Comparison of Pain and Comfort in Patients Following Cardiac Surgery: Opioid- Morphine Managed Versus Multimodal Pain-management
Phase: PHASE4
Conditions: Postoperative Pain, Postoperative Delirium
Sponsor: University Hospital, Ghent

Department of anesthesia | Intensive care Unit 
Ghent University Hospital 
Protocol version 3 
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Part I: Trial related part of the protocol  
 
 
1 
Title of the trial 
Comparison of pain and comfort in patients following cardiac surgery: Opioid- morphine managed 
versus multimodal pain-management. 
Short title: Mutimodal versus Opioid aNalgesia in carDiAc surgery: MONDAY-study 
 
 
2 
Trial number 
Protocol: AGO/2018/ 
EudraCT number 
Clinical trial number 
 
 
 
3 
Objective of the study 
To compare standard “Fentanyl – Tramadol – Paracetamol – Oxycodon” regimen to a multimodal 
painmanagement “pregebaline- minimal fentanyl-ketamine-lidocain-dexmedetomedine- 
paracetamol” to determine which therapy provides the most comfort, the fastest extubation time, 
the least pain and the least delirium. 
 
 
4 
Primary endpoints 
4.1 Primary Endpoint 
The primary endpoint of this study is postoperative pain (at rest, when coughing and at movement) 
at 8-h, 16-h, 24-h, 32-h, 40-h and 48-h after cardiac surgery. Pain is measured by a NRS-scale if the 
patient is awake, and by the Critical-Care Pain Observation Tool(CPOT) in the sedated patient. 
 
4.2 Secondary Endpoints 
Secondary endpoints include delirium in the direct postoperative phase measured by the ICDSC- 
score. Also included in the secondary endpoints are: time till extubation, length of hospital stay, 
length of stay at the ICU department and total consumption of pain medication registered in mg/kg. 
 
 
 
4 
General information 
 
Investigators 
Dr. Simon Bogaert 
Dr. Harlinde Peperstraete 

Department of anesthesia | Intensive care Unit 
Ghent University Hospital 
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Dr. Annelies Moerman 
Dr. Stefaan Bouchez 
Dr. Wim Vandenberghe 
Dr. Ingrid Herck 
 
Sponsor 
Ghent University Hospital 
 
 
Departments involved in the study 
Department of Anesthesia 
Intensive Care Unit 
 
 
5 
Introduction 
Cardiac surgery for the adult, performed by sternotomy is associated with moderate to severe acute 
postoperative pain. Postoperative pain is the primary reason for prolonged convalescence [2] and 
one of the main concerns of the surgical patient in the ICU department. This pain is multifactorial and 
multifocal; and can be caused by incision, intraoperative tissue retraction and dissection, surgical 
manipulation of the parietal pleura, posterior rib dislocation or fracture, possible brachial plexus 
injury, chest tube insertion and harvesting of the saphenous vein and internal mammarian artery. (1- 
3) 
 
The most common analgesic schemes for postoperative pain in cardiac surgery are based on 
intravenous opioids by bolus, with patient- or nurse-controlled delivery systems. Although there is no 
doubt they have a beneficial effect on pain, opioids are associated with dose-related side effects 
including “over”sedation, ileus, urinary retention, nausea, vomiting, pruritus, mental confusion and 
respiratory depression leading to a prolonged extubation time. (1, 3, 4) 
 
In the last decades many has been written about the value of multimodal pain protocols to treat 
acute postoperative pain in non-cardiac surgery. This is not only to reduce the dose and side effects 
of opioids. By blocking both the central and peripheral pain mechanisms the aim is to find a holy 
grale, by which the patient suffers the least, by which central neural hyper-excitability that increases 
postoperative pain is minimized (3, 5) and by which the transformation of acute into chronic pain is 
reduced to a minimum. 
 
