The Effect of Obeticholic Acid on Gut Microbiota, Gastric Motility, Accommodation, Gastrointestinal Peptide in Healthy Volunteers
Phase: NA
Conditions: Healthy
Sponsor: Universitaire Ziekenhuizen KU Leuven

[Type here]
[Type here]
[Type here]
Le
LEUVEN
 
CLINICAL TRIAL PROTOCOL
The effect of obeticholic acid on gut microbiota, gastric motility, accommodation, gastrointestinal peptide
in healthy volunteers
OCARINA
Version number: vl
= Date 30/08/2021
EudraCT Nbr: 2020-004 180-13
Internal ref. nbr: S64643
Sponsor
UZ Leuven
Herestraat 49, B-3000 Leuven
Coordinating Investigator
Prof. Dr. Jan Tack
Confidentiality Statement
The information in this documentis 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 Leuven - KUL
Protocol: OCARINA
Internal Ref.: SS64643
Version: 1.0_03082021
 
LIST OF PARTICIPATING SITES
 
(as applicable)
List Of Participating Sites
Principal Investigator
UZ Leuven
Jan Tack
CTC ALG-TMP-001-1.0_28Jul2020
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Internal
Ref.: SS64643
Version: 1.0_03082021
 
SIGNATURES
 
Title: The effect of obeticholic acid on gut microbiota, gastric motility, accommodation,gastrointestinal
peptide in healthy volunteers
Protocol: OCARINA
The undersigned confirm that the above referenced protocol has been acknowledged and accepted, and
agree to conduct the Trial in compliance with the approved protocol, and will adhere to: the principles
outlined in the requirements for the conductof clinical trials in the EU as provided for in Directive
2001/20/EC or the EU Clinical Trial Regulation 536/2014 (as soon as in effect) and any subsequent
amendments thereto, the ICH guidelines, the most recent version of the Declaration of Helsinki,
the
Belgian law of May 7" 2004 regarding experiments on the humanperson(as amended)or the Belgian law
of May 7" 2017 related to clinical trials on medicinal products for humanuse (as soon as in effect), the EU
General Data Protection Regulation 2016/679 (GDPR), relevant Belgian laws implementing the GDPR,the
Belgian Law of August 22"! 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 conductof the Trial, without prior written consentof the Sponsor.
The undersigned also commit to making the findings of the Trial 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 accountof the Trial; and to explain
any discrepancies or deviations from the approvedTrial protocol.
Coordinating Investigator
Prof. Dr. Jan Tack
Name & Title
 
Principal Investigator (Participating Site) (in case of monocentric Trial, the Principal Investigator is the
sameas the Coordinating Investigator)
Prof. Dr. Jan Tack
 
Name & Title
Signature
Date
\LG-TMP-001-1.0_28jul2020
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Version: 1.0_03082021
  
TABLE OF CONTENTS
 
GLINIGAL TRIAL. PROTOCOL seseutcousnssrnsssrensensensesinanaessesy sess seponsonnvonseosvassssstecastortesrrrevsevectervasvessteseitesvessveescsetmieeTbstiosoes |
LISTOF PARTICIPATINS SITES,navaressnnnnecioneineitnannsrnemssneemnes 2
SIGNATURES
 
  
TABLE OF CONTENTS …
LIST OF ABBREVIATIONS
FUNDING AND SUPPORT.
ROLES AND RESPONSIBILITIES..
TRIAL SYNOPSInennenneeennues Il
TRIAL FLOWCHARTnn 13
|
__Baekground, Rationale and Risk Assessmentss 16
2
Trial ObjectivesandDesigns 17
2.1
Trial objectivessn 17
2.2
Primary ENdpOints.sssrenenannndternunmnnununenen |raareoatesi. 17
2.3
Secondary ENAPOING.nennenennenen 17
2.4
Trial Design...sense 17
2.5
Expected Duration of the Ttalss 17
3
Trial Population j'Eligibility Criterfaseems 17
3.1
\nelùston eritetieumarmeneenege 17
3.2
Exclusion criteria... 18
4
Trial Procedures.……...…......….AIETRNURTS 18
4.1
Participant consent and withdrawal ofconsent... 18
42
Selection of Participants / RecruitMEntsiennes 19
4,3
Randomization Procedure / Blinding (ifapplicable)... 19
44
Unblinding...........sise 19
4,5
Premature discontinuation of Trial treatment... 19
5
Trial Medication {Digimonmioraneverwertenss20
5.1
Investigational Medicinal Product and Dosing Regimen20
5.2
Drug Accountabilitynn 21
5.3
Concomitant/ Prohibited Medication / Treatmentsenc 21
54
Rescue MedicationunsererDT22
CEartenrennenassen22
6.l
Adverse Event (AB)rennes22
6.2
Adverse Reaction (AR)nnen ooonsanservenssansereeresanssenerenaanseessersaansenseeensansenoseensannseneveensanseeseeenennn22
6.3
Serious Adverse: Evert: (SAB)rancune22
64
Suspected Unexpected Serious Adverse Reaction (SUSAR)aac onaanannsanananrennseososseeseeesnnnnans22
CTC ALG-TMP-001-1,0_28Jul2020
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Protocol templatefor
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6.5
Adverse Events of Special Interest (AESI) .....ssssssssssssscsssssssssssssssssesssseseeeessssssssssussunsssusnesssssssseeeeseessensens23
6.6
Safety Events that do not require reportinglune23
6.7
Recording and Réporting of Safety EVENTSneten23
6.7.1 ASSESSMENT...23
6.7.2,
Timelines for reporting.nmmrgn24
6.7.3
 FolloW-Upnn24
6:74
PregNaNCÿissrsisnsninnmnnenanneenananensnnennnnaneonnnenuenaeninannnienanss25
675
 Téchnial'CoMplaintSsensenananas25
MACH DLnn25
6.8
Reporting requirements to Ethics Committees (ECs) and Competent Authorities (CAs).........25
6.8.1
Sponsor’s reporting of Suspected Unexpected Serious Adverse Reactions (SUSARS)...........+25
6.8:2
Annual reportifigarsssmaemrnenennnennesnnnnnnensnnmaenanineanenesrie25
68:3
Overview reporting: teguir@mentsnnmrsnreenegenrenenee25
6.9
Data Safety Monitoring Board (DSMB)nn26
6.10
Dissemination update safety information...26
7
Statistics and Data Analysisove rvavvaesooreeniwerstnoadventsonteainctechredie toesetsandieseats26
7.1
Sample: Size Determination.nammeemee27
72
Statistical Analysissienne27
TAN
\Efficacy Analysis sanirseorosserwerssrrenernensensmaeBirnsrneiadtedtvs8iaRST6ee27
722
Other Analyserensconstavacasas27
73
Interim Analysis and Final Database Locke...nansernsasoeonanseen eeoenseeonneneensanseernnanveennwneenananeersnnne27
iB;
DAE MANONannccconsnconsensesnnneseennnenerensesorancessonn ontanesarendane/luessnnbibdinnbsandeedenindeed28
8.1
Data Collection Tools and Source DocumentIdentification...ennemie28
8.1.1
Operational ASPECESonerosavdonneeteteoreveneens28
8.1.2
Legal requirements...29
8.2
Audits and. Inspection.aanne29
8.3
MeönitorhgsannekennensanneURTS29
8.4
Archivingrennes 30
9
_Ethiealand Regulatory Considerationsminasoaps30
9.1
Ethics Committee (EC) review & reports... 30
9.2
PROP POVIOWnmeengageren 30
9.3
Regulatory COripliatice.....rrernecaccsserersnsecaronseenessseenensosorsisectisvogsOboeedshnsoosnbepsnboasdetaniboonspesstnnssodbanniddonbavsngbniaead30
   
  
 
9.4
Protocol! GCPicompliance. sovssscavsorssuscourssacisvsensseavicosssinecassosensnnsestonssotonsessnnnessatnssbootsnencananeesnencivennniseseniiness 31
95
Data protection and participant confidentialit
31
9.6
INSUPANCE ...csssssesssscsssssssstscsssssseseccnssnseescenssssenssensssssusseensssnsuesseessssusseessssnsessensssnsesseesssnuesseeenssnsuseessensassneseeeseenssnnees 31
9.7
AMENMENTScream 32
9.8
Pest:Trial sctivitiesenen 32
10
Research Registration, Dissemination of Results and Publication Policy... 32
CTC ALG-TMP-001-1.0_28}ul2020
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Protocol template for
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Protocol: OCARINA
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Version: 1.0_03082021
 
 
II
Intellectual Property
12
Joint Commission International (JC)...ire 33
13
References.
 
