZ/KU Leuven 
 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
(e)CRF 
(electronic) Case Report Form 
CI 
Coordinating Investigator 
DPA 
Data Processing Annex 
DTA 
Data Transfer Agreement 
EC 
Ethics Committee 
EU 
European Union 
GCP 
Good Clinical Practice (latest version of ICH E6) 
GDPR 
General Data Protection Regulation 
ICH 
International Conference on Harmonisation 
JCI 
Joint Commission International 
PI 
Principal Investigator (Participating Site) 
SOP 
Standard Operating Procedure 
VLCKD 
Very Low Calorie Ketogenic Diet 
NB 
Naltrexone/bupropion 
 
 
 
 

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FUNDING AND SUPPORT 
Funder 
Type of Financial or Non-Financial Support 
Pro Well 
• 
VLCKD (Appendix 2) 
• 
Lifestyle program (Appendix 3) 
Goodlife Pharma 
• 
Mysimba tablets 
This is an investigator driven trial in which trial staff is funded through KULeuven. Patients are not 
reimbursed for participation in this study. 
A PhD student will be part-time (50%) appointed for this trial. He/she will be accountable for both sites 
(AZ Sint-Jan Brugge & UZ Leuven). The financial remuneration will be split between Goodlife Pharma and 
Pro Well. The PhD student will assist with 
 
• 
Recruitment of patients: The PhD student will have access to the medical records of the patients 
of UZ Leuven and to the pseudomized data of AZ Sint-Jan Brugge by using Redcap. 
• 
Data collection and monitoring 
• 
Planning and monitoring 
• 
Adverse event reporting 
• 
Scientific report writing and dissemination 
 
Goodlife Pharma 
The pharmaceutical company (Goodlife Pharma) will provide the “Study drugs” (MYSIMBA) free of charge. 
For this multicenter study, Goodlife Pharma will supply the coordinating site (UZ Leuven) as well as the 
participating site (AZ Sint-Jan Brugge). 
Pro Well 
The study diet (VLCKD) and lifestyle program will be provided by the Company (Pro Well). For this 
multicenter study, Pro Well will supply the coordinating site (UZ Leuven) as well as the participating site 
(AZ Sint-Jan Brugge). 
Both Goodlife Pharma as Pro Well 
No payments other than those explicitly foreseen shall be made by Company to Institution with respect 
to the Study, unless agreed in writing. Such agreement must be executed by authorised personnel, must 
include a specific statement of any fees or costs to be paid and the reasons for payment, and must be 
attached as an annex to this Agreement. 
An overview of the budget is displayed on the next page. 
 
 
 
 
 
 
 
 
 
 
 
 

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Budget  
 
Items/Staff 
Per unit Cost 
Quantity 
Total 
VLCKD 
- 
- 
Provided by Pro Well 
Lifestyle program 
- 
- 
Provided by Pro Well 
Mysimba tablets 
- 
- 
Provided by Goodlife Pharma 
PhD student (50%) 
- 
- 
Split between Pro Well and Goodlife Pharma 
Pregnancy test 
€ 10.00 
20 tests 
€ 200.00 by Internal fund (KUL/UZ Leuven 
krediet) 
UZ Leuven 
Study specific lab tests 
(fasting glucose, lipids) 
€ 10.86 
62 samples 
€ 673.32 by Internal fund (KUL/UZ Leuven 
krediet) 
Pharmacy transit  
€ 2,426.40 
1 site 
€ 2,426.40 by Internal fund (KUL/UZ Leuven 
krediet) 
AZ Sint-Jan Brugge  
Study specific lab tests 
(fasting glucose, lipids) 
 
Start-up fee 
 
Annual fee 
 
€ 21.54  
 
 
€ 250.00 
 
€ 100.00 
 
62 samples  
 
 
1 
 
2 years 
€ 1,335.48 by Internal fund (KUL/UZ Leuven 
krediet) 
 
€ 250.00 by Internal fund (KUL/UZ Leuven 
krediet) 
€ 200.00 by Internal fund (KUL/UZ Leuven 
krediet) 
 
Pharmacy transit 
€ 340.00 
1 site  
€ 340.00 by Internal fund (KUL/UZ Leuven 
krediet) 
Total 
 
 
€ 5,425.20 
 
 
 
 
 
ROLES AND RESPONSIBILITIES 
The Principal Investigator (PI) is responsible for the conduct of the Study at his/her Participating Site, and 
for protecting the rights, safety and well-being of Study participants. As such the PI must ensure adequate 
supervision of the Study conduct at the Participating Site. If any tasks are delegated, the PI will maintain a 
log of appropriately qualified persons to whom he/she has delegated specified Study-related duties. The PI 
will ensure that adequate training is provided and documented for all Study staff, prior to conducting 
assigned Study-related activities. Even when certain activities are delegated, the PI will ultimately remain 
responsible for the conduct of the Study at his/her Participating Site. 
It is the Coordinating Investigator's (CI’s) responsibility to supervise the general conduct (e.g. Study 
progress, communication, protocol training and support of the participating sites, annual reporting to the 
Ethics Committee (EC), end of Study notification(s) and results reporting…) of the Study. The CI fulfils 

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both Investigator and Sponsor responsibilities, as outlined in International Conference on Harmonisation 
– Good Clinical Practice (ICH-GCP) E6(R2) and applicable regulations. 
PI and CI shall each be referred to as «Investigator(s)». 
 
 
STUDY SYNOPSIS 
 
Title of clinical Study 
(«Study») 
Naltrexone/bupropion with or without very low calorie ketogenic diet 
for weight regain after bariatric surgery 
Protocol Short Title 
Acronym 
RELAY 
Sponsor name 
University Hospitals Leuven (UZ Leuven) 
Coordinating Investigator 
Fien Van der Borght 
           Contact Address CI 
Herestraat 49 – bus 7003, 3000 Leuven 
           Contact Email CI 
roman.vangoitsenhoven@uzleuven.be 
           Contact Phone CI 
016/34 47 75 
Public database nbr  
Clinicaltrials.gov 
Principal Investigators and 
Participating Sites 
Prof. Dr. R. Vangoitsenhoven 
UZ Leuven – Herestraat 49, 3000 Leuven 
Dr. B. Dillemans 
AZ Sint-Jan Brugge – Ruddershove 10, 8000 Brugge 
Medical condition or disease 
under investigation 
Obesity 
Study rationale  
Bariatric surgery induces substantial weight loss and reduction in 
obesity-related comorbidities. Despite the major benefits of bariatric, 
some patients still regain weight post-operatively. This is the reason why 
we want to investigate the influence of a pharmacotherapeutic treatment 
(naltrexone/bupropion) on weight regain after bariatric surgery. This 
multicenter, randomized clinical trial will compare the outcomes of two 
different groups: all participants will receive intensive lifestyle 
management and naltrexone/bupropion, and one experimental group 
will in addition follow a very low calorie ketogenic diet (VLCKD). 
Primary objective 
To evaluate the superiority of combined VLCKD, intensive lifestyle 
intervention and naltrexone/bupropion versus standard of care with 
naltrexone/bupropion on weight loss. 
Secondary objective(s) 
To describe changes in metabolic health parameters and health-related 
quality of life during combined treatment of VLCKD, intensive lifestyle 
program and naltrexone/bupropion versus standard of care alone with 
naltrexone/bupropion. 
Study design 
Prospective Multicentric Longitudinal Randomized Controlled Study 
Endpoints 
Primary endpoints 
• 
The percentage of weight loss at 26 weeks 
 
Secondary endpoints 
• 
A weight loss percentage at 10 weeks, 16 weeks and at end of trial 
(= 52 weeks from start) 

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• 
A proportion of patients with a weight loss percentage of 5% or 
more at 10, 16, 26 and 52 weeks 
• 
A proportion of patients with a weight loss percentage of 10% or 
more at 10, 16, 26 and 52 weeks 
• 
The time to reach a weight loss percentage of 5% and 10% 
• 
The dose of naltrexone/bupropion used at 10, 16, 26 and 52 weeks 
and at the end of the trial 
• 
The tolerability of VLCKD and NB 
• 
The adherence to VLCKD and NB 
• 
The Patient-Reported Outcome Measures (PROMs) of hunger and 
cravings at 0, 4, 10, 16, 26 and 52 weeks  
• 
The change in fasting glucose, lipids and blood pressure at 10, 16, 
26 and 52 weeks  
Sample Size  
• 
Experimental/treatment arm: 31 patients 
• 
Comparator arm: 31 patients 
• 
Total: 62 patients 
Third parties 
• 
Pro Well 
o 
Provide VLCKD 
o 
Provide Lifestyle program 
 
• 
Goodlife Pharma 
o 
Provide Mysimba tablets 

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STUDY FLOWCHART 
 
 
Procedures/assessments 
 
 
 
Phase 0: Screening 
and randomization 
 
Phase 1: Lifestyle + NB with vs without VLCKD 
  
Phase 2: Lifestyle + NB  
(all participants) 
 
Follow-up 
(all participa nts) 
 
Screening  
(In-clinic) 
Randomization 
(in-clinic) 
 
Remote  
 
Remote 
 
Remote 
 
Remote 
 
Remote 
 
Remote 
In-clinic 
(study specific) 
 
Remote 
 
Remote 
In-clinic 
(Routine) 
 
Remote 
 
Remote 
In-clinic 
(study specific) 
In-clinic 
(routine) 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
Timing of visits (weeks) 
 
Start 
Start 
W3 
W4 
W6 
W8 
W10 
W10 
W12 
W16 
W16 
W20 
W26 
W26 
W52 
Visit window (days) 
 