Pregabalin has his role in treating various neuropathic pain syndromes. It inhibits central neuronal 
sensitisation and prevents hyperalgesia by decreasing excitatory amino acid neurotransmission in the 
spinal cord through a direct postsynaptic or presynaptic inhibition of Ca²+ influx. It has been shown 
that gabapentin reduced pain scores and opioid requirements in different surgical settings. (3, 6-8) 
Literature is not conclusive and because of conflicting results the routine use of gabapentin and 
pregabalin to reduce opioid consumption in the cardiac surgical patients is not yet recommended.(6, 
8) 

Department of anesthesia | Intensive care Unit 
Ghent University Hospital 
Protocol version 3 
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Dexmedetomedine is an alpha-2 adrenergic receptor agonist that can be directly applied to the 
peripheral nervous system, causing a dose-dependent inhibition of C-fibers and Aα-fibers(1, 9). It is 
widely used for sedation and anxiolysis in ICU settings. The clinical efficacy has been proven in non- 
cardiac surgery by augmenting anesthesia and analgesia, and allowing a reduction in opioid 
requirements.(1) Additionally, there was a significantly lower incidence of postoperative delirium.(1, 
10, 11) 
 
Ketamine isn’t only an anesthetic agent but also has an analgesic effect. The exact mechanism is not 
yet known but some of the pathways are already identified.(12) It binds to the opioid receptors 
κ(kappa) δ(delta) μ(mu) and it was proven that ketamine induces phosphorylation of mitogen- 
activated protein kinases by 2–3 times that of traditional opioid drugs.(10, 13) Another way of 
producing its analgesic effect is by the muscarinic acetylcholine receptors in the central nervous 
system.(10) Ketamine also effects other ion channels including sodium channels and voltage sensitive 
calcium channels leading to local anesthetic and gabapentin like effects.(12) Because of the unique 
effect of keeping hemodynamic stability during induction, ketamine can be useful in cardiac surgery. 
The analgesic effect, the absence of respiratory depression and hemodynamic stability make it an 
excellent drug to use in the ICU. (12) 
 
Intravenous lidocaine during the perioperative period has many beneficial effects in open 
procedures, such as an earlier return of gastrointestinal tract function, less postoperative opioid 
consumption, improvement of postoperative cognitive dysfunction and reduced stay in the 
hospital.(8, 14, 15) The exact working mechanism isn’t 100% identified but the anti-inflammatory 
effects of LA mediated through interactions with polymorphonuclear cells and the inhibition of G 
protein-coupled receptors may play a crucial role for the observed effects in the perioperative 
setting.(15) 
 
Magnesiumsulfate’s analgesic mechanisms are also not fully identified, but it is thought that the 
NMDA receptor is blocked by calcium regulation mechanisms. Because the NMDA receptor plays a 
role in the transmission of pain, magnesium has become a subject of interest as potential use in 
postoperative painschemes.(16, 17) It was proven that peri-operative intravenous magnesium can 
reduce opioid consumption especially in the first 24h.(17) 
 
Our goal is to compare standard “Fentanyl – Tramadol – Paracetamol – Oxycodon” regimen to a 
multimodal painmanagement “pregabalin- magnesiumsulfate - minimal fentanyl-ketamine-lidocain- 
dexmedetomedine- paracetamol” to determine which therapy provides the most comfort, the 
fastest extubation time, the least pain and the least delirium. 
 
 
1. 
Bigeleisen PE, Goehner N. Novel approaches in pain management in cardiac surgery. Curr 
Opin Anaesthesiol. 2015;28(1):89-94. 
2. 
Mueller XM, Tinguely F, Tevaearai HT, Revelly JP, Chiolero R, von Segesser LK. Pain location, 
distribution, and intensity after cardiac surgery. Chest. 2000;118(2):391-6. 
3. 
Rafiq S, Steinbruchel DA, Wanscher MJ, Andersen LW, Navne A, Lilleoer NB, et al. Multimodal 
analgesia versus traditional opiate based analgesia after cardiac surgery, a randomized controlled 
trial. J Cardiothorac Surg. 2014;9:52. 
4. 
White PF, Rawal S, Latham P, Markowitz S, Issioui T, Chi L, et al. Use of a continuous local 
anesthetic infusion for pain management after median sternotomy. Anesthesiology. 2003;99(4):918- 
23. 
5. 
Weinbroum AA. Non-opioid IV adjuvants in the perioperative period: pharmacological and 
clinical aspects of ketamine and gabapentinoids. Pharmacol Res. 2012;65(4):411-29. 