 
APPENDICES
14
Appendix |: Clinical trial protocol history...sn36
15
Appendix 2: Data Processing Annex (DPA)......sssssssssssssssssssssssssssoossssesensasssssssssssvsssesseesssseessesesonsssnsssssssssssssssees37
CTC ALG-TMP-001-1.0_28Jul2020
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Protocol template for
Confidential & Proprietary
interventionalclinical trial with IMP

UZ Leuven - KUL
Internal Ref.: $S64643
Protocol: OCARINA
Version: 1.0_03082021
 
 
 
LIST OF ABBREVIATIONS
 
Abbreviation
(e)CRF
AE
AESI
APR
ASR
AR
CA
CI
CIOMS
CM
CSR
CTP
DMP
DPA
DTA
DSMB
DSUR
EC
EU
ECG
EoT
FPFV
GCP
GDPR
ICF
ICH
IMP
ISF
jet
LPLV
MAH
MP
Pl
PRO
SAE
SAP
SAR
CTC ALG-TMP-001-1,0 28Jul2020
Definition
(electronic) Case Report Form
Adverse Event
AdverseEventof Special Interest
Annual Progress Report
Annual Safety Report
Adverse Reaction
Competent Authority
Coordinating Investigator
Council for International Organizations of Medical Sciences
Concomitant Medication
Clinical Study Report
Clinical Trial Protocol
Data ManagementPlan
Data Processing Annex
Data Transfer Agreement
Data Safety Monitoring Board
DevelopmentSafety Update Report
Ethics Committee
European Union
Electrocardiogram
End ofTrial
First Patient First Visit
GoodClinical Practice (latest version of ICH E6)
General Data Protection Regulation
Investigator’s Brochure
Informed Consent Form
International Conference on Harmonisation
Investigational Medicinal Product
Investigator Site File
Joint Commission International
Last Patient Last Visit
Marketing Authorisation Holder
Monitoring Plan
Principal Investigator (Participating Site)
Patient Reported Outcome
Serious Adverse Event
Statistical Analysis Plan
Serious Adverse Reaction
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Protocol template for
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Internal Ref.: SS64643
Protocol: OCARINA
Version: 1.0_03082021
 
SOP
SmPC
SUSAR
TMF
Gl
MMC
IGP
GLP-|
GLP-2
GIP
FD
EPS
PDS
BA
FXR
OCA
PBC
NASH
UDCA
BMI
CTC ALG-TMP-001-1.0_28Jul2020
Standard Operating Procedure
Summary of Product Characteristics
Suspected Unexpected Serious Adverse Reaction
Trial MasterFile
GastroIntestinal
Migrating motor complex measurement
Intragastric pressure measurement
Glucagon-like peptide-|
Glucagon-like peptide-2
Gastric inhibitory polypeptide
Functional dyspepsia
Epigastric pain syndrome
Postprandial distress syndrome
Bile acids
Farnesoid X receptor
Obeticholic acid
Primary biliary cirrhosis
Non-alcoholic steatohepatitis
Ursodeoxycholic acid
Body Mass Index
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Protocol: OCARINA
Internal Ref.: SS64643
Version: |.0_03082021
 
 
FUNDING AND SUPPORT
Funder
Typeof Financial or Non-Financial Support
Methusalem funding
Financial Support
Reasonable time investment and travel expenses incurred by Trial participants and directly related to
participation in the Trial, will be reimbursed by the Sponsor, as follows:
(i)
Ata flat rate of € 950
When the subject does not complete the study, but terminates the study earlier, the
compensation will be calculated as follow:
Stop at the end ofvisit 2: € 225
At the end ofvisit 4: € 575
At the end ofvisit 6: € 950
(ii)
If the subject require contraception to take part in this study, the subject will be reimbursed
for the actual cost incurred.
A reimbursement paymentlog will be kept by the Investigator Site staff and madeavailable for monitoring
and verification purposes.
CTC ALG-TMP-001-1.0_28Jul2020
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Protocol template for
Confidential & Proprietary
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Protocol: OCARINA
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Version: 1.0_03082021
 
ROLES AND RESPONSIBILITIES
 
The Principle Investigator (PI) is responsible for the conductof the Trial at his/her Participating Site, and
for protecting the rights, safety and well-being of the Trial participants. As such the PI must ensure
adequate supervision of the Trial conduct at the Participating Site. If any tasks are delegated, the PIwill
maintain a log of appropriately qualified persons to whom he/she hasdelegated specified Trial-related
duties. The PI will ensure that adequate training is provided and documentedforall Trial staff, prior to
conducting assigned Trial-related activities.
It is the Coordinating Investigator's (Cl’s) responsibility to supervise the general conduct(e.g. Trial
progress, communication, protocol training and supportof the participating sites, annual reporting to the
Ethics Committee (EC), end of Trial notification(s) and results reporting...) of the Trial. The Clfulfils
both Investigator and Sponsor responsibilities, as outlined in International Conference on Harmonisation
— GoodClinical Practice (ICH-GCP) E6(R2) and applicable regulations.
Pl and CI shall each be referred to as «Investigator(s)».
CTC ALG-TMP-001-1.0_28Jul2020
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Protocol template for
Confidential & Proprietary
interventionalclinical trial with IMP

UZ Leuven - KUL
Internal Ref.: SS64643
Protocol: OCARINA
Version: 1.0_03082021
 
 
 
 
TRIAL SYNOPSIS
 
 
Title of clinical Trial
The effect of obeticholic acid on gut microbiota, gastric motility,
 
 
 
 
(«Trial»)
accommodation, gastrointestinal peptide in healthy volunteers
| protoco| ShortTitle
OCARINA
cronym
Trial Phase(I,Il, Ill, IV)
Il
Sponsor name
UZ Leuven
 
Coordinating Investigator
Contact Address CI
Prof. Dr. Jan Tack
Herestraat 49, bus 701
 
Contact Email CI
Contact Phone Cl
jan.tack@kuleuven.be
+32-16-344225
 
EudraCT number
2020-004180-13
 
Other public database nbr
 
 
 Principal Investigators and
| Participating Sites
|
:
Le
:
| Medical condition or disease
| underinvestigation
Prof. Dr. Jan Tack/ KU Leuven
Functional dyspepsia
 
 
 
 
 
 
 
Trial rationale
Randomized controlled
| pri
à
To detect changes in appetite/hunger after administration of obeticholic
rimary objective
;
acid compared to placebo
(1)
To detect changes in the release of gastrointestinal peptide after
administration of obeticholic acid compared to placebo.
on
À
To detect changes in
gastric motility, accommodation after
Secondary objective(s)
(2) a
.
anges
8
Y
ie
administration of obeticholic acid compared to placebo.
(3)
To detect changes in gut microbiota after administration of
obeticholic acid compared to placebo.
Trial Design
PhaseII, placebo-controlled, randomized, single-blind, crossover study
Primary endpoint:
-
 Appetite-related
sensations
compared
between
placebo
and
treatment with obeticholic acid
| Secondary endpoints:
Endpoints
-
Gastrointestinal hormone release compared between placebo and
treatment with obeticholic acid
-
Gastric motility, accommodation compared between placebo and
treatment with obeticholic acid
changes
in gut microbial
diversity abundance
of
specific
bacteria
compared between placebo and treatment with obeticholic acid
SampleSize
12 healthy individuals
 
 
 
 
CTC ALG-TMP-001-1.0_28Jul2020
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Protocol template for
interventional clinical trial with IMP

UZ Leuven - KUL
Internal Ref: SS64643
IMP, dosage and route of
| administration
 
Active comparator
product(s)
ere
Maximum duration of
oral administration
Obeticholic acid
 
 
Onetablet containing obeticholic acid (10 mg) once per day
Protocol: OCARINA
Version: 1.0_03082021
 
 
treatment and Follow Up of
21 days
a Participant
Maximum duration of entire
;
3 months
Trial
Date anticipated First
Patient First Visit (FPFV)
01/10/2021
Date anticipated Last Patient
Last Visit (LPLV)
EURE
 