 
 
 
 
 
 
 
±30 
 
 
±30 
 
 
±30 
±30 
Lifestyle program 
 
 
X 
 
X 
 
X 
 
 
X 
X 
 
X 
X 
 
 
Naltrexone/bupropion (NB) 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
VLCKD 
 
 
(X)1 
(X)1 
(X)1 
(X)1 
(X)1 
(X)1 
 
 
 
 
 
 
 
 
Screening assessments and randomization 
Informed consent 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anthropometric data (height, 
weight, waist circumference) 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 

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Clinical examination  
(Blood pressure, heart and lung 
auscultation, abdominal 
palpitation and percussion) 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
Laboratory tests 
Fasting glucose 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
Hemoglobin A1c 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Lipids: LDL-cholesterol, HDL-
cholesterol, triglycerides 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
Liver test: AST, ALT, gamma-
GT, alkaline phosphatase, total 
bilirubin, albumin 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Kidney function: creatinine, 
eGFR 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Thyroid function: TSH, free T4 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Uric acid 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Questionnaires 
The PsyEndoAUDIT 
questionnaire3 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
The PsyEndoCIDI 
questionnaire3 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
The PsyEndoEDE 
questionnaire3 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
The PsyEndoHADS 
questionnaire3 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
Nederlandse vragenlijst voor 
eetgedrag3 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
The ObesitasIPAQ 
questionnaire 3 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 

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The quality of life (SF-36) 
questionnaire 3 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
The outtake questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Reason for discontinuation 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
(Serious) Adverse event (S)(AE) 
assessment 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
• 
Depending on randomization in eiter intervention (with VLCKD) or comparator group (without VLCKD). 
• 
Informed Consent must be obtained prior to performing any other Trial-related procedures as part of the standard of care. 
• 
See appendix 4 for the respective questionnaires. 

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1 
Background and Rationale   
The world-wide prevalence of obesity has increased to the extent where it is considered as an epidemic. 
According to the World Health Organization (WHO) the population of people with obesity almost tripled 
in a time period of 40 years. Obesity is a medical condition in which excessive fat accumulation causes 
secondary health issues. This corresponds clinically to a body mass index (BMI) greater or equal to 30 
kg/m2.(1) 
 
Initially, the patient will be advised to change his/her lifestyle. This includes increasing physical activity as 
well as being on a diet and behaviour modification. A tailored lifestyle program usually consists out of 2-3 
hours of exercise per week. Here, it is especially important to engage in aerobic sports such as walking at 
a higher than usual pace, cycling or swimming. This ensures that patients use their fat storage as source of 
energy instead of carbohydrates. Unfortunately, lifestyle modification alone in terms of physical activity will 
result in only limited short-term weight loss. Therefore, a diet containing of a calorie restriction is an 
important additional part of the new lifestyle.(2) 
 
Calorie restriction is an important part of the very low-calorie ketogenic diet (VLCKD). This diet typically 
consists out of a limited intake of carbohydrates and a daily energy restriction of 800 kcal. Also an increase 
in protein percentages is favourable in these patients.(3) A dietitian is usually appointed for this intervention 
because VLCKD is an important factor in the possible eligibility for surgery as well as weight loss results 
after bariatric surgery.(4) Studies also showed that VLCKD given prior to pharmacotherapy can have an 
additional benefit. It will help to reset the metabolic state and impose nutritional structure. (5) (6) 
 
Pharmacotherapy is the last resort for patients before bariatric surgery. The medication used in this trial 
is naltrexone/bupropion (NB) with extended release. Naltrexone is an opioid antagonist that is currently 
used in the treatment of dependency, like alcoholism an drug addiction. Bupropion on the other hand is an 
antidepressant used not only in the treatment of depression but also to reduce cigarette cravings with the 
ultimate goal of inducing a smoking cessation. A common side effect of bupropion is weight loss. The use 
of both drugs separately has almost no effect on the patients’ weight, but the combination of naltrexone 
and bupropion has showed a synergistic effect.(7) NB has promising results in terms of weight loss prior 
to or post-bariatry with an influence on food intake, cravings and a high sense of satiety.(8) 
 
Conservative therapy may already make a difference, but the majority of patients experience a lack of 
beneficial effect from this. For these patients, bariatric surgery (BS) may be the solution. Bariatric surgery 
is considered as the best treatment for morbid obesity (BMI > 40 kg/m2 or BMI > 35 kg/m2 with one or 
more weight related comorbidities) in maintaining weight loss.(9) The biggest weight loss occurs the first 
year after surgery. Unfortunately, from then on weight stabilization or even weight regain can occur post-
bariatry.(10) 
 
Despite the fact these patients already tried conservative therapy prior to bariatric surgery, they still benefit 
to monitor their lifestyle in terms of physical activity, behaviour and dieting. Recent studies show a beneficial 
role for pharmacotherapy for post-bariatric weight regain.(11) Given the mechanism of action of NB, 
specific benefit can be expected in patients with insufficient reduction or relapse of food cravings and 
snacking after bariatric surgery. (8) Although these possible desirable effects may occur, yet patients may 
suffer from some side effects of the study drug. The most common adverse events are gastrointestinal 
disorders (nausea, vomiting, constipation), anxiety, insomnia, agitation and a headache.(12) 
 
Generally, there is a lack of published data on the effectiveness of pharmacotherapies for post-bariatric 
weight regain. Therefore, this trial aims to investigate a structured follow-up with lifestyle intervention 
combined whether or not with a VLCKD and supported by naltrexone/bupropion on the evolution of 
bodyweight in patients with weight regain post-bariatry. This multi-center, randomized clinical trial will 
compare the outcomes of two different groups. The patients in both groups need to undergo lifestyle 
changes in combination with the intake of naltrexone/bupropion, but the experimental group needs to 
follow a VLCKD on top of it for a period of 10 weeks. 

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2 
Study Design and Objectives  
2.1 Study objectives 
The aim of this trial is to evaluate the superiority of combined VLCKD, intensive lifestyle intervention and 
naltrexone/bupropion versus standard of care with naltrexone/bupropion on weight loss. 
2.2 Primary Endpoints 
Weight loss percentage at 26 weeks; calculated as: (weight at 26 weeks – baseline weight)/baseline weight. 
2.3 Secondary Endpoints 
• 
A weight loss percentage at 10 weeks, 16 weeks and at end of trial (= 52 weeks from start) 
• 
A proportion of patients with a weight loss percentage of 5% or more at 10, 16, 26 and 52 weeks 
• 
A proportion of patients with a weight loss percentage of 10% or more at 10, 16, 26 and 52 weeks 
• 
The time to reach a weight loss percentage of 5% and 10% 
• 
The dose of naltrexone/bupropion used at 10, 16, 26 and 52 weeks and at the end of  the trial 
• 
The tolerability of VLCKD and NB 
• 
Adherence to VLCKD and NB 
• 
The Patient-Reported Outcome Measures (PROMs) of hunger and cravings at 0, 4, 10, 16, 26 and 52 
weeks  
• 
The change in fasting glucose, lipids and blood pressure at 10, 16, 26 and 52 weeks  
2.4 Study design 
This is a parallel multicentric longitudinal randomized controlled trial in which prospective data will be 
collected from the electronic health record. The inclusion and exclusion criteria will be checked and 
afterwards patients will be randomized to (unblinded) medication only or combination with VLCKD. Both 
groups include NB and lifestyle changes for 26 weeks but the patients belonging to the experimental group 
must follow a VLCKD in the first 10 weeks on top of it.  Like the other group, the remaining 16 weeks will 
consist of NB combined with lifestyle interventions. Afterwards there is a follow-up extension of 26 weeks. 
See appendix 4 for detailed overview of clinical and biochemical parameters to be collected during the trial. 
 
 
 
2.5 Expected duration of the Study 
This trial will have a duration of 2 years in total. 1 year is taken into account to include the patients into 
the study according to the inclusion and exclusion criteria. Afterwards patients will be randomly inserted 
into the comparator arm (NB + lifestyle interventions) or experimental arm (NB + Lifestyle interventions 
+ VLCKD). Both arms of the study design will be evaluated for 52 weeks. 26 weeks will consist of the 
treatment after which another 26 weeks will be used as a follow-up extension. 
 
The End of Study is defined as Last Patient Last Visit (LPLV). The CI shall notify the EC of the end of the 
Study. The CI will submit a final report with the results of the study, including any publications/abstracts, 
to the EC within 1 year of study termination. 