Department of anesthesia | Intensive care Unit 
Ghent University Hospital 
Protocol version 3 
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6. 
Maitra S, Baidya DK, Bhattacharjee S, Som A. [Perioperative gabapentin and pregabalin in 
cardiac surgery: a systematic review and meta-analysis]. Rev Bras Anestesiol. 2017;67(3):294-304. 
7. 
Ucak A, Onan B, Sen H, Selcuk I, Turan A, Yilmaz AT. The effects of gabapentin on acute and 
chronic postoperative pain after coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth. 
2011;25(5):824-9. 
8. 
Wick EC, Grant MC, Wu CL. Postoperative Multimodal Analgesia Pain Management With 
Nonopioid Analgesics and Techniques: A Review. JAMA Surg. 2017;152(7):691-7. 
9. 
Tang C, Xia Z. Dexmedetomidine in perioperative acute pain management: a non-opioid 
adjuvant analgesic. J Pain Res. 2017;10:1899-904. 
10. 
Mazzeffi M, Johnson K, Paciullo C. Ketamine in adult cardiac surgery and the cardiac surgery 
Intensive Care Unit: an evidence-based clinical review. Ann Card Anaesth. 2015;18(2):202-9. 
11. 
Mu JL, Lee A, Joynt GM. Pharmacologic agents for the prevention and treatment of delirium 
in patients undergoing cardiac surgery: systematic review and metaanalysis. Crit Care Med. 
2015;43(1):194-204. 
12. 
Frenkel C, Urban BW. Molecular actions of racemic ketamine on human CNS sodium 
channels. Br J Anaesth. 1992;69(3):292-7. 
13. 
Gupta A, Devi LA, Gomes I. Potentiation of mu-opioid receptor-mediated signaling by 
ketamine. J Neurochem. 2011;119(2):294-302. 
14. 
Weibel S, Jokinen J, Pace NL, Schnabel A, Hollmann MW, Hahnenkamp K, et al. Efficacy and 
safety of intravenous lidocaine for postoperative analgesia and recovery after surgery: a systematic 
review with trial sequential analysis. Br J Anaesth. 2016;116(6):770-83. 
15. 
Kranke P, Jokinen J, Pace NL, Schnabel A, Hollmann MW, Hahnenkamp K, et al. Continuous 
intravenous perioperative lidocaine infusion for postoperative pain and recovery. Cochrane Database 
Syst Rev. 2015(7):CD009642. 
16. 
Castro J, Cooney MF. Intravenous Magnesium in the Management of Postoperative Pain. J 
Perianesth Nurs. 2017;32(1):72-6. 
17. 
Albrecht E, Kirkham KR, Liu SS, Brull R. Peri-operative intravenous administration of 
magnesium sulphate and postoperative pain: a meta-analysis. Anaesthesia. 2013;68(1):79-90. 
 
 
 
 
6 
The present study 
Study design 
Prospective randomised double-blinded (for participant and study staff) study 
 
 
Medication, producer administration route and dosing 
 
Classic protocol 
Medication 
Dose 
Route Time of administration 
Fentanyl 
Max. 15µg/kg 
IV 
Per-op 
Ultiva (Remifentanyl) 
0.02-0.1µg/kg/h 
IV 
Post-op 
4x1g /24h 
IV 
Post-op 
Tradonal (Tramadol) 
100mg IV 4/d 
IV 
Post-op (Break through pain) 
Oxynorm (Oxycodon) 
5-10mg 4-6/d 
PO 
Post-op (Break through pain) 
Paracetamol 
4x1g /24h 
IV 
Post-op 