 Third parties
CTC ALG-TMP-001-1.0_28Jul2020
 None
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Confidential & Proprietary
 
Protocol template for
interventionalclinical trial with IMP

UZ Leuven - KUL
Internal Ref.: SS64643
Protocol: OCARINA
Version:
1.0_03082021
 
 
RIAL FLOWCHART
Schedule of Events — Trial specific Procedures / Assessments
Pleaseindicate in the flowchart with different colors whether a procedureis performedas part ofthe standard ofcare or specifically for the Trial.
Describe thevisits and applicable procedures/investigations (with a reference numberorletter) in more detail in a footnote below the Trial flowchart
 
Procedures/
Assessment
Screening
Rando-
misation
Treatment Period
|
 
Visits / Contacts
Visit 0
Visit 0
Visit [
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
 
Timing (weeks)
0
0
3
3
10
10
 
Visit Window (days)
-30 Days to
-30 Days to
day -7 to 0
day -7 to 0
day 17 to 21
day 17 to 21
day 66 to 70
day 66 to 70
 
Informed consent
 
Inclusion / Exclusion criteria
 
Demographics
 
Medical, Surgical history
 
Physical examination
 
Weight / Height
 
Vital Signs 
Pregnancy Test
 
Urinalysis 
Randomisation
 
Study drug administration
 
Migrating
motor
complex
easurement?
 
Intragastric
pressure
easurement*
 
 
Bloodcollection *
 
 
Duodenal aspirates ®
X
X
[XX
X|
X
x
[XX
 
Patient Reported Outcomes
(PRO)
1 (questionnaire) #5
 
 
ndoscopy 7 
Duodenal biopsy”
XIX
 
Diary
 
 
Stool specimens ®
|X [><[ ><
 
 
erious) Adverse event
(S)(AE) assessment
 
x
x
x
x
 
Concomitant Medication
(CM)
 
 
 
 
 
  
 
 
 
 
 
 
 
CTC ALG-TMP-001-1.0_28]ul2020
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Confidential & Proprietary
Protocol template for
interventionalclinical trial with IMP

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Protocol: OCARINA
Internal Ref.: SS64643
Version: 1.0_03082021
| Enrollment and screening questionnaires: thefollowing questionnaires will be used for screening: Patient Health Questionnaire, Dutch version of Rome IVcriteria questionnaire for functionalGI disorders. Enrollment andscreeningwill be done via an online system
(Qualtrics).
:
2 Study drug administration:
assignment oftreatment(placebo and obeticholic acid) will be randomized before study visit |. Either placebo or obeticholic acid will be administered orally in a single-blind fas|
placebo or obeticholic acid will be administered as appropriate for an additional 2! days.
n for 21 days. After a washout period of28 days, either
3 Migrating motor complex measurement (MMC): Subjects will come to the dinic within 7 days prior to study start medication. On that day, subjects will come in the morning after an overnightfast of 12 hours. Prior to the start of the study, an intravenouscatheter
will be placed in an antecubital vein by a trained nurse forcollecting blood samples continually. The catheter will be infused continuously with saline during the entire study visit.
A manometry probe, a small, flexible tube,will be passed through the noseinto the stomach ofthe subject. The probe contains 36 channels that measure pressure. The manometry probewill be positioned in the duodenum. Anaspiration catheteris advanced via the
nostril into the second part ofthe duodenum using the manometry catheteras a guide, with brieffluoroscopic check (2-3 seconds, never morethan |5 seconds). After positioning, the manometry probe andthecatheterwill be fixed and subjects will be askedto take
placein a bedin a comfortablesitting position with the trunk upright.
Migrating motor complex measurement (MMC) cycleis a pattern of electrical activity observedin the gastrointestinaltract in a regular cycle during fasting. To evaluate this MMCcycle, the duration of two consecutive phasesII! will be measured. Blood samples for
motilin and ghrelin will be taken every 20 min between the two phasesIll (maximum 300 min). After 60 min to 120 min, blood samples will be taken every 10 min, becausetherise ofmotilin levels and MMCphaseII! are known to be observedin time zonein most
cases (11). Thefirst sample will be taken 10 min after the end ofthe first phaseIll. The subject will be asked tofill in a visual analogue scale for hunger and satiation and6 epigastric symptoms(fullness, nausea, belching ofair, cramps in the abdomen, bloating and
pain) at 10-minute intervals. Duodenalaspirates will be taken for analysis of the luminal microbiota and BA composition in the beginning ofthe test and at around MMCphaseIll. Duodenal fluids will be then centrifuged at 4°C for 5 min at maximum speed and
stored at -20°C and -80°C in the TARGID lab and the Laboratory ofMolecular Bacteriology (Rega Institute) until further analysis, respectively.
4 Intragastric pressure measurement(IGP): Gastric accommodation will be assessed subsequently after MMC measurement. The drinking test will start from phaseII ofMMC. Forthe drinking test, nutrient drink (Nutridrink, Nutricia 150 Kcal/!00m) will be taken
orally at a constant speed of60 mllmin, The maximum ofliquid nutrient drink will be total 600ml, The subject will be askedto fill in a visual analogue scale for hunger andsatiation and 6 epigastric symptoms(fullness, nausea, belching of air, crampsin the abdomen,
bloating and pain) at 5-minute intervals. In addition, the subject also will have to score his/her satiation at I-minute intervals byusing a graphic rating scale that combines verbal descriptors on a scale gradedfrom 0-5 (I, threshold; 5, maximum satiety). Blood samples
will be taken every |0 min.Orally feeding will be stopped as soon as the subject reached the maximum scoreof5 on their satiation scale or when they score maximally on oneofthe epigastric symptoms.In that case, the timeofstop drinking will be recorded. One
hour hereafter the catheters will be disconnected and removed.
5 Bloodcollection: During MMC measurement, blood samples (4mpercollection for motilin, octa-ghrelin) will be taken every 20 min within thefirst 60 min ofMMC measurement, then every 10 min until the end ofMMC phaseIll. If over 120 min, then blood
samples will be collected every 20 min until the end ofMMC measurement (maximum 300 min). During IGP measurement, blood samples (12 ml per collection for motilin, octa-ghrelin, GLP-1, GLP-2, GIP, insulin) will be collected every 10 min withinthefirst 60 min.
Plasma C4 will be evaluated at thefirst collected sample. A maximum amountofcollected blood will be 150 ml.
6 Duodenal aspirates: Duodenal aspirates will be taken at aroundMMC phaseIll. Bile acid analysis: Concentration ofbile acids, including, glyco-cholic acid (GCA), tauro-cholic acid (TCA), glyco-chenodeoxycholic acid (GCDCA), and tauro-chenodeoxycholic acid (TCDCA),
slyco-deoxycholic acid (GDCA), tauro-deoxycholic acid (TDCA), glyco-ursodeoxycholic acid (GUDCA), and tauro-ursodeoxycholic acid (TUDCA), for each participant will be measured with liquid chromatography-mass spectrometry (LC-MS) selected ion monitoring by the
Pharmacotechnology and biopharmacy group ofProf. Patrick Augustijns (KU Leuven) according to a previously published protocol (2) . The pH ofevery duodenalfluid sample will be measured with pH-Meter 766 Calimaticon at room temperature.
7 Endoscopy: Endoscopywill be performed after a minimalfasting period of8 hours, First, a sheathed andsealed biopsy forceps for aseptic mucosa sampling and outer diameter 1.8mm (MTW, Wesel, Germany) will be used for taking a maximum of3 small biopsies
(approximately | mm3). Second, a single-use cytology brush will be used for superficial mucosal sampling. Finally, a RadialJaw3 with needle forceps and outside diameter 2.2mm (Boston Scientific, Heredia, Costa Rica) will be used for 6 biopsies (approximately 2
mm3) from the duodenum,All endoscopies will be performed by an experienced endoscopist. Before the procedure, local anesthetic xylocaine sprayis applied in the throat with no sedation, unless demanded by subject in which case intravenousaccess is obtained
before administration of IV Midazolam (maximium of 4mg). Aseptic biopsies (maximum 3) and brushings will be separately collected in sterile tubes, snap frozenin liquid nitrogen and stored at -80°C in the Laboratory ofMolecular Bacteriology (Rega Institute) until
microbial analysis,
Ofthe conventional biopsies (n= 9 per subject pervisit), 2 will be collected in RNAlater and stored at -80° in the Biobank until analysis ofgene expression, 2 will be snap frozenin liquid nitrogen and stored at -80° in the Biobank until analysis of
protein expression, 2 will be fixed in formalin orfixative with(-out) glutaraldehyde and stored at 4°C in the TARGID lab until later analysis ofhistology and 3 will be collected in ice-cold Hanks’ Balanced Salt Solution (HBSS) buffer and analyzed immediatelyin the
TARGIDlab for permeability.
8 Stool sampleswill be collected before administration ofplacebo or obeticholic acid (day 0 forintervention |, day 28for intervention 2), after administration (day 2, 4, 7, 14, 21 forintervention I, day 30, 32, 35, 42, 49forintervention 2). Samples are temporarily
stored by the participants in their homefreezer. Within 2 weeks, sampleswill be brought back to UZ Leuven.
CTC ALG-TMP-001-1.0_28Jul2020
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Protocol template for
Confidential & Proprietary
interventionalcl
cal trial wich IMP