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The Sponsor or EC can decide to halt or prematurely terminate the Study when new information becomes 
available whereby the rights, safety and well-being of Study participants can no longer be assured, when the 
integrity of the Study has been compromised, or when the scientific value of the Study becomes obsolete 
and/or unjustifiable. 
3 
Study Population / Eligibility Criteria 
3.1 Inclusion criteria 
Participants eligible for inclusion in this Trial must meet all of the following criteria: 
1. Voluntary written informed consent of the participant or their legally authorized representative 
has been obtained prior to any screening procedures 
2. Use of highly effective methods of birth control; defined as those that, alone or in combination, 
result in low failure rate (i.e., less than 1% per year) when used consistently and correctly; such 
as implants, injectables, combined oral contraceptives, some IUDs, true sexual abstinence (i.e. 
refraining from heterosexual intercourse during the entire period of risk associated with the 
Trial treatment(s)) or commitment to a vasectomised partner. 
3. Miminum 18 years of age at the time of Informed Consent signature 
4. Underwent bariatric surgery (RYGB or SG) with weight regain ≥10% of nadir weight  
5. People without Type 2 diabetes (T2D) 
• 
No history, no drugs, HbA1c < 6,5% and FPG <126 mg/dl) 
All participants that are considered for Trial participation, per the above criteria will be documented on 
the Screening Log, including Screen Failures.  
3.2 Exclusion criteria 
Participants eligible for this Trial must not meet any of the following criteria: 
1. Participant has a history of  type 2 diabetes mellitus (also drugs, HbA1c > 6,5% and FPG >126 
mg/dl) 
2. IFemale who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using an adequate, highly effective contraceptive 
3. Participation in an interventional Trial with an investigational medicinal product (IMP) or  device  
4. Not willing to sign informed consent 
5. Younger than 18 years of age at the time of Informed Consent signature 
6. Other types of bariatric surgery other than RYGB or SG (including LAGB, BPD) 
7. Underwent bariatric surgery (RYGB or SG) with weight regain <10% of nadir weight  
8. Contraindication for VLCKD, including CKD stage 4-5, liver cirrhosis, type 1 diabetes mellitus, 
active gout 
9. Contraindication for NB including the use of opioids, history of CNS tumor or seizures, severe 
psychiatric disorder or > 2 psychotropic medications, uncontrolled hypertension 
10. Use of other drugs for weight management (e.g. GLP1Ra) in the last 3 months prior to trial 
intervention 
11. Any disorder, which in the Investigator’s opinion might jeopardise the participant’s safety or 
compliance with the protocol 
Participants who meet one or more of the above exclusion criteria must not proceed to be 
enrolled/randomized in the Trial and will be identified on the Screening Log as Screen Failure. 

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4 Study Procedures 
4.1 
Participant consent and withdrawal of consent 
The Study will be conducted only on the basis of prior informed consent by the Study participants and/or 
their legally authorized representative(s). As such, no Study-related procedures will be conducted prior to 
obtaining written informed consent from potential Study participants. 
The process for obtaining and documenting initial and continued informed consent from potential Study 
participants will be conducted in accordance with ICH-GCP E6(R2), applicable regulatory requirements 
and internal Standard Operating Procedures (SOPs). 
All originally signed obtained Informed Consent Forms (ICFs) must be retained/archived in the Investigator 
Site File (ISF) at the Participating Site and must not be destroyed (even when a scanned copy is available) 
before expiration of the legal archiving term as defined in the protocol section entitled “Archiving”.  
Participants may voluntarily withdraw consent to participate in the Study for any reason at any time. The 
participant’s request to withdraw from the Study must always be respected without prejudice or 
consequence to further treatment. Consent withdrawal will be documented in the participant’s medical 
record.  
Study data and samples collected before withdrawal can be used  in the study.  No new study data or 
samples will be collected after withdrawal of the participant. 
4.2 Selection of Participants / Recruitment 
Potential participants will be identified and recruited during patient consultations in one of the participating 
sites. No additional recruitment material (such as for example flyers, social media advertising, audio/video 
recordings) will be used. 
4.3 Randomization Procedure  
To ensure the integrity of the Study, the following randomization procedures have been established: 
During the initial study visit, participants will be randomized in a 1:1 ratio to either the experimental arm 
(with VLCKD) or the comparator arm (without VLCKD), while receiving naltrexone/bupropion and 
lifestyle intervention. Allocation to one of these two groups will be conducted using a central randomization 
procedure accessible in the eCRF (RedCap). A computer-generated block randomization schedule will be 
created using the PLAN procedure in SAS software. 
A randomization list will be prepared by the Sponsor’s designated staff, not involved in recruiting Study 
participants, medical care, drug administration or follow-up. 
4.4 
Premature discontinuation 
Participants may voluntarily discontinue from Study treatment and/or prematurely end their participation 
in the Study for any reason at any time. In such case the Investigator must make a reasonable effort to 
contact the participant (e.g. via telephone, e-mail, letter) in order to document the primary reason for this 
decision. 
The Investigator may also decide at any time during the course of the Study, to temporarily interrupt or 
permanently discontinue the Study treatment if it is deemed that continuation would be detrimental to, 
or not in the best interest of the participant.  
For participants whose status is unclear because they fail to appear for Study visits without stating an 
intention to discontinue or withdraw, the Investigator must make every effort to demonstrate “due 
diligence" by documenting in the source documents which steps have been taken to contact the 
participant to clarify their willingness and ability to continue their participation in the Study (e.g. dates of 
telephone calls, registered letters, etc.). 
A participant should not be considered lost to follow-up until due diligence has been completed. 

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4.5 
By visit  
There are five scheduled in-clinic visits, each involving a blood draw. Among these, three visits are routine 
for naltrexone/bupropion, which include the initial intake and visits after 16 and 52 weeks. The study-
specific visits occur at 10 weeks and 26 weeks. During the routine visits, only fasting glucose and lipid levels 
(LDL-cholesterol, HDL-cholesterol, triglycerides) will be assessed in the blood. However, during the study-
specific visits, in addition to fasting glucose and lipids, the following parameters will also be examined in the 
blood: Hemoglobin A1c, liver function (AST, ALT, gamma-GT, alkaline phosphatase, total bilirubin, 
albumin), kidney function (creatinine, eGFR), thyroid function (TSH, free T4), and uric acid. For a detailed 
overview of the visit schedule, please refer to the Study Flowchart. 
 
4.6 
Very Low Calorie Ketogenic Diet (VLCKD) 
Participants in the experimental arm follow the Very Low-Calorie Ketogenic Diet (VLCKD) for the first 
10 weeks of the study. This entails adhering to the VLCKD for 10 weeks while also receiving support from 
a coach. The coach provides explanations, follow-ups, and moments for progression and reflection 
throughout this period. The VLCKD begins with a strict phase of 800 kcal/day (consisting of 50g of 
carbohydrates, >100g of proteins, and low-carb vegetables), followed by a gradual increase in daily calorie 
intake (1000 kcal, 1200 kcal for women/1400 kcal for men, 1500 kcal for women/1800 kcal for men) based 
on a Mediterranean diet. For further details on the schedule of contact moments and the content of the 
VLCKD, please refer to Appendix 2. 
4.7 
Naltrexone/bupropion 
After starting the treatment, the dose should be increased over a 4-week period as follows: 
• 
Week 1: One tablet in the morning 
• 
Week 2: One tablet in the morning and one tablet in the evening 
• 
Week 3: Two tablets in the morning and one tablet in the evening 
• 
Week 4 and onward: Two tablets in the morning and two tablets in the evening 
The maximum recommended daily dose of Mysimba is two tablets twice daily with a total dose of 32 mg 
of naltrexone hydrochloride and 360 mg of bupropion hydrochloride. Patients with too many side effects 
at high dose may return to the previous dose and continue with it (maximum tolerated dose). 
Naltrexone/bupropion need to be taken orally. The tablets should be swallowed whole with some water. 
The tablets should preferably be taken with some food. The tablets must not be cut, chewed or crushed. 
The formulation of naltrexone/bupropion exists of the following: 
• 
Tablet core: cysteine hydrochloride, microcrystalline cellulose, hydroxypropyl cellulose, 
magnesium stearate, lactose anhydrous, lactose monohydrate, crospovidone type A, indigo 
carmine aluminium paint (E132), hypromellose, disodium deetate, colloidal silicon dioxide 
• 
Film coating: titanium dioxide (E171), macrogol (3350), talc, indigo carmine aluminium paint (E132) 
The package size consists of 112 tablets naltrexone/bupropion. 
4.7.1 Concomitant / Prohibited Medication / Treatment 
Permitted: 
• 
Concomitantly used blood glucose-lowering agents. Assess the dose to minimize the risk of 
hypoglycaemia because treatment with naltrexone/bupropion may result in decreased glucose 
levels. 
• 
Digoxin. Monitor digoxin levels when used concurrently because bupropion may lower the plasma 
level of digoxin. Upon discontinuation of naltrexone/bupropion, digoxin levels may increase; 
monitor patient for possible digoxin toxicity. 
• 
Concomitant administration of a serotonergic agent (SSRI or SNRI). There have been reports of 
serotonin syndrome, a potentially life-threatening condition. Careful observation is therefore 
required, especially at initiation and after each dose increase. Watch for changes in mental status, 