Department of anesthesia | Intensive care Unit 
Ghent University Hospital 
Protocol version 3 
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Multimodal protocol 
Medication 
Dose 
Route 
Time of administration 
Lyrica (Pregabalin) 
75mg 
PO 
Pré-op 
Dexdor (Dexmedetomidine) 
0.8µg/kg/h 
IV 
Per-op / Post-op 
Ketalar (Ketamine) 
Bolus (0.5mg/kg) + 0.3mg/kg/h 
IV 
Per-op until stop propofol 
Linisol (Lidocaïne) 
Bolus (1.5mg/kg) + 1.3mg/kg/h 
IV 
Per-op until 12h post-op 
Magnesium Sulfate 
Induction (25mg/kg) + 25mg/kg 
weaning ECC 
IV 
Per-op 
Fentanyl 
2.5µg/kg 
IV 
Per-op 
Paracetamol 
4x1g /24u 
IV 
Post-op 
Tradonal (Tramadol) 
100mg IV 4/d 
IV 
Post-op (Break through pain) 
Oxynorm (Oxycodon) 
5-10mg 4-6/d 
PO 
Post-op (Break through pain) 
 
Distributor 
Pharmacy department, Ghent University Hospital 
 
 
Packaging 
Commercially available packaging 
 
 
Labelling 
Following the rules of both the department of Anesthesia and Intensive Care Unit. In case of tablets 
packaging is double: the commercially available monopackage is found in little tear-off plastic bags, 
produced by the pharmacy department of Ghent University Hospital. 
 
 
Storage conditions 
All medication will be stored by the general recommendations of the pharmacy department of our 
hospital. 
 
 
Known side effects of the medication 
The frequency of possible side effects , is defined by using the following terminology. 
 
Very common 
May affect more than 1 in 10 people 
Common 
May affect up to 1 in 10 people 
Uncommon 
May affect up to 1 in 100 people 
Rare 
May affect up to 1 in 1000 people 
Very rare 
May affect up to 1 in 10000 people 
Not known 
Frequency cannot be estimated from available data 

Department of anesthesia | Intensive care Unit 
Ghent University Hospital 
Protocol version 3 
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1. Fentanyl 50micrograms/ml Solution for Injection/Infusion 

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2. Remifentanyl (ULTIVA® 2g) for Injection: 
 
 
3. Paracetamol 10mg/ml Solution for Infusion 

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4. TRAMADOL 50MG/ML SOLUTION FOR INJECTION OR INFUSION 
 
 
5. Oxycodon (OxyNorm®) 5 mg, 10 mg and 20 mg capsules 

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6. Pregabaline (Lyrica) 75 mg hard capsules: 

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7. Dexmedetomidine (Dexdor) 100 micrograms/ml concentrate for solution for 
infusion: 
 
8. Ketamine (Ketalar®) 50 mg/ml INJECTION: 
 

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9. Lidocaine 1% solution for injection (Lidocaine Hydrochloride): 
 

Department of anesthesia | Intensive care Unit 
Ghent University Hospital 
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10. Magnesium sulfate 10% w/v Solution for injection or infusion: 
 
 
Drug accountability 
Drug accountability will be documented. The batch number and expiry date of the used vials will be 
documented in the CRF which will be available in the trial cell of ICU. 
 
 
 
 
Study subjects 
Number of subjects 
Each group will contain 50 subjects; in total there will be 100 subjects. 
Inclusion criteria 
• 
Patients undergoing first time cardiac surgery by median sternotomy 
• 
Elective surgery or semi-urgent: there needs to be time to provide 8 hours 
before surgery the intake of pregabalin 
• 
≥ 18 years 
• 
Possibility to communicate with the patient to score pain and comfort 

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• 
Signed Informed Consent, signed by subject or authorized representative, able 
and willing to provide written informed consent for study participation 
 
 
Exclusion criteria 
• 
Urgent surgery 
• 
Pregnancy and lactation 
• 
Hypersensitivity to any of the study medication 
• 
In case of direct postoperative revision the patient is NOT excluded. 
 
 
Replacements of subjects 
Subjects, who fall out the study, will be replaced 
 
 
Restrictions and prohibitions for the subjects 
None 
 
 
Possible advantages and disadvantages for the subjects 
A possible advantage can be for the subject that the pain management is done more meticulously. 
A possible disadvantage: none. 
 