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Protocol: OCARINA
Internal Ref.: SS64643
0_0308202 |
CTC ALG-TMP-001-1.0_28Jul2020
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Protocol template for
Confidential & Proprietary
interventional
al trial with IMP

UZLeuven - KUL
Protocol: OCARINA
Internal Ref.: SS64643
Version: 1.0_03082021
 
 
|
Background, Rationale and Risk Assessment
Functional dyspepsia (FD) is a commonfunctional gastroduodenal disorder that has a great social and
economic impactin patients. It is subdivided in two groups depending on the symptom pattern. Epigastric
pain syndrome(EPS)is characterize by meal-unrelated symptoms suchas epigastric pain and epigastric
burning; and postprandial distress syndrome (PDS) characterize by meal-related symptoms such as
postprandialfullness and early satiation (1). The pathophysiology of FD remains poorly understood andis
mostlikely heterogeneous,butlikely candidates are genetic factors, stress and duodenal luminal factors,
including bile acids (BA) (2).
Bile acid and Gut microbiota
BA are essential moleculesin fat absorption byacting as a surfactant that emulsifies them into micelles (3).
It is well established that the majority of patients with FD report onset or worsening of symptoms after a
meal, which coincides with the release of BA into the duodenum (4). Furthermore, we provedthatpatients
with FD are characterized by a decreased duodenal BA concentration in fasted state compared to healthy
volunteers (2).
Another important feature ofbile acids is their strong antimicrobialactivity. In fact, oral administration of
bile acid regulates the composition of gut microbiotain rats (5). The gut microbiota maintains a symbiotic
relationship with the host and regulates several important functions including host metabolism, immunity,
and intestinal barrier function. Intestinal inflammation is commonly associated with dysbiosis of the gut
microbiota (6). Duodenalinflammation has been observed in up to 40% of patients with FD and, hence,it
is thought to be an important factorin the pathogenesis of FD (7). A decreased duodenal BA might play a
role in duodenal inflammation via duodenal dysbiosis in the pathophysiology of FD, while it is not well
proventhe relationship between the pathogenesis of FD and BA(2).
Gastric sensorimotorfunction
Impaired gastric sensorimotorfunction, such as decreasedgastric accommodation, delayed gastric emptying
and gastric hypersensitivity, has been implicated in symptom generation in FD (8). These alterations may
represent new targets for therapy (e.g. improving gastric accommodation). We have already established a
new minimally invasive technique that measures the intragastric pressure (IGP) drop during a liquid meal
challenge as a method to assess gastric accommodation in FD patient (9, 10).
The migrating motor complex (MMC)is a cyclic motorpattern in the gastrointestinal tract that occurs
during the interdigestive state and is responsible for the rumbling experience when hungry (1 1). Its absence
has been associated with FD, gastroparesis and small intestinal bacterial overgrowth (11). IGP and MMC
techniques use the same catheter as in esophageal high-resolution manometry and, therefore, have the
potential to gain a similar acceptanceandfeasibility level for clinical routine diagnostic test.
Gastrointestinal hormones
Thegastrointestinal (GI) hormones constitute a group of hormones secreted by enteroendocrinecells in
the stomach, pancreas, and small intestine that control various functions of the digestive organs, including
gastric motility. Motilin and ghrelin are the GI hormonesreleased in a fasting state to stimulate the Gl
motility of the MMC (12). Recent research has shownthat both the MMC and motilin play a role in hunger
signaling and changes in both occurin food intake disorders (13). Glucagon-like peptide-| and 2 (GLP-I,
GLP-2) inhibits gastric emptying with secondary effects on the release of insulin in fed state (14, 15). BA
stimulate GLP-1, GLP-2 andinsulin (16, 17).
Farnesoid X receptor (FXR)agonist
Farnesoid X receptor (FXR) is a bile acid receptor, which is mainly expressed in the liver andintestine.
FXR regulate synthesis, secretion and transportof bile acids (18). It has been considered as a promising
target for the treatment of cholestatic disorders, including primary biliary cirrhosis (PBC) (19). FXRis also
important for the regulation of the lipid and glucose metabolism (18). The activation of FXR showed
beneficial effects on various metabolic diseases, includingfatty liver diseases, type 2 diabetes, dyslipidemia,
and obesity (18). Obeticholic acid (OCA), a FXR agonist, is proven as an effective drug for PBC (19). In
2016, OCA wasapprovedin U.S. and Europefor the treatment of PBC. OCAis used together with another
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medicine, ursodeoxycholic acid (UDCA), in patients who do not respond sufficiently to UDCA alone, and
on its own in patients who cannot take UDCA. Now,phaseIll study for NASH is ongoing. In healthy
volunteers, patients with primarybiliary cholangitis (PBC) and patients with non-alcoholic steatohepatitis
(NASH), single and multiple doses of obeticholic acid were well tolerated (19, 20). The most frequently
reported adverse events considered to be drug-related werepruritus and fatigue (19, 20). Some abdominal
pain and discomfort were reported. Based on a multiple-center phase
Ill study in PBC patients, the
recommendedstarting dosage of OCAis 5 mg orally oncedaily for 3 months with titration to 10 mg once
daily based upontolerability and response(21). In conclusion, obeticholic acid was found to besafe.
Recently, Friedman ES et al showedalteration of gut microbiome by OCA.
In this study, male C57BL/6
mice were gavaged daily with water, vehicle, or OCA (10 mg/kg) for 2 weeks. Small intestine luminal
contents were collected by flushing with saline and fecal pellets were collected at baseline and day 14.
Culture experiments were performed to determine taxonomic-specific effects of bile acids and OCA on
bacterial growth. As a result, administration of OCA dramatically led lower endogenousbile acid levels and
an increased proportion of Firmicutes, specifically in the small intestine but not in stool, compared to
control in mice (22). Friedman ES et al
also conducted healthy volunteers on OCAdoses of 5, 10 or
25mg/d and analyzed their microbiome in stool (22), however
it
is
still unclear how the intestinal
microbiomechanges in human.
OCA
might
alter
the
gut
microbiota
and
duodenal
inflammation.
Moreover,
gastric
motility,
accommodation
and
gastrointestinal
peptide
might be
affected
through
the change
of duodenal
circumstance. Therefore, the aim of the current research protocol
is to investigate the relationship
between FXRagonist and gut microbiota, gastric motility, accommodation, gastrointestinal peptide in
healthy volunteers.
2
Trial Objectives and Design
2.1
Trial objectives
The aim ofthis study is to investigate the effect of OCA (FXR agonist) on gut microbiota, gastric motility,
gastrointestinal peptide in healthy individuals.
2.2
Primary Endpoints
The primary endpointofthis study is to compare appetite/hunger between placebo and treatment with OCA .
2.3
Secondary Endpoints
The secondary endpoint
is to compare gastric motility, the distribution of gut microbiota and BA
composition between placebo and treatment with OCA .
Gastric motility and the release of the hormones motilin, ghrelin, GLP-1, GLP-2, GIP andinsulin will be
compared betweenplacebo and treatment with OCA .
2.4
Trial Design
This study is a single-blind, placebo-controlled, randomized,study in healthy individuals.
2.5
Expected Durationofthe Trial
01/10/2021-31/12/2022
3
Trial Population / Eligibility Criteria
3.1
Inclusion criteria
Participantseligible for inclusion in this Trial must meetall of the followingcriteria:
|.
Voluntary written informed consent of the participant or their legally authorized representative
has been obtained prior to any screening procedures
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2.
Use of highly effective methods ofbirth 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.
Subject is between 18 and 65 years of age
4.
Subject has a BMI between 18 and 25 kg/m?
All participants that are considered for Trial participation, per the abovecriteria will be documented on