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autonomic instability, neuromuscular dysfunction, and/or gastrointestinal symptoms. If serotonin 
syndrome is suspected, consider discontinuing treatment. 
Not permitted: 
• 
Concomitant treatment with bupropion or naltrexone. 
• 
Concomitant administration of MAO-inhibitors (MAOIs). There should be at least a 14-day period 
between 
discontinuation 
of 
irreversible 
MAOIs 
and 
initiation 
of 
treatment 
with 
naltrexone/bupropion. For reversible MAOIs, a 24-hour period is sufficient. 
• 
Opioids such as codeine, loperamide and opioid analgesics, may be less effective. If (temporary) 
treatment 
with 
opioids 
is 
necessary, 
discontinue 
(or 
interrupt) 
treatment 
with 
naltrexone/bupropion. Use naltrexone/bupropion cautiously after chronic opioid use has been 
stopped for 7-10 days, to avoid occurrence of withdrawal symptoms. 
• 
CYP2D6 substrates: Bupropion and hydroxybupropion are CYP2D6 inhibitors. Exposure to drugs 
metabolized by CYP2D6 may be increased; examples include certain antidepressants (SSRIs and 
many TCAs, including imipramine, paroxetine, venlafaxine), antipsychotics (haloperidol, 
risperidone), β-blockers (metoprolol) and class 1C antiarrhythmics (flecainide, propafenone). Dose 
reductions of these agents may be necessary, especially with narrow therapeutic breadth (such as 
TCAs); consider blood level guided dosing (TDM). Exposure to citalopram increases by about 40%. 
Tamoxifen may be less effective due to CYP2D6 inhibition. 
• 
Influence on CYP2B6: Bupropion is converted by CYP2B6 to its major active metabolite 
hydroxybupropion. Use caution with concomitant use of drugs that induce CYP2B6 (e.g., 
carbamazepine, efavirenz, phenytoin, ritonavir) because the efficacy of bupropion is affected. Use 
caution with concomitant use of drugs that may inhibit CYP2B6 (e.g., clopidogrel, 
cyclophosphamide, ifosfamide); the clinical consequences of this interaction are unknown but may 
decrease the efficacy of bupropion. 
• 
Avoid or minimize the use of alcohol, as neuropsychiatric side effects and decreased alcohol 
tolerance have rarely been reported with the use of alcohol during bupropion treatment. 
• 
concomitant use of drugs that lower the insult threshold, such as antidepressants, antipsychotics, 
sedative antihistamines, antimalarial drugs, tramadol, quinolones, theophylline and systemic 
corticosteroids. 
• 
Concomitant use of levodopa or amantadine, there is evidence of a higher incidence of adverse 
events (e.g., nausea, vomiting, and neuropsychiatric side effects). 
 
4.8 
Lifestyle 
Lifestyle support, excluding the VLCKD, is offered to both the experimental and comparator arms and is 
regarded as part of the standard care protocol. Consequently, both groups will both have a total of 11 
contact sessions, during which 30 minutes will be allocated for individual coaching and routine personal 
follow-up via telephone. Additionally, there are three modules comprising 12 educational presentations 
and 12 practical tasks designed for application in everyday life. For a comprehensive schedule outlining 
specific time points, please refer to Appendix 3. 
5 Assessment of Safety 
 
5.1 
Adverse Event Reporting 
 
5.1.1 
Definitions 
 
5.1.1.1 
Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient or subject during an experiment, and which does 
not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), 
symptom or disease temporally associated with the use of a product, whether or not considered related 

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to the product. Any worsening (i.e., any clinically significant adverse change in the frequency or intensity of 
a pre-existing condition) should be considered an AE. 
 
5.1.1.2 
Adverse Reaction (AR) 
An AR is any untoward and unintended responses to an investigational medicinal product or to an 
experiment and, when an investigational product is concerned, related to any dose administered. 
 
5.1.1.3 
Serious Adverse Event (SAE) 
An SAE is any untoward medical occurrence that results in any of the following: 
• 
Death 
• 
A life-threateninga experience 
• 
In-patient hospitalisation or prolongation of existing hospitalisation 
• 
A persistent or significant disability or incapacity 
• 
A congenital anomaly or birth defect 
• 
Important medical events that may be considered an SAE when - based on appropriate medical 
judgement - they may jeopardise the subject and may require medical or surgical intervention to 
prevent one of the above outcomes 
 
a The term “life threatening” in the definition of SAE refers to an event in which the subject was at risk of death at the time of 
the event. It does not refer to an event which hypothetically might have caused death if it was more severe. 
 
 
5.1.2 Adverse Events that do not require reporting 
In general, the following should not be reported as AEs: 
• 
Pre-existing conditions, including those found as a result of screening (these should be reported 
as medical history or concomitant illness). 
• 
Pre-planned procedures unless the condition for which the procedure was planned has worsened 
from the first study-related activity after the subject has signed the informed consent. 
 
The following events are commonly observed and are therefore not considered  as adverse events for the 
purpose of the study: 
• 
Gastrointestinal events (constipation, nausea, vomitting, dry mouth) 
• 
Headache 
• 
Insomnia (especially if naltrexone/bupropion taken at night) 
Although these events should not be reported to the Sponsor, these should be recorded in the patient’s 
medical notes according to routine practice.  
The following events not to be considered as SAEs are: 
• 
Pre-planned hospitalisations unless the condition for which the hospitalisation was planned has 
worsened from the first study-related activity after the subject has signed the informed consent.  
• 
Hospitalisation as part of a standard procedure for protocol therapy administration. However, 
hospitalisation or prolonged hospitalisation for a complication of therapy administration will be 
reported as an SAE. 
• 
Hospitalisation or prolongation of hospitalisation for technical, practical, or social reasons, in 
absence of an AE. 
5.1.3 Recording and reporting of Adverse Events 
The study-specific visit does not entail any additional risk compared to the routine visit. 
 
Investigators will seek information on AEs during each patient contact. All events, whether reported by the 
patient or noted by study staff, will be recorded in the patient’s medical record and in the (e)CRF within a 

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reasonable time after becoming aware. If available, the diagnosis should be reported on the AE page, rather 
than the individual signs or symptoms. If no diagnosis is available, the Investigator should record each sign 
and symptom as individual AEs. 
The following minimum information should be recorded for each AE: 
- AE description 
- start and stop date of the AE 
- severity 
- seriousness 
- causality assessment to the study interventions 
- outcome 
 
5.1.3.1 
Assessment  
All AEs must be evaluated by an Investigator as to: 
• 
Seriousness: whether the AE is an SAE. See above for the seriousness criteria. 
 
• 
Severity:  
o 
Severity must be evaluated by an Investigator according to the following definitions: 
§ 
Mild – no or transient symptoms, no interference with the subject’s daily activities 
§ 
Moderate – marked symptoms, moderate interference with the subject’s daily 
activities 
§ 
Severe – considerable interference with the subject’s daily activities, unacceptable 
• 
Causality: 
§ 
None – An AE which is not related to the study-related interventions 
§ 
Unlikely – An AE for which an alternative explanation is more likely (e.g. concomitant 
medication(s), concomitant disease(s)), and/or the relationship in time suggests that a 
causal relationship is unlikely 
§ 
Possible – An AE which might be due to the study-related interventions. An alternative 
explanation is inconclusive. The relationship in time is reasonable; therefore the causal 
relationship cannot be ruled out. 
§ 
Probable - An AE which might be due to the study-related intervention. The relationship 
in time is suggestive (e.g. confirmed by dechallenge). An alternative explanation is less 
likely. 
§ 
Definitely – An AE which is known as a possible adverse reaction and cannot be reasonably 
explained by an alternative explanation. The relationship in time is very suggestive (e.g. it 
is confirmed by dechallenge and rechallenge). 
 
5.1.3.2 
Timelines for reporting 
- 
After informed consent has been obtained and after initiation of study-related interventions:  
o 
All AEs and SAEs will be reported in a “written diary” in between visits during the first 12 
weeks after initiation of the study-related interventions. 
o 
After 12 weeks until the last follow-up visit, only SAEs causally related to a study-specific 
intervention will be reported.  
All SAEs as defined in the protocol must be reported to the Sponsor within 24 hours of the study staff 
becoming aware of the event. The immediate report shall be followed by detailed, written reports. The 
immediate and follow-up reports shall identify subjects by Study identification. 
 
SAE details will be reported by the Investigator to the Sponsor:  
• 
By completing the SAE form in the (e)CRF 
If an authorised Investigator from the reporting site is unavailable, initial reports without causality and 
expectedness assessment should be submitted to the Sponsor by a healthcare professional within 24 hours 

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of becoming aware of the SAE, but must be followed-up by medical assessment as soon as possible 
thereafter. 
5.1.3.3 
Follow-up  
The Investigator must record follow-up information by updating the medical records and the appropriate 
forms in the (e)CRF. The worst case severity and seriousness of an event must be kept throughout the 
study. 
SAE follow-up information should only include new (e.g. corrections or additional) information and must 
be reported within 24 hours of the Investigator’s first knowledge of the information. This is also the case 
for previously non-serious AEs which subsequently become SAEs. 
• 
All SAEs must be followed up until the outcome of the event is ‘recovered’, ‘recovered with 
sequelae’, ‘not recovered’ (in case of death due to another cause) or ‘death’ (due to the SAE) and 
until all related queries have been resolved, or until end of study (whichever occurs first). 
• 
Non-serious AEs must be followed up until the patient’s last study visit, and until all related queries 
have been resolved. 
 
SAEs after the end of the study: If the Investigator becomes aware of an SAE with suspected causal 
relationship to the study-related interventions after the subject has ended the study, the Investigator should 
report this SAE within the same timelines as for SAEs during the study. 
 
5.1.3.4 
Pregnancy 
Female subjects must be instructed to notify the Investigator immediately if they become pregnant during 
the study. The Investigator must report any pregnancy in subjects during the study to the Sponsor. 
 
5.1.3.5 
Death 
All deaths will be reported without delay to the Sponsor (irrespective of whether the death is related to 
disease progression, study procedure or is an unrelated event). The sponsor will notify all deaths, as soon 
as possible after becoming aware, to the Central EC and the EC of the concerned site and provide 
additional information if requested. 
 
5.1.4 Reporting requirements to Ethics Committee’s (EC’s) 
The Investigator is responsible for ensuring that all safety events are recorded in the (e)CRF and reported 
to the Sponsor in accordance with instructions provided below. 
The Sponsor will promptly evaluate all SAEs against medical experience to identify and expeditiously 
communicate possible new safety findings to Investigators and to EC(’s) based on applicable legislation. 
5.1.4.1 
Annual reporting 
The sponsor has the obligation to, once a year throughout the study (or on request), submit a progress 
report to the EC’s containing an overview of all SARs occurred during the reporting period and taking into 
account all new available safety information received during the reporting period. 
 