 
7 
Procedures and flowcharts 
Procedures 
Postoperative pain (at rest, when coughing and at movement) at 8-h, 16-h, 24-h, 32-h, 40-h and 48-h 
after cardiac surgery is measured by an NRS-scale if the patient is awake, and by the Critical-Care 
Pain Observation Tool(CPOT) in the sedated patient. 
Secondary endpoints as delirium in the direct postoperative phase is measured by the ICDSC-score. 
Also included in the secondary endpoints are: time till extubation, length of hospital stay, length of 
stay at the ICU department and total consumption of painmedication registerd in mg/kg 
 
8 
Randomisation and blinding 
Patients will be randomised automatically by computer randomization. 
Patients and study nurses will be blinded to the pain-management. 
 
 
9 
Adverse event reporting 
List of abbreviations 
AE 
Adverse Event 
CA 
Competent Authority 

Department of anesthesia | Intensive care Unit 
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EC 
Ethics Committee 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SSAR 
Suspected Serious Adverse Reaction 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
Adverse Event (AE) 
The following information will be recorded: 
• 
Nature of adverse event 
• 
Date and time of occurrence and disappearance 
• 
Intensity: mild, moderate , severe 
• 
Frequency: once, continuous or intermittent 
• 
Decision regarding study: continuation or withdrawal 
• 
Relation to the study medication (see below) 
An AE is the development of an undesirable medical condition or the deterioration of a pre-existing 
medical condition following or during exposure to a pharmaceutical product, whether or not 
considered causally related to the product. An undesirable medical condition can be symptoms (eg, 
nausea, chest pain), signs (eg, tachycardia, enlarged liver) or the abnormal results of an investigation 
(eg, laboratory findings, electrocardiogram). In clinical studies, an AE can include an undesirable 
medical condition occurring at any time, including run-in or washout periods, even if no study 
treatment has been administered. 
AEs will be recorded from the first drug administration until the end of the trial. Special attention will 
be given to those subjects who have discontinued the trial for an AE, or who experienced a severe or 
serious AE. 
The term AE is used to include both serious and non-serious AEs. 
Serious Adverse Event (SAE) 
A SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, follow-up), that 
fulfils one or more of the following criteria: 
• 
Results in death 
• 
Is immediately life-threatening (life-threatening in this context refers to an event in which 
the patient 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 more severe) 
 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions 
 
• 
Is a congenital abnormality or birth defect 
 
Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above. Medical and scientific 

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judgment should be exercised in deciding whether other situations should be considered 
serious adverse event. 
 
Note: medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require intervention to prevent one of the outcomes listed 
in the definition above. 
 
 
 
 
Unexpected Adverse event 
An adverse event, the nature or severity of which is not consistent with the applicable product 
information (e.g., Investigator’s Brochure for an unapproved investigational product or package 
insert/summary of product characteristics for an approved product). 
Associated with the use of the drug 
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable or definitive. 
Attribution definitions 
 
Not related: An adverse event which is not related to the use of the drug. 
Unlikely: An adverse event for which an alternative explanation is more likely- e.g. concomitant 
drug(s), concomitant disease(s), and/or the relationship in time suggests that a causal relationship is 
unlikely. 
Possible: An adverse event which might be due to the use of the drug. An alternative explanation - 
e.g. concomitant drug(s), concomitant disease(s) is inconclusive. The relationship in time is 
reasonable; therefore the causal relationship cannot be excluded. 
Probable: An adverse event which might be due to the use of the drug. The relationship in time is 
suggestive (e.g. confirmed by dechallenge). An alternative explanation is less likely e.g. concomitant 
drug(s), concomitant disease(s). 
Definitely: An adverse event which is listed as a possible adverse reaction cannot be reasonably 
explained by an alternative explanation – e.g. concomitant drug(s), concomitant disease(s). The 
relationship in time is very suggestive (e.g. it is confirmed by dechallenge and rechallenge). 
Adverse events will be reported between the first dose administration of trial medication and the last 
trial related activity. All AE and SAEs will be recorded in the patient’s file and in the CRF. All SAEs will 
be reported as described below. 
Medical events that occur between the signing of the informed consent and the first intake of trial 
medication will be documented on the medical and surgical history section and concomitant disease 
page of the CRF. SAEs occurring within a period of 2 days following the last intake of trial medication 
will also be handled as such if spontaneously reported to the investigator. 
All serious adverse events (SAE) and pregnancies occurring during clinical trials must be reported by 
the local Principal Investigator within 2 working days after becoming aware of the SAE to: 