the Screening Log, including Screen Failures.
3.2
Exclusion criteria
Participantseligible for this Trial must not meet any of the following criteria:
|.
Participant has a history of gastrointestinal or other significant somatic or psychiatric diseases or
drug allergies, diabetes, a significant heart, lung, liver or kidney disease, a neurological disorder,
abdominal
surgery
(including
gallbladder
removal,
but those
having
undergone
a
simple
appendectomy morethan
| year prior to the screening visit may participate),
2.
Any disorder, which in the Investigator’s opinion might jeopardise the participant’s safety or
compliance with the protocol
3.
Any prior or concomitant treatment(s) that might jeopardise the participant’s safety or that
would compromisethe integrity of the Trial
4.
Female who is pregnant, breast-feeding or intends to become pregnant oris of child-bearing
potential and not using an adequate, highly effective contraceptive
5.
Participation in an interventional Trial with an investigational medicinal product (IMP) or device
6.
High caffeine intake (> 500 mlcoffee daily or equivalent).
7.
Subject consumes excessive amountsof alcohol, defined as >21 units per weekfor men, >14 units
per week for women.
8.
Subject is currently (defined as within approximately
| year of the screening visit) a regular or
irregular user (including “recreational use”) ofanyillicit drugs (including marijuana) or has a history
of drug (including alcohol) abuse. Further, patient is unwilling to refrain from the use of drugs
during this study.
9.
Inability or unwillingness to perform all of the study procedures, or the subject is considered
unsuitable in any way by theprincipalinvestigator.
10. Recentparticipation (<30 days) or simultaneousparticipation in anotherclinical study.
LL. Prior participation in a clinical trial of obeticholic acid
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 ScreenFailure.
4
Trial Procedures
4.1
Participant consent and withdrawal of consent
The Trial will be conducted only onthe basis of prior informed consent by the Trial participants and/or
their legally authorized representative(s). As such, no Trial-related procedureswill be conducted prior to
obtaining written informed consentfrom potential Trial participants.
The process for obtaining and documenting initial and continued informed consent from potential Trial
participants will be conducted in accordance with ICH-GCP E6(R2), applicable regulatory requirements
andinternal Standard Operating Procedures (SOPs).
All originally signed obtained Informed Consent Forms (ICFs) must be retained/archivedin the Investigator
Site File (ISF) at the Participating Site and must not be destroyed (even when a scanned copyis available)
before expiration of the legal archiving term as defined in the protocolsection entitled “Archiving”.
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Participants may voluntarily withdraw consent to participate in the Trial for any reason at any time. The
participant's request to withdraw from the Trial must always be respected without prejudice or
consequence to further treatment. Consent withdrawal will be documented in the participant's medical
record,
Trial data and samples collected before withdrawal can be used
in the trial. No new trial data or samples
will be collected after withdrawal of the participant.
4,2
Selection of Participants / Recruitment
Potential subjects will be recruited by means of an existing volunteer database from the research group of
the Sponsor-Investigator.
Potential subject will be contacted by phone or per email with a short
introduction on the study purpose and the proposal to make an appointment if they are interested in
participating, through oral advertisement and through advertisement on the UZ Leuven intranet and on
notice boards of the KU Leuven.
4.3
Randomization Procedure / Blinding (if applicable)
Randomization
To ensure theintegrity of the Trial, the following randomization procedures have beenestablished:
A randomization online software (http://www.randomization.com)will be used to generate randomization
plan.
A randomizationlist will be prepared by the Sponsor’s designatedstaff, not involved in recruiting Trial
participants, medical care, drug administration or follow-up.
Blinding
To avoid bias, treatment armswill be blinded to the Drug provider, as follows:
The IMP will be manufactured, packaged andlabelled in such a waythatthe visual appearance, nor the
smell and/or touch of the IMP can bedistinguished from the comparator treatment and/or placebo.
Furthermore, to maintain the blind, the IMP and any comparator treatment(s) and/orplacebowill follow
the same administration route and process.
4,4
Unblinding
After all participants have completed the Trial, the database will be locked andthe collected Trial data will
be unblindedto allow analysis of the Trial data.
In case of an emergencyin a blinded Trial, the Investigator has the sole responsibility for determiningif
premature unblinding of a participant's treatment assignmentis warranted. Participant safety must always
be the first consideration in making such a determination. Every effort should be made to contact the
Sponsor prior to unblinding a participant's treatment assignment, unless this would delay emergency
treatment of the participant. The Sponsor mustbe notified as soon as possible and no later than within 24
hours after breaking the blind. The date and reason for unblinding must be recorded in the source
documentation and electronic Case Report Form (eCRF), as applicable.
4.5
Premature discontinuation of Trial treatment
Participants may voluntarily discontinue from Trial treatment and/or prematurely end their participation in
the Trial for any reason at any time. In such case the Investigator must make a reasonableeffort to contact
the participant(e.g. via telephone, e-mail, letter) in order to documentthe primary reason for this decision.
TheInvestigator may also decide at any time during the courseof the Trial, to temporarily interrupt or
permanently discontinuethe Trial treatmentif it is deemed that continuation would be detrimental to, or
notin the bestinterest of the participant.
Similarly, de Sponsor, Ethics Committee or authorized regulatory authority can decide to halt or
prematurely terminate the Trial when new information becomesavailable whereby the rights, safety and
well-being of Trial participants can no longer be assured, whendeintegrity of the Trial has been
compromised, or whenthescientific value of the Trial becomes obsolete and/or unjustifiable.
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Circumstances requiring premature treatmentinterruption or discontinuation of the Trial, include but
are notlimited to:
e
Safety concerns related to IMP or unacceptable intolerability
e
Trial participation while in violation of the inclusion and/or exclusion criteria
e
Pregnancy
e
Intention of becoming pregnant
In any suchcase ofearly Trial termination and/or treatmentinterruption/discontinuation,the Investigator
will continue to closely monitor the participant’s condition and ensure adequate medical care and follow-
up.It is recommended that follow-up informationwill be collected as follows:
TheInvestigator will assess physical damage at the end oftreatment and provide medical care and follow-up as
necessary
For participants whosestatus is unclear because theyfail to appear for Trial 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 continuetheir participation in the Trial (e.g. dates of
telephonecalls, registered letters, etc.).
A participant should not be considered lost to follow-upuntil due diligence has been completed.
5
Trial Medication / Drug
 
 
 
 
 
 
 
 
 
Generic Drug
IMP or
Used within
Route af
Doseldosage and
Name
non-IMP
Indication?
administration
ünits
(& company brand name)
(¥ or N)
(po,sc,iv,...)
Obeticholic
acid
po
10 mg
(OCALIVA®)
ee
N
Placebo
IMP
N
po
placebo
 
5.1
Investigational Medicinal Product and Dosing Regimen
In this study, participants will receive in total one dose of OCA (OCALIVA®, Intercept Pharmaceuticals,
New York, United States) and one dose of placebo (Intercept Pharmaceuticals, New York, United States)
in a phaseIl, single-blind, randomized crossoverfashion.
MMC+IGP
MMC+IGP
MMC+IGP
EGD
EGD
EGD
      
  
 
LE.
a
group À
RE acid J
Placebo
„Washout
Start
period
 
 
Obeticholic acid
 
 
 
 
   