 
 
 
 
 

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5.1.4.2 
Overview reporting requirements 
 
 
WHAT 
HOW 
TO 
TIMELINES 
Investigator 
AE 
AE form 
sponsor 
Within 7 calendar days 
SAE 
SAE form 
sponsor 
Immediately (within 24 
hours 
of 
becoming 
aware of the event) 
Exceptions: as defined in 
protocol 
death 
SAE form 
sponsor 
asap 
Sponsor 
death 
SAE form + 
narrative 
Ethics Committees 
asap 
Annual Progress 
Report 
APR template 
Ethics Committees 
annually 
 
 
5.1.5 Pharmacovigilance  
Any adverse reactions related to the medicinal products used by the participants in the study, can be 
reported to the Marketing Authoridation Holder and/or the Compentent Authorities according to the 
pharmacovigilance guidelines. 
 
6 
Statistics and Data Analysis 
Statistical analysis will be performed in accordance with ICH E9; a detailed description of the analysis is 
provided in the Trial-specific Statistical Analysis Plan (SAP). ICH E3 and E8 will guide the structure and 
content of the clinical trial report. 
The hypothesis for this trial is that the percentage of weight loss will be greater for the experimental arm 
than the comparator arm. 
6.1 Sample Size Determination 
The sample size was determined for a two-sided two-sample t-test to test the difference in mean weight 
loss percentage between both treatment arms, assuming a mean weight loss of 6.75% (SD 7.12%) 
[unpublished, own retrospective data] in the control arm and a mean weight loss of 12% (SD 5.3) 
[unpublished, data provided by Pro Well] in the intervention arm. Assuming a 20% drop-out rate, a 5% 
significance level and 80% of power, a total sample size of 62 patients is indicated, or 31 patients per study 
arm 
6.2 Statistical Analysis 
The primary analysis will be performed using a two-sample two-sided t-test to test the difference in mean 
weight loss percentage between both treatment arms. Mean weight loss percentages and the mean 
difference in weight loss percentage wil be estimated and presented with 95% confidence intervals. A 5% 
significance level will be adopted for the primary analysis. Given the pragmatic nature of the trial, the 
primary analysis will be performed following the intention-to-treat (ITT) principle, in that all randomized 
patients will be analyzed in the study arm in which they were randomized, regardless of adherence to the 
therapy assigned to the patient. In presence of missing outcome data due to drop-out of patients for whom 

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no follow-up data were collected, the method of multiple imputation will be used. Fully conditional 
specification will be used to create 10 complete data sets, of which each will be analyzed and analysis results 
combined according to multiple imputation principles. Treatment arm and previous weight loss measures 
will be used as predictors in the imputation model. 
 
A per protocol (PP) analysis will be performed as a secondary analysis, including patients adherent to the 
randomized treatment. Missing data will be dealt with as described above, using multiple imputation. 
Linear mixed models for longitudinal data will be used for the analysis of a treatment effect on weight loss 
percentage at other time points. The explanatory model will contain treatment arm, time point and the 
interaction thereof. A random effect for patient will be modelled to deal with data clustering. Results will 
be presented as mean differences per time point with 95% confidence intervals.  
The treatment effect on the proportion of patients with weight loss at various time points will be analyzed 
using logistic regression analysis, with generalized estimating equations (GEE) to account for data clustering. 
The explanatory model will contain treatment arm, time point and the interaction thereof. Results will be 
presented as odds ratios per time point with 95% confidence intervals 
The treatment effect on the time to reach a pre-defined weight loss percentage will be analyzed using a 
log-rank test for time-to-event outcomes. Additionally, a Cox model will be used for the estimation of the 
hazard ratio with 95% confidence interval. 
Descriptive analyses will be used for tolerability or adherence to treatment. 
6.2.1 
Efficacy Analysis 
Endpoint 
Statistical Analysis Methods 
Primary 
Two-sided two sample t-test, with analysis 
following the intention-to-treat principle and 
multiple imputation to deal with missing data. 
Secondary (if applicable) 
Linear mixed models for continuous and 
longitudinal data. Logistic regression for binary 
and longitudinal data. Log-rank test and Cox 
model for time-to-event data. Descriptive 
statistics for adherence and tolerability. 
6.3 Other Analysis 
Pharmacokinetic, pharmacodynamic, and biomarker exploratory analysis/analyses will be described in the 
statistical analysis plan and finalized before database lock. The population for pharmacokinetic analysis and 
pharmacodynamic analysis will be presented separately from the main clinical Trial report. 
7 
Data handling  
The investigator shall ensure that all procedures defined in this Protocol and in the Agreement are complied 
with, so that all cata coming from the Participating site are reliable and have been processed correctly 
(especially the randomization lists) and shall ensure that the contentof the case report form (CRF) shall 
accurately reflect source documents. Findings of the Study will be reported by the Participating Site through 
Investigator to Sponsor in the form of case reports. The collected data will be pseudonymized. 
7.1 Data Collection Tools and Source Document Identification 
7.1.1 
Operational aspects  
Data collection, handling, processing and transfer for the purpose of this Trial will be performed in 
compliance with applicable regulations, guidelines for clinical trials and internal procedures. 

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7.1.1.2 Data collection  
Source Data will be collected and recorded in the Trial participant’s files/medical records. 
Patient-related socio-demographic and health-related data will be gathered in the (e)CRF. 
RedCAP will be used to capture study related data. 
If applicable, worksheets may be used for capturing some specific data in order to facilitate completion of 
the (e)CRF. Any such worksheets will become part of the Trial participant's source documentation and 
will be filed together with or as part of the medical records (during but also following completion of the 
Trial). 
It remains the responsibility of the Investigator to check that all data relating to the Trial, as specified in 
the Trial protocol, are entered into the (e)CRF in accordance with the instructions provided and that the 
forms are filled out accurately, completely and in a timely manner. 
(e)CRFs are provided by the Sponsor for each participant. The Trial data will be transcribed from the 
source records (i.e. participant’s medical file or Trial-specific source data worksheets) into an (e)CRF by 
Trial Staff. Transcription to the (e)CRF will be done as soon as possible after a participant visit and in a 
pseudonymized manner using a unique identifier assigned by the Sponsor.  
The (e)CRFs will be available for review at the next scheduled monitoring visit (as applicable) and shall 
under no circumstances capture personal data such as but not limited to the participant or their relative(s) 
name, home address, contact details, full date of birth medical record number (e.g. UZ Leuven EAD 
number), social security number etc.  
7.1.1.3 Data Validation  
All data relating to the Trial must be prepared and validated by the Investigator. Any (e)CRF entries, 
corrections and alterations must be made by the Investigator or other authorized Trial staff.  
Proper audit trails must be available to demonstrate the validity of the Trial data collected. This includes 
historical records of original data entries, by whom and when the data was entered, as well as detailed 
records of any corrections or additions made to the original data entry (i.e. who made the 
correction/addition, when and why), without obliterating the original data entry information. 
7.1.1.4 Data Management 
The Trial Data Manager will perform extensive consistency checks on the received data. Queries will be 
issued in case of inconsistencies in accordance with internal procedures.  
7.1.1.5 Data Transfer 
Any participant records or datasets that are transferred to the Sponsor or any partners of the Sponsor 
will contain the Trial-specific participant identifier only; participant names or any information which would 
make the participant identifiable will not be transferred. All pseudonymized data relating to the Trial must 
be transmitted in a secure manner to the Sponsor or any partners of the Sponsor(see 8.1.2. legal 
requirements). 
7.1.2 
Legal requirements 
All source data will be kept at a secured location with restricted access at all times. These data must be 
collected and processed with adequate precautions to ensure confidentiality and compliance with applicable 
data protection laws and regulations and more in particular the EU General Data Protection Regulation 
2016/679 (GDPR) and relevant national laws implementing the GDPR. Appropriate technical and 
organizational measures to protect the data against unauthorized disclosure or access, accidental or 
unlawful destruction, or accidental loss or alteration must be established. Trial staff whose responsibilities 
require access to personal data agree to keep the data confidential. 
The Investigator and the Participating Site(s) (as applicable) shall treat all information and data relating to 
the Trial disclosed to them as confidential and shall not disclose such information to any third parties or 
use such information for any purpose other than the objectives of the Trial as described in this protocol. 
The collection, processing and disclosure of personal data, such as participant health and medical 

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information is subject to compliance with applicable laws and regulations regarding personal data protection 
and the processing of personal data. 
The Investigator will maintain all source documents and completed (e)CRFs that support the data 
collected from each Trial participant, and will maintain a Trial Master File (TMF)/Investigator Site File 
(ISF) containing all Trial documents as specified in ICH-GCP E6(R2) Chapter 8 entitled “Essential 
Documents for the Conduct of a Clinical Trial”, and as specified by applicable regulatory requirement(s). 
The Investigator will take appropriate measures to prevent accidental or premature destruction of these 
documents. 
Transfer of the pseudonymized data will be performed via a secured method of transfer taking into 
account all applicable security arrangements and regulations (such as the European General Data 
Protection Regulation). The receiving party will be bound by contractual agreement to keep the 
transferred data confidential at all times and to only process the data for the purpose of the Trial. To this 
end, appropriate Data Transfer Agreements (DTAs) will be established.  
 
7.2 
Audits and Inspections 
The Investigator will permit direct access to Trial data and documents for the purpose of monitoring, audits 
and/or inspections by authorized entities such as but not limited to: the Sponsor or its designees and 
competent regulatory or health authorities. As such (e)CRFs, source records and other Trial related 
documentation (e.g. Investigator Site File, the Trial Master File, pharmacy records, etc.) must be kept 
current, complete and accurate at all times.  
 