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• 
The EC 
• 
The Trial Bureau of Ghent University Hospital 
• 
The Principle Investigator 
This reporting is done by using the appropriate SAE form. For the contact details, see below. 
It is the responsibility of the local Principal Investigator (PI) to report the local SAEs to the EC and the 
CA. 
In case the investigator decides the SAE is a Suspected Unexpected Serious Adverse Reaction(SUSAR), 
the Trial Bureau will report the SUSAR to the EC and the CA within the timelines as defined in 
national legislation. The National Coordinating Investigator reports the SUSAR to all local Principal 
Investigators. 
In case of life-threatening SUSAR the entire reporting process must be completed within 7 calendar 
days. In case of non-life-threatening SUSAR the reporting process must be completed within 15 
calendar days. 
The first report of a serious adverse event may be made by telephone, e-mail or fax. 
Contact details of the Trial Bureau: 
e-mail: trialbureau@uzgent.be 
 
tel 09 332 05 00 
fax 09 332 05 20 
 
 
Contact details of the PI and National Coordinating Investigator: 
e-mail: harlinde.peperstraete@ugent.be 
tel 09 332 51 85 
fax 09 332 4995 
 
 
The investigator must provide the minimal information: i.e. trial number, subject’s initials and date of 
birth, medication code number, period of intake, nature of the adverse event and the invesigator’s 
attribution. This report of a serious adverse event by telephone, must always be confirmed by a 
written, more detailed report. For this purpose the appropriate SAE form will be used. Pregnancies 
occurring during clinical trials are considered immediately reportable events. They must be reported 
as soon as possible using the same SAE form. The outcome of the pregnancy must also be reported. 
If the subjects are not under 12-hour supervision of the investigator or his/her staff 
(outpatients/volunteers), they ( or their designee, if appropriate) must be provided with a “trial card” 
indicating the name of the trial, the trial number, the medication used, the investigator’s name and 
24-hour emergency contact number. 
Annual Safety reporting 

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The trial bureau will ask the Principal Investigator for an annual report containing an overview of all 
SSARs (suspected serious adverse reaction) and a summary regarding the safety of the trials subjects. 
The trial Bureau will send this report to the EC within the timelines as defined in national legislation. 
 
10 Study analysis 
Sample size calculation 
We used an online sample size calculator where we used following data : Two independent study 
groups, continuous endpoints, anticipated incidence of VAS-score 4 (±1,5) vs 3 based on literary 
study, a probability of type 1 error of 5% and power of 80%. This is all similar to most medical 
literature. After this calculation we become two groups of 35 patients. 
Pain and comfort scales 
VAS-Scale. 
Delirium 
ICDSC-score. 
Time to extubation 
In hours. 
Length of stay in ICU and In hospital 
In hours. 
Cumulative use of analgetics in the postoperative period 
Calculated per kilogram. 
Statistical analysis 
Parametric data: unpaired t-test, or student t-test 
Non-parametric data: Wilcoxon’s test 
Level of significance (p)= 0.05 
 
11 Quality control and quality assurance 
Quality control of data of the CRFs will be done by comparing the data of the original documents 
with those of the eCRFs by a person who was not associated with filling in the CRFs. All data will be 
reported in the eCRF files following GCP rules and the internal Trial Bureau Office (Ghent University 
Hospital) will monitor closely the study. eCRF’s will be created by Redcap. 
 
12 Indemnity insurance 
No Fault Insurance Ghent University Hospital 
 
13 Publication policy 
The results of this study will be published in an A1-journal. The privacy of the subjects will be 
respected at all times. Results derived from this study will only be published with the permission of 
the investigators. 