Placebo
nd
J
10mg
4
9
we
wv
CTC ALG-TMP-001-1.0_28}ul2020
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One dose of study medication consists of
| tablet (10mg) of placebo or OCA. OCAandplacebowill be
orally administered with water in the morning for 2! days after the examinations at preintervention.
OCALIVA®is a drug which is only available on prescription,it is indicated for the treatment of primary
biliary cholangitis (ATC code AOSAA04). OCALIVA © tablets contain 10 mg obeticholic acid and 176 mg
Microcrystalline cellulose, 12 mg Sodium starchglycolate, 2 mg Magnesium stearate, tablets are film coated
and dissolve in the acidic environment of the stomach. One doseof study medication will contain 10 mg
obeticholic acid.
Placebo tabletswill be obtained from Intercept Pharmaceuticals, New York, United States and will contain
320 mg
lactose
monohydrate,
10 mg carmellose
sodium,
70 mg corn
starch,
55 mg
cellulose
microcrystalline, 20 mg silicium dioxide anhydrous and 13 mg magnesium stearate per tablet.
Administered medications will be properly registered in KWS system.
|
Participants will take each OCAandplacebofor 2| days across washoutperiod at home. Drug compliance
will be monitored with a daily questionnaire and subjects will state the time of taking the medication. When
participant forgets to take dose at regular time, participant canstill take drug until 12 hours to next dose.
The bottles with the tablets will be collected after the end of each treatment period and the number of
tablets will be counted and registered. With regard to medication compliance,
it is not considered a
deviationif the rate of taking study medication is more than 80%.
5.2
Drug Accountability
Participants will take medication home. The investigators will prepare blinded containers which contain the
study medication to assure single blinding. Therefore, each subject’s medication kit will be labelled as
following:
  
 
Seulement pour les étudescliniques
Alleen voorklinische studies
Nurfür klinische Studien
Numéro de protocole: OCARINA
Protocolnummer: OCARINA
Protokollnummer: OCARINA
Numéro EudraCT: 2020-004180-13
EudraCT-Nummer: 2020-004180-13
EudraCT Nummer: 2020-004180-13
Contenu: Acide obéticholique 10 mg ou placebo
Inhoud: Obeticholzuur 10 mg of placebo
Inhalt: Obeticholsäure 10 mg oder Placebo
Conditions de stockage: 20-25°C
Opslag condities: 20-25°C
Lagerbedingungen: 20-25°C
Posologie: 1 comprimé unefois par jour le matin.
Dosering:1 tablet 1 keer per dagin de ochtend
Dosierung: 1 tablette einmal täglich morgens
Utilisation
orale
Oral gebruik
Oraler Gebrauch
Numéro d'identification: XX
ID nummer: XX
ID Nummer: XX
Numéro de personnage: XXXXXXXX
Chargenumber: XXXXXXXX
Chargenumber: XXXXXXXX
Date d'expiration: MM / DD/ YYYY
Vervaldatum: MM / DD / YYYY
Ablaufdatum: MM / DD / YYYY
Docteur: Prof Dr Jan tack, University of Leuven, UZ
Dokter: Prof Dr Jan tack, University of Leuven, UZ
 Doktor: Prof Dr Jan tack, University of Leuven, UZ
Gasthuhuisberg, Belgium, tel: +32-16-344225
Gasthuhuisberg, Belgium, tel: +32-16-344225
Gasthuhuisberg, Belgium, tel: +32-16-344225
 
 
Tenir hors dela portée etdela vue desenfants
Buiten het bereik en zicht van kinderen houden
Darf nichtin die Hände von Kinderngelangen
 
5.3
Concomitant / Prohibited Medication / Treatment
The following drugs must not be used 2 weeks before, during and
| week after the study
* Drugs that can affect gastrointestinal function, motility or sensitivity or gastric acidity.
* Centrally acting medication, including antidepressants, antipsychotics and/or benzodiazepines
* Warfarin
* Proton pumpinhibitors
If these drugs are taken during study medication, IMP medication will be discontinued and the subject will
be excludedfrom the studyat that time. Study data up to the timeof exclusionwill be available.
If these drugs are taken during the washout period, a period of at least 2 weeks should be allowed before
starting the second medication.
The following drugs must not be used
| year before, during and
| week after the study
* Centrally acting medication, including antidepressants, antipsychotics and/or benzodiazepines(in the last
year before screeningvisit).
If these drugs are taken during study medication, IMP medication will be discontinued and the subjectwill
be excluded from the study at that time. Study data up to the time ofexclusionwill be available.
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5.4
Rescue Medication
None
6
Safety
Definitions!”
6.1
Adverse Event (AE)
An AEis any untoward medical occurrence in a patient,clinical investigation participant or participant of
the treated group during an experiment who had been administered a pharmaceutical product, and which
does not necessarily have a causal relationship with this treatment.
An AEcan therefore be any unfavourable and unintended sign (including an abnormal laboratory finding),
symptom or disease temporally associated with the use of a medicinal (investigational) product, whether
or not considered to be related to the product. Any worsening(i.e. anyclinically significant adverse change)
in the frequency or intensity of a pre-existing condition, should be considered an AE.
6.2
Adverse Reaction (AR)
An AR is any untoward and unintended response to an investigational medicinal product or to an
experiment and, when an
investigational product
is concerned, related to any dose administered.
This means that a causal relationship between a medicinal product and an adverse event is at least a
reasonablepossibility,i.e. the relationship cannot beruled out.
6.3
Serious Adverse Event (SAE)
A SAEis any untoward medical occurrence that at any dose, results in any of the following:
e
Death
e
life-threatening" experience
e
In-patient hospitalisation or prolongation of existing hospitalisation
e
A persistent orsignificant disability or incapacity
e
_A congenital anomaly or birth defect
e
Important medical events that may be considered an SAE when- based on appropriate medical
judgement - they could jeopardise the participant’s safety and may require medical or surgical
intervention to prevent oneof the above outcomes?
° The term “life threatening”in the definition ofSAE refers to an eventin which the participant wasatrisk ofdeath atthe timeofthe event.
It does not refer to an event which hypothetically might have caused deathifit were more severe.
6.4
Suspected Unexpected Serious Adverse Reaction (SUSAR)
A SUSARis an AR, the nature or severity of which
is not consistent with the information on the
experiment, and, when a clinical Trial
is concerned, with the applicable product information
(e.g.
Investigator's brochure(IB) for an unauthorised investigational product or the patientleaflet joined to the
summaryof product characteristics for an authorised product).
' Guideline for goodclinical practice E6(R2) Step 5 EMA/CHMP/ICH/1 35/1995 dated
| December 2016
2 Belgian law of May 7th 2004 regarding experiments on the human person (as amended)or the Belgian law of
May 7th 2017 related to clinical trials on medicinal products for human use(as soonasin effect),
 
 
3 ICH E2AClinical Safety Data Management: Definitions and Standards for Expedited Reporting
CPMP/ICH/377/95 dated Jun 1995
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Version: 1.0_0308202|
6.5
Adverse Events of Special Interest (AESI)
The following events should always be reported within the same timelines as SAEs:
-
Overdose
-
Misuse/abuse
-
Medication error
6.6
Safety 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 concomitantillness), unless the condition worsens during Trial treatment
The following AEs are commonly observed and expected, and/or arepart of the well-knownsafety profile
of OCALIVA® as documented in the Summary of Product Characteristics (SmPC) when used within the
approvedindication, and are therefore not considered adverse events for the purposeof the Trial:
=
stomachpain
=
feeling tired
*
thyroid hormoneirregularity
=
dizziness
"
fast or irregular heart beat (palpitations)
"pain in the mouth and throat
=
constipation
=
itchy, dry and/or red skin (eczema)
=
rash
=
pain in yourjoints
=
swelling in the hands and feet
=
fever
Although these events should not be reported to the Sponsor, these should be recorded in the participants
medical notes according to routine practice.
6.7
Recording and Reporting of Safety Events
Investigators will seek information on the occurrence of safety events at each participant contact. All
events, whether reported by theparticipant or notedby Trialstaff, will be recorded in a timely mannerin
the participant's medical record and in the (e)CRF.If available, the diagnosis should be reported on the
appropriate (S)AE page in the (e)CRF, rather than the individual signs or symptoms.
If no diagnosis is
available, the Investigator should record each sign and symptom asindividual safety events.
The following minimum information should be recorded for each event:
-
event description
-
start and stop date of the event
-
severity
-
seriousness
-
causality assessmentto the IMP and/or Trial procedures
-
outcome
6.7.1
Assessment
All safety events must be evaluated by an Investigator with regardsto:
"
Seriousness: determine whether the AE is an SAE. See abovefor the seriousnesscriteria.
=
Severity:
o
Severity grading must be evaluated by the Investigator according to the current version of the
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, most
recent version)
©
Severity must be evaluated by the Investigator according to the following definitions:
CTC ALG-TMP-001-1.0_28)ul2020
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Version: 1.003082021
 