7.3 
Monitoring 
In accordance with GCP the Sponsor is responsible for monitoring the Trial to ensure compliance with 
GCP and current legislation, and to verify, among other requirements, that proper written informed 
consent has been obtained and documented, that the Trial procedures have been followed as shown in the 
approved protocol, and that relevant Trial data have been collected and reported in a manner that assures 
data integrity.  
 
For those trials with UZ Leuven as Sponsor, UZ Leuven Clinical Trial Center (CTC) monitors only 
prospective interventional IMP/ IMD trials which are categorized as high risk trials, according to UZ/KU 
Leuven policy. Therefore, monitoring by CTC is not applicable for this study without IMP/IMD.  
 
Hence, based on the above policy and as permitted by GCP, the Sponsor of the trial accepts the minimal 
risks associated with this trial and determines that monitoring activities (as defined by GCP) by a qualified 
individual, independent of the study team, is not necessary as it will provide little or no added value in 
protecting the safety of trial participants and assuring the integrity of collected trial data. Nonetheless, 
the UZ Leuven study team will take all possible measures to assure the quality and integrity of trial data 
and to safeguard the safety and wellbeing of trial participants, in accordance with the requirements set 
out in GCP. 
 
7.4 
Archiving  
As specified in ICH-GCP E6(R2) section 8.1 Addendum, the Sponsor and Investigator/Participating Site will 
maintain a record of the location(s) of all respective Essential Trial Documents (including but not limited 
to Source Documents, completed and final (e)CRF and ISF/TMF). The Sponsor should ensure that the 
Investigator has control of and continuous access to the (e)CRF data reported to the Sponsor during the 
Trial.  
The Investigator/Participating Site should have control of all Essential Documents and records generated 
by the Investigator/Participating Site before, during and following termination of the Trial. 

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The Sponsor is responsible for archiving Trial specific documentation (such as but not limited to the Trial 
protocol, any amendments thereto, the final Clinical Study Report (CSR) and the Trial database) according 
to ICH-GCP E6(R2). Source data and site-specific Trial documents (such as but not limited to the original 
signed ICFs) will be archived by the participating site(s) according to local practice, and for at least 25 years 
following termination of the Trial. Archived data may be held on electronic record, provided that media 
back-up exists, hard copies can be obtained, if required and measures are taken to prevent accidental or 
premature loss or destruction of data. Destruction of Essential Documents prior to, during or upon 
completion of the required archival period, will require written authorisation from the Sponsor. 
8 Ethical and Regulatory Considerations 
7.5 Ethics Committee (EC) review & reports  
 
Before the start of the Study, this protocol and other related documents will be submitted for review to 
the EC for Study authorization. The Study shall not commence until such approvals have been obtained 
and until other relevant essential Study documents, such as duly signed contract agreements, evidence of 
adequate Study financing etc. are in place. 
It is the responsibility of the CI to produce the Annual Progress Report (APR) and submit to the EC within 
30 days of the anniversary date on which favourable opinion to start the Trial was given, and annually until 
the Trial is declared ended. 
8.3 Regulatory Compliance 
The Study will be conducted in compliance with ICH-GCP E6(R2) guidelines, other GxP guidelines, the 
most recent version of the Declaration of Helsinki,  the Belgian law of May 7th 2004 regarding experiments 
on the human person (as amended)  and with the EU General Data Protection Regulation 2016/679 
(GDPR), the relevant Belgian laws implementing the GDPR, the Belgian Law of August 22nd 2002 on patient 
rights and all other applicable legal and regulatory requirements. 
 
8.4 Protocol / GCP compliance 
The Study must be performed in accordance with the protocol, current ICH and ICH-GCP guidelines, and 
applicable regulatory and country-specific requirements. ICH guidelines are an international ethical and 
scientific quality standard for designing, conducting, recording, and reporting studies that involve the 
participation of human participants. Compliance with this standard provides public assurance that the rights, 
safety, and well-being of Study participants are protected, consistent with the principles that originated in 
the most recent version of the Declaration of Helsinki, and that the Study data are credible, reliable and 
reproducible. 
The Investigator and Trial team acknowledge and agree that prospective, planned deviations or waivers to 
the protocol are not permitted under applicable regulations on clinical studies. However, should there be 
an accidental protocol deviation, such deviation shall be adequately documented in the source documents 
and on the relevant forms and reported to the CI and Sponsor. Deviations should also be reported to the 
EC as part of the EC’s continued review of the Trial (e.g. through the ASR, APR, etc.). Protocol deviations 
which are found to frequently recur, will require (immediate) action. The Investigator acknowledges that 
such recurring protocol deviations could potentially be classified as a serious violation of ICH and/or the 
protocol. 
It is understood that “a serious violation” is likely to affect to a significant degree: 
- 
the safety or physical or mental integrity of the Trial participants; or 
- 
the scientific validity of the Trial 
The Investigator is expected to take any immediate action required to protect the safety of any 
participant included in the Trial, even if this action represents a deviation from the protocol. In such 
cases, the Sponsor should be notified of this action and the EC at the Trial site should be informed 
according to local procedures and regulations. 
 

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8.5 Data protection and participant confidentiality 
The Study will be conducted in compliance with the requirements of the EU General Data Protection 
Regulation 2016/679 (GDPR), and the relevant Belgian laws implementing the GDPR including the Belgian 
Privacy Act of 30 July 2018 on the protection of privacy in relation to the processing of personal data. 
Any collection, processing and disclosure of personal data, such as participant health and medical 
information is subject to compliance with the aforementioned personal data protection laws (cfr. Data 
Processing Annex (DPA) in Appendix 1). In case personal data is transferred outside the European 
Economic Area, safeguards will be taken by the Sponsor to ensure that appropriate protection travels 
with the data in accordance with the GDPR. (https://ec.europa.eu/info/law/law-topic/data-
protection/international-dimension-data-protection/rules-international-data-transfers_en#documents) 
Any personal data shall be treated as confidential at all times including during collection, handling and use 
or processing, and the personal data (including in any electronic format) shall be stored securely at all times 
and with all technical and organizational security measures that would be necessary for compliance with 
EU and national data protection legislation (whichever is more stringent). The Sponsor shall take 
appropriate measures to ensure the security of all personal data and guard against unauthorized access 
thereto or disclosure thereof or loss or destruction while in its custody. 
 
8.6 Insurance 
The Participating Site, the Investigator and Sponsor shall have and maintain in full force and effect during 
the term of this Trial, and for a reasonable period following termination of the Trial, adequate insurance 
coverage for: (i) medical professional and/or medical malpractice liability, and (ii) general liability. 
For Belgian Participating Sites 
Art 29 of the Belgian Law relating to experiments on human persons dated May 7th, 2004 applies. 
Prior to the start of the Trial, the Sponsor shall enter into an insurance contract in order to adequately 
cover Trial participants from Belgian sites in accordance with art. 29 of the said law. 
8.7 Amendments 
Unless for urgent reasons as specified in ICH-GCP E6(R2) section 4.5.4, amendments must not be 
implemented prior to EC review and/or approval. 
In accordance with the Belgian law of May 7th 2004 regarding experiments on humans, the Sponsor may 
develop a non-substantial amendment at any time during the Trial. If a substantial amendment to the clinical 
Study agreement or the documents that supported the original application for the clinical Trial authorisation 
is needed, the Sponsor must submit a valid substantial amendment to the EC for review and approval. The 
EC will provide a response in accordance with timelines defined by applicable regulations. It is the Sponsor’s 
responsibility to assess whether an amendment is substantial or non-substantial for the purpose of 
submission to the EC. 
Amendments to the Study are regarded as ‘substantial’ when they are likely to have a significant impact on 
the safety or physical or mental integrity of the clinical Study participants, or the scientific value of the 
Study. 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/2010_c82_01/2010_c82_01_en.pdf  
8.8  
Post-Trial activities 
After completing the clinical trial, participants will not be provided with study medication nor VLCKD. The 
study drug and VLCKD programs are approved and available to patients on the Belgian market, at own 
expense, and after medical advice and prescription as needed.  
9 Human Body Material 
The investigator and study team will comply with all applicable laws and patient and privacy rights and all 
applicable laws regarding the use of human body material (HBM) when collecting, processing, storing and/or 
using samples of HBM for scientific research..  