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Part II: General part of the protocol  
 
14 Independent Ethics Committee / Institutional Review Board 
This trial can only be undertaken after full approval of the protocol and addenda has been obtained 
from the IEC/IRB. This document must be dated and clearly identify the protocol, amendments (if any), 
the informed consent form and any applicable recruiting materials and subject compensation 
programs approved. 
During the trial, the following documents will be sent to the IEC/IRB for their review: 
• 
reports of adverse events that are serious, unexpected and associated with the 
investigational drug 
• 
all protocol amendments and revised informed consent form (if any). 
Amendments should not be implemented without prior review and documented approval / favorable 
opinions form the IEC/IRB except when necessary to eliminate an immediate hazard to trial subjects 
or when the change involves only logistical or administrative aspects of the trial. 
Reports on, and reviews of the trial and its progress will be submitted to the IEC/IRB by the investigator 
at intervals stipulated in their guidelines. 
At the end of the trial, the investigator will notify the IEC/IRB about the trial completion. 
 
 
 
15 ICH / GCP guidelines 
This trial will be conducted in accordance with the protocol, current ICH-GCP guidelines and applicable 
law(s). 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, 
conducting, recording and reporting trials that involve the participation of human subjects. Compliance 
with this standard provides public assurance that the rights, safety and well-being of trial subjects are 
protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that 
the clinical trial data are credible. 
 
 
16 Subject information and informed consent (IC) 
Prior to entry in the trial , the investigator must explain to potential subjects or their legal 
representatives the trial and the implication of participation. Subjects will be informed that their 
participation is voluntary and that they may withdraw consent to participate at any time. 
Participating subjects will be told that their records may be accessed by competent authorities and 
by authorized persons without violating the confidentiality of the subject, to the extent permitted by 
the applicable law(s) and/or regulations. By signing the Informed Consent Form (ICF), the subjects or 
legally acceptable representatives are authorizing such access. After this explanation and before 
entry to the trial, written, dated and signed IC should be obtained from the subject or legally 
acceptable representative. The ICF should be provided in a language sufficiently understood by the 
subject. Subjects must be given the opportunity to ask questions. 

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The subject or legally acceptable representative will be given sufficient time to read the ICF and to 
ask additional questions. After this explanation and before entry to the trial, consent should 
appropriately recorded by means of either the subject’s or his/her legal representative’s dated 
signature or the signature of an independent witness who certifies the subject’s consent in writing. 
After having obtained the consent, a copy of the ICF must be given to the subject. In case the subject 
or the legally acceptable representative is unable to read, an impartial witness must attest the IC. 
Subjects who are unable to comprehend the information provided can only be enrolled afeter 
consent of a legally acceptable representative. 
 
17 Case report forms 
The source documents are to be completed at the time of the subject’s visit. The CRFs are to be 
completed within reasonable time after the subject’s visit. The investigator must verify that all data 
entries in the CRFs are accurate and correct. If certain information is Not Done, Not Available or not 
Applicable, the investigator must enter “ND”,” NAV”, “NAP”, respectively in the appropriate space. 
 
 
18 Direct access to source data : documents 
The investigator will permit trial-related monitoring, audits, IRB /IEC review, and regulatory 
inspection(s), providing direct access to source data / documents. 
 
 
19 Data handling and record keeping 
The investigator and sponsor specific essential documents will be retained for at least 20 years. At 
that moment, it will be judged whether it is necessary to retain them for a longer period, according 
to applicable regulatory or other requirements. 

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20 Signature page 
 
INVESTIGATOR: 
NAME : DR. HARLINDE PEPERSTRAETE 
TITLE : PRINCIPLE INVESTIGATOR 
DATE: 
SIGNATURE : 
 
 
INVESTIGATOR: 
NAME : DR. SIMON BOGAERT 
TITLE : INVESTIGATOR 
DATE: 
SIGNATURE : 
 
 
INVESTIGATOR: 
NAME : DR. ANNELIES MOERMAN 
TITLE : INVESTIGATOR 
DATE: 
SIGNATURE : 
 
 
INVESTIGATOR: 
NAME : DR. STEFAAN BOUCHEZ 
TITLE : INVESTIGATOR 
DATE: 
SIGNATURE : 
 
 
INVESTIGATOR: 
NAME : DR. INGRID HERCK 
TITLE : INVESTIGATOR 
DATE: 
SIGNATURE : 
 
 
INVESTIGATOR: 
NAME : DR. DR. WIM VANDENBERGHE 
TITLE : INVESTIGATOR 
DATE: 
SIGNATURE :