=_Mild — no or transient symptoms, nointerference with the participant’s daily activities
-
Moderate — marked symptoms, moderate interference with the participant's daily activities
-
Severe — considerable interference with the participant's daily activities, unacceptable
«
Causality:
o
None — The AE is notrelated to the IMP or participation in the experiment
o
Unlikely — It is unlikely that the AE is related to the IMP or participation in the experiment; 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 — The AE might be due to the use of the IMP orparticipation in the experiment. An
alternative explanation is inconclusive. The relationship in time is reasonable; therefore the causal
relationship cannot be ruled out
©
Probable - The AE might be due to the use of the IMP or participation in the experiment. The
relationship in time is suggestive (e.g. confirmed by dechallenge). An alternative explanation is less
likely
o
Definitely — The AEis listed as a possible adverse reaction and cannotbe reasonably explained by an
alternative explanation. The relationshipin timeis very suggestive (e.g. it is confirmed by dechallenge
and rechallenge)
6.7.2,
Timelines for reporting
After obtaining informed consent and priorto initiation of Trial treatment, only (serious) adverse events
caused bya Trial specific procedure should be reported in the (e)CRF.
After initiation of Trial treatment, safety events will be reported as follows:
=
All AEs, SAEs and AESIs occurring during Trial treatment or within 30 daysafter last Trial treatment
administration, or last follow-up visit (whichever occursfirst) will be reported.
«
All SAEs and AESls as defined in the protocol must be reported to the Sponsor within 24 hours of the
Trial staff becoming aware of the event. Theinitial report shall be followed by detailed, written reports.
Boththeinitial and follow-up reportsshall identify participants only by their Trial-specific identification.
®
SAEdetails 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 Sponsorby a healthcare professional within 24
hours of becoming aware of the SAE, but must be followed-up by a medical assessment performed by
an authorised Investigator, as soonas possible thereafter.
6.7.3
Follow-up
The Investigator must record follow-up information by updating the participant’s medical records and the
appropriate form(s) in the (e)CRF.
SAEfollow-up information should only include new information (e.g. corrections or additions) and must
be reported within 24 hours of the Investigator’s first awareness of the information. This is also the case
for previously non-serious AEs which subsequently become SAEs.
e
All SAEs must be followed until the outcome of the event is ‘recovered’, ‘recovered with
sequelae’, ‘not recovered’(in case of death due to another cause than the SAE) and until all related
queries have beenresolved, or until the end of the Trial (whicheveroccursfirst)
e
Non-serious AEs must be followed until the participant's last Trial visit, and until all related
queries have been resolved
SAEsafter the end of the Trial: If the Investigator or Trial team becomes aware of an SAE with
suspected causal relationship to the IMP or experiment, after the participant has ended theTrial, than this
SAE must be reported within the same timelines as for SAEs occurring during the Trial.
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6.7.4
Pregnancy
Female participants must be instructed to notify the Investigator immediately if they become pregnant
during the Trial, The Investigator must report to the Sponsor, any pregnancy in participants who have
received Trial product(s).
6.7.5
Technical Complaints
Technical complaints with the IMP or comparator treatment should be reported to the Sponsor and to
the Marketing Authorisation Holder (MAH)
(e.g. change
in colour, unequal sizes, broken vials/pills,
sedimentation, inconsistent packaging or labelling etc.).
If the technical issue puts the safety of Trial
participants at risks and/or jeopardises the integrity of the Trial (e.g. when the issue causes unblinding),
than the Ethics Committee must be notified immediately and no later than 24 hours of the Trial team
becoming aware.
6.7.6
Death
All deaths (except those defined under section 6.6 ) will be reported without delay to the Sponsor
(irrespective of whether the death
is related to disease progression, the IMP, participation
in the
experiment or an unrelated event). The Sponsorwill notify all deaths as soon as possible after becoming
aware to the central EC and the local EC of the concerned researchsite (via the contact person of the
local research site, as applicable) and provide additional information if requested.
6.8
Reporting requirements to
Ethics Committees (ECs) and Competent
Authorities (CAs)
The Investigatoris responsible for ensuring thatall safety events are recorded in the (e)CRF and reported
to the Sponsorin accordance with instructions provided in the protocol.
The Sponsor will promptly evaluate all SAEs and AESls against medical experience to identify and
expeditiously communicate possible new safety findings to Investigators, EC(s) and applicable CA(s) and
participants as appropriate, in accordance with applicable legislation.
6.8.1
Sponsor’s reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs)
After receiving the SAE report form from the Investigator, the Sponsor must perform a causality
(relationship) assessment. The term Serious Adverse Drug Reaction (SADR)is to be used whenevereither
the Investigator or the Sponsor deemsthe SAEis possibly or probably related to the IMP.
The Sponsor must evaluate (and documenttheevaluation of) the expectedness for each SADRagainst the
Reference Safety Information, e.g. the Investigator’s Brochure or applicable productinformation. In case
the event is Unexpected(i.e. a SUSAR)it must be reported by the Sponsor to the EC(s), CA(s) (through
the EudraVigilance database or other local process) and other participating Investigators using the Council
for International Organizations of Medical Sciences (CIOMS) form within the following timelines:
°
7 calendardaysif the eventis fatalorlife-threatening (follow-up information to be provided within
an additional 8 calendar days)
e
15 calendardaysif non-fatal or non-life-threatening event(follow-up information be provided as
soon aspossible)
6.8.2
Annual reporting
It is the Sponsor's legal obligation to, at least once a year and for as long as the clinical Trial runs (or ad
hoc on request), submit a progress report to the EC(s) and CA(s) containing an overview ofall Serious
Adverse Reactions (SARs) that occurred during the reporting period and taking into accountall new
available safety information received during the reporting period. This information can be communicated
as part of the Annual Progress Report (APR) or as a separate Development Safety Update Report (DSUR,
cfr. ICH E2F) or an AnnualSafety Report (ASR)
6.8.3
Overview reporting requirements
 
WHO
WHAT
HOW
TO
TIMELINES
 
 
 
 
 
 
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AE
AE form
Sponsor
as defined in protocol
Initial & follow-up
information:
Immediately (within 24
Investigator
SAE
SAE form
Sponsor
hours of becoming
aware of the event)
Exceptions: as defined
in protocol
Death
SAE form
Sponsor
asap
For fatal or life-
threatening SUSAR:
asap, but no later than:
CIO or
Unblinded report:
- 7 calendardays (initial
à EC-reporting:
- EC(s)
report)
according to EC
- CA(s)
- 8 calendar days
SUSAR
pe
- MAH(if applicable)
(follow-up report)
~ Reporting to CA(s):
Blinded report to:
For non-fatal and non-
OLEN
icipating
life-threatening SUSAR:
EudraVigilance or
~ PI's of participating
8
+
Sponsor
local CA process
sites
~ [5 calendar days
(initial report)
- asap (follow-up
report)
Death
SAEform + narrative
- EC(s)
asap
Annual
Progress.
DSUR or APRASR
El C0
Safety
template
- CA(s) participating
annually
Report
countries
 