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Particularly, the investigator shall act in accordance with the Law of 19 December 2008 regarding the 
procurement and use of human biological material intended for human medical applications or for scientific 
research purposes and its royal decree. To this end, the investigator will obtain approval from the notified 
UZ/KU Leuven Biobank prior to the start of the research. The investigator and his team shall ensure the 
traceability of the HBM during the complete lifecycle of the HBM. 
The investigator will use the HBM for the purposes as described in the Protocol. If the HBM is to be used 
for any other purposes than those stated in the Protocol, the investigator shall first obtain approval from 
the UZ/KU Leuven Biobank and the appropriate Ethics Committee (EC).  
The Participating Site warrants that these Samples have been collected in accordance with the legislation 
in force in the country of origin and in accordance with the (inter)national standards on ethics and 
protection of privacy and personal data, and can be legitimately used for the Study. The providers of the 
Samples in particular warrant that the donor has consented to the use of his/her Samples for the Study 
and/or has not objected to it to the extent required under the legislation in force in the country of origin. 
Since UZ Leuven will receive coded/pseudonymized Samples from the Participating Site/Collaborating 
Hospital, UZ Leuven is subject to the rights and obligations as ‘data controller’ set forth under GDPR in 
relation to the processing of Personal Data. The providers of the Samples are subject to the rights and 
obligations as ‘data processor’ set forth under the GDPR  in relation to the processing of Personal Data. 
UZ Leuven and the providers of the Samples’ rights and obligations with respect to Personal Data are 
further detailed in the data processing agreement attached in Addendum I. 
10 Research Registration, Dissemination of Results and   
Publication Policy 
The Declaration of Helsinki (latest version) and European and Belgian regulations require that every 
research Study involving human participants be registered in a publicly accessible database before 
recruitment of the first participant. The CI is responsible for registering the Study.  
In addition, the CI will fulfil their ethical obligation to disseminate and make the research results publicly 
available. As such the CI is accountable for the timeliness, completeness and accuracy of the reports. 
Researchers, authors, Sponsors, editors and publishers must adhere to accepted guidelines for ethical 
reporting. Negative and inconclusive, as well as positive results must be published or otherwise made 
publicly available. Sources of funding, institutional affiliations and conflicts of interest must be declared in 
publication.  
Publications will be coordinated by the CI. Authorship to publications will be determined in accordance 
with the requirements published by the International Committee of Medical Journal Editors and in 
accordance with the requirements of the respective medical journal.  
For multicentre Trials, it is anticipated that the primary results of the overall Trial shall be published in a 
multicentre publication. 
Participating Sites are not allowed to publish any subset data or results from the Trial prior to such 
multicentre publication.  
Any publication by a Participating Site must be submitted to the Sponsor for review at least thirty (30) 
calendar days prior to submission or disclosure. Sponsor shall have the right to delay the projected 
publication for a period of up to three (3) months from the date of first submission to the Sponsor in order 
to enable the Sponsor to take steps to protect its intellectual property rights and know-how.  
11 Intellectual Property 
Any know how, inventions, methods, developments, innovations, discoveries and therapies, whether 
patentable or not, arising from the Trial or made in the performance of the Trial protocol (“Inventions”) 
shall vest in the Sponsor. The Participating Site, its employees and Investigator(s) shall promptly disclose 
to the Sponsor any such Inventions. Parties have expressly agreed that any and all Trial data as collected 
and prepared in the performance of the Trial protocol shall be the sole property of Sponsor unless 
otherwise agreed in the clinical trial agreement. 

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12 References 
 
1. 
World Health Organization. Obesity and overweight. 2021. Available from: https://www.who.int/news-
room/fact-sheets/detail/obesity-and-overweight 
 
2. 
Wadden TA, Tronieri JS, Butryn ML. Lifestyle modification approaches for the treatment of obesity in 
adults. Vol. 75, The American psychologist. NLM (Medline); 2020. p. 235–51.  
 
3. 
Muscogiuri G, El Ghoch M, Colao A, Hassapidou M, Yumuk V, Busetto L. European Guidelines for 
Obesity Management in Adults with a Very Low-Calorie Ketogenic Diet: A Systematic Review and Meta-
Analysis. Vol. 14, Obesity Facts. S. Karger AG; 2021. p. 222–45.  
 
4. 
Barrea L, Verde L, Schiavo L, Sarno G, Camajani E, Iannelli A, et al. Very Low-Calorie Ketogenic Diet 
(VLCKD) as Pre-Operative First-Line Dietary Therapy in Patients with Obesity Who Are Candidates for 
Bariatric Surgery. Vol. 15, Nutrients. MDPI; 2023.  
 
5. 
Lundgren JR, Janus C, Jensen SBK, Juhl CR, Olsen LM, Christensen RM, et al. Healthy Weight Loss 
Maintenance with Exercise, Liraglutide, or Both Combined. New England Journal of Medicine. 2021 May 
6;384(18):1719–30.  
 
6. 
Wadden TA, Hollander P, Klein S, Niswender K, Woo V, Hale PM, et al. Weight maintenance and 
additional weight loss with liraglutide after low-calorie-diet-induced weight loss: The SCALE Maintenance 
randomized study. Int J Obes. 2013 Nov;37(11):1443–51.  
 
7. 
Billes SK, Sinnayah P, Cowley MA. Naltrexone/bupropion for obesity: An investigational combination 
pharmacotherapy for weight loss. Vol. 84, Pharmacological Research. Academic Press; 2014. p. 1–11.  
 
8. 
Sherman MM, Ungureanu S, Rey JA. Naltrexone/Bupropion ER (Contrave). 2016 Mar.  
 
9. 
UZ Leuven. Maagchirurgie obesitas. Available from: 
https://www.uzleuven.be/nl/obesitaskliniek/obesitas/behandeling/maagchirurgie 
 
10. 
Courcoulas AP, Christian NJ, Belle SH, Berk PD, Flum DR, Garcia L, et al. Weight change and health 
outcomes at 3 years after bariatric surgery among individuals with severe obesity. JAMA. 
2013;310(22):2416–25.  
 
11. 
Gazda CL, Clark JD, Lingvay I, Almandoz JP. Pharmacotherapies for Post-Bariatric Weight Regain: Real-
World Comparative Outcomes. Obesity. 2021 May 1;29(5):829–36.  
 
12. 
Apovian CM, Aronne L, Rubino D, Still C, Wyatt H, Burns C, et al. A randomized, phase 3 trial of 
naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II). Obesity. 2013 
May;21(5):935–43. 
 
 
 
 
 
 
 
 
 

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APPENDICES 
Appendix 1: Data Processing Annex (DPA) 
Definitions: 
• 
“Protocol” means the document entitled  Naltrexon/bupropion with or withour very low calorie 
ketogenic diet for weight regeain after bariatric surgery containing the details of the academic 
Study as developed by the Sponsor and approved by the relevant Ethics Committee. 
• 
“Sponsor” means University Hospitals Leuven (UZ Leuven). 
• 
Participating site acts as a data processor as defined under article 4, 8) of the Regulation (EU) 
2016/679 (“Data Processor”) for the Sponsor who acts as data controller as defined under article 
4, 7) of the Regulation (EU) 2016/679 (“Data Controller”). 
• 
“Applicable Law” means any applicable data protection or privacy laws, including:  
b) the Regulation (EU) 2016/679 also referred as the General Data Protection Regulation 
("GDPR");  
c) other applicable laws that are similar or equivalent to or that are intended to or implement 
the laws that are identified in (a) of this definition;  
• 
"Personal Data" means any information relating to an identified or identifiable natural person 
(”Data Participant”), including without limitation pseudonymized information, as defined in 
Applicable Law and described in the Protocol. 
Rights and obligations: 
1. The Data Processor is instructed to process the Personal Data for the term of the Study and only 
for the purposes of providing the data processing tasks set out in the Protocol. The Data Processor 
may not process or use Personal Data for any purpose other than a Data Participant’s medical 
records, or other than provided in the instructions of the Study protocol, including with regard to 
transfers of personal data to a third country or an international organization, unless the Data 
Processor is required to do so according to Union or Member State law.  
2. Data Processor shall at all times maintain a record of processing of Personal Data in accordance 
with Applicable Law and if the Data Processor considers an instruction from the Data Controller 
to be in violation of the Applicable Law, the Data Processor shall promptly inform the Data 
Controller in writing about this. 
3. The Data Processor must ensure that persons authorized to process the Personal Data have 
committed themselves to confidentiality or are under an appropriate statutory obligation of 
confidentiality. 
4. The Data Processor shall implement appropriate technical and organizational measures to prevent 
that the Personal Data processed is: 
(i) accidentally or unlawfully destroyed, lost or altered, 
(ii) disclosed or made available without authorization, or 
(iii) otherwise processed in violation of Applicable Law.  
5. The appropriate technical and organizational security measures must be determined with due 
regard for: 
(i) the current state of the art, 
(ii) the cost of their implementation, and 
(iii) the nature, scope, context and purposes of processing as well as the risk of varying likelihood 
and severity for the rights and freedoms of natural persons. 

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6. Taking into account the nature of the processing, the Data Processor shall assist the Data 
Controller, by means of appropriate technical and organizational measures, insofar as this is 
possible, in fulfilling its obligation to respond to requests from Data Participants pursuant to laws 
and regulations in the area of privacy and data protection (such as, the right of access, the right to 
rectification, the right to erasure, the right to restrict the processing, the right to data portability 
and the right to object) 
7. The Data Processor shall upon request provide the Data Controller with sufficient information to 
enable the Data Controller to ensure that the Data Processor's obligations under this DPA are 
complied with, including ensuring that the appropriate technical and organizational security 
measures have been implemented. 
8. The Data Controller is entitled to appoint at its own cost an independent expert, reasonably 
acceptable to the Data Processor, who shall have access to the Data Processor's data processing 
facilities and receive the necessary information for the sole purpose of auditing whether the Data 
Processor has implemented and maintained said technical and organizational security measures. 
The expert shall upon the Data Processor's request sign a non-disclosure agreement provided by 
the Data Processor, and treat all information obtained or received from the Data Processor 
confidentially, and may only pass on, after conferral with the Data Processor, the findings as 
described under 10) (ii) below to the Data Controller. 
9. The Data Processor must give authorities who by Union or Member State law have a right to 
enter the Data Controller's or the Data Controller's processors’ facilities, or representatives of 
the authorities, access to the Data Processor's physical facilities against proper proof of identity 
and mandate, during normal business hours and upon reasonable prior written notice. 
10. The Data Processor must without undue delay in writing notify the Data Controller about: 
(i) any request for disclosure of Personal Data processed under the Protocol by authorities, 
unless expressly prohibited under Union or Member State law, 
(ii) any  finding of (a) breach of security that results in accidental or unlawful destruction, loss, 
alteration, unauthorized disclosure of, or access to, Personal Data transmitted, stored or 
otherwise processed by the Data Processor under the Protocol, or (b) other failure to comply 
with the Data Processor's obligations, or 
(iii) any request for access to the Personal Data (with the exception of medical records for which 
the Data Processor is considered data controller) received directly from the Data Participants 
or from third parties. 
11. Such a notification from the Data Processor to the Data Controller with regard to a breach of 
security as meant in 10) (ii)(a) above will contain at least the following information: 
(i) the nature of the Personal Data breach, stating the categories and (by approximation) the 
number of Data Participants concerned, and stating the categories and (by approximation) the 
number of the personal data registers affected (datasets); 
(ii) the likely consequences of the Personal Data breach; 
(iii) a proposal for measures to be taken to address the Personal Data breach, including (where 
appropriate) measures to mitigate any possible adverse effects of such breach. 
12. The Data Processor shall document (and shall keep such documentation available for the Data 
Controller) any Personal Data breaches, including the facts related to the Personal Data breach, 
its effects and the corrective measures taken. After consulting with the Data Controller, the Data 
Processor shall take any measures needed to limit the (possible) adverse effects of Personal Data 
breaches (unless such consultation cannot be awaited due to the nature of the Personal Data 
breach). 
13. The Data Processor must promptly and reasonably assist the Data Controller (with the handling 
of (a) responses to any breach of security as described in 10) (ii) above and (b) any requests from 
Data Participants under Chapter III of the GDPR, including requests for access, rectification, 
blocking or deletion. The Data Processor must also reasonably assist the Data Controller by 

UZ/KU Leuven 
 
 
Protocol: RELAY 
Internal Ref.: S68952 
 
 
Version: 1.3_19Nov2024 
 
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implementing appropriate technical and organizational measures for the fulfilment of the Data 
Controller's obligation to respond to such requests.  
14. The Data Processor must reasonably assist the Data Controller with meeting the other obligations 
that may be incumbent on the Data Controller according to Union or Member State law where 
the assistance of the Data Processor is implied, and where the assistance of the Data Processor is 
necessary for the Data Controller to comply with its obligations. This includes, but is not limited 
to, at the request to provide the Data Controller with all necessary information about an incident 
under 10) (ii), and all necessary information for an impact assessment in accordance with Article 
35 and Article 36 of the GDPR.  
Subprocessor: 
15. The Data Processor may only engage a subprocessor, with prior specific or general written 
consent from the Data Controller. The Data Processor undertakes to inform the Data Controller 
of any intended changes concerning the addition or replacement of a subprocessor by providing a 
reasonable prior written notice to the Data Controller. The Data Controller may reasonably and 
in a duly substantiated manner object to the use of a subprocessor. The Data Processor must 
inform the Data Controller in writing of the discontinued use of a subprocessor. 
16. Prior to the engagement of a subprocessor, the Data Processor shall conclude a written agreement 
with the subprocessor, in which at least the same data protection obligations as set out in this 
DPA shall be imposed on the subprocessor, including obligations to implement appropriate 
technical and organizational measures and to ensure that the transfer of Personal Data is done in 
such a manner that the processing will meet the requirements of the Applicable Law. 
17. The Data Controller has the right to receive a copy of the relevant provisions of Data Processor's 
agreement with the subprocessor related to data protection obligations. The Data Processor shall 
remain fully liable to the Data Controller for the performance of the subprocessor obligations 
under this DPA. The fact that the Data Controller has given consent to the Data Processor's use 
of a subprocessor is without prejudice for the Data Processor's duty to comply with this DPA. 
 
 

UZ/KU Leuven 
 
 
Protocol: RELAY 
Internal Ref.: S68952 
 
 
Version: 1.3_19Nov2024 
 
 CTC GEN-TMP-…-1.0_11APR2024  
Page 36 of 39                                                            Protocol template 
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Appendix 2: [Pro Well VLCKD protocol] 
• 
BMI 27+ program: 10 weeks 
o 4 weeks VLCKD strict phase: 800 kcal/day (<50g carbs, >100g proteins, vegetables 
with a low carb content 
o 3 x 2 weeks of progressive increase of daily kcal: 1000 kcal, 1200 kcal (W) / 1400 kcal 
(M), 1500 kcal (W) / 1800 kcal (M) based on Mediterranean diet 
o Coaching minutes: 2 hours 15 minutes 
 
Intake 
30 minutes 
Explanation VLCKD & App 
Follow-up 1: after 3 weeks 
15 minutes 
Follow-up 
Follow-up 2: after 4 weeks 
15 minutes 
Explanation 1000 kcal meal plan 
Follow-up 3: after 6 weeks 
15 minutes 
Explanation 1200/1400 kcal meal plan 
Follow-up 4: after 8 weeks 
15 minutes 
Explanation 1400/1800 kcal meal plan 
Outtake after 10 weeks 
15 minutes 
Progress & Reflection 
 
 

UZ/KU Leuven 
 
 
Protocol: RELAY 
Internal Ref.: S68952 
 
 
Version: 1.3_19Nov2024 
 
 CTC GEN-TMP-…-1.0_11APR2024  
Page 37 of 39                                                            Protocol template 
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Appendix 3: [Pro Well Lifestyle protocol] 
• 
Lifestyle e-learning program :  
- 
30 minutes 1-on-1 coaching and regular personal follow-up by telephone (if possible 
regular videocall Whatsapp/FaceTime)  
- 
3 modules including 12 educational presentations 
- 
12 practical tasks to apply in daily life 
 
o Lifestyle e-learning program in addition to Naltrexon/bupropion 
 
Lifestyle coaching 1: at the start 
15 minutes 
Intake: overview e-learning modules and 
tasks 
Lifestyle coaching 1: month 1 & 2 
e-learning 
Module :  nutrition & 4 tasks about nutrition 
Lifestyle coaching 1: after 1 month 
Telephone 
Follow-up  
Lifestyle coaching 1: after 2 months  
Telephone 
Follow-up 
Lifestyle coaching 1: month 3 & 4 
e-learning 
Module : physical exercise & 4 tasks 
Lifestyle coaching 1: after starting module 2 
15 minutes 
Introducing a personal exercise program 
Lifestyle coaching 1: after 3 months 
Telephone 
Follow-up 
Lifestyle coaching 1: after 4 months 
Telephone 
Follow-up 
Lifestyle coaching 1: month 5 & 6 
e-learning 
Module : Lifestyle topics sleep, stress 
management, relaxation and focus 
Lifestyle coaching 1: after month 5 
Telephone 
Follow-up 
Lifestyle coaching 1: at the end of month 6 
Telephone 
Outtake questionnaire: reflection & future 
goals 
 
o Lifestyle e-learning program as a follow-up after 10 weeks BMI 27+ starting 
after 3 months 
 
Lifestyle coaching 1: after 3 months 
15 minutes 
Intake: overview e-learning modules and 
tasks 
Lifestyle coaching 1: month 4 
e-learning 
Module :  nutrition & 4 tasks about nutrition 
Lifestyle coaching 1: halfway month 4 
Telephone 
Follow-up  
Lifestyle coaching 1: at the end of month 4 Telephone  
Follow-up 
Lifestyle coaching 1: month 5 
e-learning 
Module : physical exercise & 4 tasks 
Lifestyle coaching 1: after starting module 
2 
15 minutes 
Introducing a personal exercise program 
Lifestyle coaching 1: halfway month 5 
Telephone 
Follow-up 
Lifestyle coaching 1: at the end of month 5 Telephone 
Follow-up 
Lifestyle coaching 1: month 6 
e-learning 
Module : Lifestyle topics sleep, stress 
management, relaxation and focus 
Lifestyle coaching 1: halfway month 6 
Telephone 
Follow-up 
Lifestyle coaching 1: at the end of month 6 Telephone 
Outtake questionnaire: reflection & future 
goals 
 
 
 

UZ/KU Leuven 
 
 
Protocol: RELAY 
Internal Ref.: S68952 
 
 
Version: 1.3_19Nov2024 
 
 CTC GEN-TMP-…-1.0_11APR2024  
Page 38 of 39                                                            Protocol template 
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Lifestyle e-learning program in addition to Naltrexon/bupropion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BMI 27+ and Lifestyle Coaching 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Follow-up 
Follow-up 
Follow-up 
Outtake 
Follow-up 
Nutrition 
Exercise 
Lifestyle 
 
 
Intake 
15’ 
Coaching 
15’ 
1 month             2 months 
  3 months 
    4 months   
    5 months              6 months           
Follow-up 
Follow-up 
Follow-up 
Outtake 
Follow-up 
1 month 
2 months 
 3 months 
   4 months 
   5 months 
    6 months 
Excercise 
Lifestyle 
Nutrition 
 
Coaching  
15’ 
 
Intake 
15’ 
FU 3 weeks 
FU 4 weeks 
FU 6 weeks 
FU 8 weeks 
BMI 27+ 
 
Intake  
BMI 27+ 
30’ 
FU 10weeks 

UZ/KU Leuven 
 
 
Protocol: RELAY 
Internal Ref.: S68952 
 
 
Version: 1.3_19Nov2024 
 
 CTC GEN-TMP-…-1.0_11APR2024  
Page 39 of 39                                                            Protocol template 
for 
                                   Confidential & Proprietary                                                    prospective study