6.9
Data Safety Monitoring Board (DSMB)
Notrelevant for this study,
6.10 Dissemination update safety information
Safety updates need to be reported yearly in the updated Investigator Brochure and/or annual safety report
andin case of substantial safety changes these needto be reflected in an updated informed consent form
and approvedbythe EC,prior to providing to the Trial participants.
7
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 oftheclinical trial report.
Twelve healthy volunteers will be enrolledin this placebo-controlled cross-over study. The numberof
volunteers to beincludedis calculated with a two-tailed t-test comparing two dependent means. We
specified the following parameters: an error probability of 5%,effectsize of 1.0 and a power of 80%.
Based on these parameters we need to include 10 volunteers in orderto highlight the expected
 
differences. Twelve volunteers will be included to anticipate a potential dropout. Data from all subjects
who completed the study will be included for analysis. Statistical analysis of the different parameters will
be performed in SPSS for Windows(SPSS Inc., Chicago, IL, USA). Curves of whole blood glucose, plasma
levels of motilin and ghrelin GLP-1, GLP-2, GIP andinsulin and hunger / appetite scores over time will be
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Internal R
 
analyzed using the mixed models procedure, taking into account the course of the curves overdifferent
time points. Gastric motility and BA composition will be compared with Two-tailed paired t tests or
Wilcoxon signed-rank tests, depending on data distribution. Non-parametric test were applied to analyse
microbiome data, with multiple testing correction wheneverapplicable (adjustment forfalse discovery
rate (FDR)).
7.1
Sample Size Determination
Twelve healthy volunteers will be enrolled
in this placebo-controlled cross-over study. The number of
volunteers to be included is calculated with a two-tailed t-test comparing two dependent means. Power
calculations were based onprevious results on the effect of cholestyramine (a bile acid sequestrant) on hunger
sensation in healthy volunteers (23). We assumea similar effect of obeticholic acid on hunger sensation and a
similar within-participant variability. We specified the following parameters: an error probability of 5%, effect
size of 1.0 and a power of 80%, Based on these parameters we need to include 10 volunteers in order to highlight
the expected differences. Twelve volunteers will be included to anticipate a potential dropout. Power
calculations were performed with GPowerversion 3.0.10.
Approximately 15 participants will be screened to achieve 6 randomlyassigned to Trial treatment and 6
evaluable participants for an estimated total of 12 evaluable participants per treatment group.
A maximum of 12 participants will be randomly assigned to Trial treatment such that approximately 10
evaluable participants complete the Trial.
7.2
Statistical Analysis
Data from all subjects who completed the study will be included for analysis. Statistical analysis of the
different parameters will be performed in SPSS for Windows (SPSS Inc., Chicago,IL, USA). Curves of whole
blood glucose, plasma levels of motilin and ghrelin GLP-1, GLP-2, GIP and insulin and hunger/ appetite
scores overtime Will be analyzed using the mixed models procedure, taking into account the course of the
curves overdifferent time points. Gastric motility and BA composition will be compared with Two-tailed
paired t tests or Wilcoxon signed-rank tests, depending on data distribution. Non-parametric test were
applied to analyse microbiome data, with multiple testing correction whenever applicable (adjustment for
false discovery rate (FDR)). Data obtained from endoscopy and gastric motility measurements prior to the
start of treatmentin the first part of the crossover study will be used as pre-treatment data in the second
part. Results will be found significant at p<0.05 significancelevel.
7.2.1
Efficacy Analysis
 
Endpoint
Statistical Analysis Methods
 
Primary
mixed models procedure (hunger / appetite)
 
Secondary
mixed models procedure (whole bloodglucose, plasmalevels of motilin and ghrelin
GLP-1, GLP-2, GIP andinsulin), Two-tailed paired t tests or Wilcoxon signed-rank tests
(Gastric motility and BA composition), Non-parametric test, multiple testing correction
(microbiome data)
 
 
Exploratory
Two-tailed paired t tests or Wilcoxon signed-ranktests (Signaling pathway analysis for
duodenal biopsies)
 
 
 
 
7.2.2
Other Analysis
For signaling pathway analysis using duodenal biopsies, Analysis of gene expression, protein expression,
histology and permeability will be evaluated.
7.3
-Interim Analysis and Final Database Lock
Nointerim analysis is planned.
The Statistical Analysis Plan will describe the plannedinterim analysis/analyses in greater detail.
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Version: 1.0_03082021
 
8
Data handling
Data handling and data flows for the Trial are summarized below and will be described in more detail in
the Trial-specific Data Management Plan (DMP).
Data for this study will be captured via electronic CRFs (open clinica) with pseudonymisation. Time and
date of entry, changes made and reasons for change will be recorded. Complete information for each
patientvisit, status, procedure, and test will be appropriately recorded, For dose administration, the date
and exact time will be captured. For each patient randomized and treated, an eCRF must be completed.If
a participant withdraws from the study, the reason must be noted on the eCRF. The Investigator will
ensure the accuracy, completeness, and timeliness of the data reported in the eCRF. Theparticipant’s name
or otheridentifiers will be stored separately from the Trial data and replaced with a unique codeto create
a new identity for the participant, for the purpose of the Trial. In such case data are encodedandsolely
the Investigator andhis/her Trial staff shall be able to link the data to an identifiable person. The codelist
must beretained onsite, in a secured place with restricted access and can under no circumstances leave
the site or be accessed by unauthorized persons.
8.1
Data Collection Tools and Source Document Identification
8.1.1
Operational aspects
Data collection, handling, processing and transfer for the purpose ofthis Trial will be performed in
compliance with applicable regulations, guidelines forclinical trials and internal procedures,as follows:
8.1.1.1
Data collection
Source Datawill be collected and recordedin the Trial participant’sfiles/medical records.
If applicable, worksheets may be usedfor capturing somespecific data in ordertofacilitate completion of
the (e)CRF. Any such worksheets will becomepart 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).
lt remains the responsibility of the Investigator to checkthat all data relating to the Trial, as specified in
the Trial protocol, are entered into the (e)CRFin accordancewith the instructions provided and that the
formsarefilled out accurately, completely andin a timely manner.
(e)CRFs are provided by the Sponsor for each participant. The Trial data will be transcribed from the
source records (ie. participants medical file or Trial-specific source data worksheets) into an (e)CRF by
Trial Staff. Transcription to the (e)CRF will be done as soonaspossible 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 nocircumstances capture personaldata suchas but notlimited to the participant ortheir relative(s)
name, home address, contact details, full date of birth medical record number(e.g. UZ Leuven EAD
number), social security number etc.
8.1.1.2
Data Validation
All data relating to the Trial must be prepared and validated by the Investigator. Any (e)CRFentries,
corrections and alterations must be madebythe Investigator or other authorized Trialstaff.
Properaudit trails must be available to demonstrate thevalidity of the Trial data collected. This includes
historical records of original data entries, by whom and whenthe data was entered,as well as detailed
records
of any corrections
or
additions made
to
the
original
data
entry
(ie. who made
the
correction/addition, when and why), without obliterating the original data entry information.
8.1.1.3.
Data Management
The Trial Data Managerwill perform extensive consistency checks on the received data. Queries will be
issued in case ofinconsistencies in accordance with internal procedures. A Data Management Plan (DMP)
will be developed to map data flows, data validation measures that will be taken, how (interim) database
lock(s) will be managed and, as applicable, the role and responsibilities of the Data Safety Monitoring
Committee (DSMB)
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8.1.1.4
Data Transfer
Anyparticipant 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 orany information which would
makethe 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).
8.1.2
Legal requirements
All source data will be kept at a secured location with restricted access atall 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 accidentalloss 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
informationis subject to compliance with applicable laws and regulations regarding personal data protection
and the processing of personal data.
TheInvestigator 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 documentsas specified in ICH-GCP E6(R2) Chapter8 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
accountall 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 purposeof the Trial. To this
end, appropriate Data Transfer Agreements (DTAs) will be established.
8.2
Audits and Inspections
The Investigatorwill permit direct access to Trial data and documents for the purpose of monitoring, audits
and/or inspections by authorized entities such as but notlimited to: the Sponsor orits 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 atall times.
8.3
Monitoring
In accordance with ICH-GCP E6(R2) 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 reportedin a manner
that assures data integrity. To this end Source Data will be compared with the data recordedin the (e)CRF.
A risk-based approach will be applied to determine the extent of monitoring activities and monitoring of
the Trial will be performed by qualified individuals (independent from the site Trial staff), as applicable.
At the time of enrollment of six patients, the status of consent acquisition,eligibility, randomization, data
collection, and serious adverse eventswill be checked in a few sampledcases. Again, at the end ofall cases,
monitoring will be conducted in the same way.
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TheSponsorandInvestigator/Participating Site will permit direct access to the Trial data and corresponding
Source Data, and to any other Trial related documents or materials to verify the accuracy and completeness
of the data collected. More details about the monitoring strategy are described in the Trial specific
Monitoring Plan (MP).
8.4
Archiving
As specified in ICH-GCP E6(R2) section 8.1 Addendum,the Sponsor andInvestigator/Participating Site will
maintain a record ofthe 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 controlof all Essential Documents and records generated
by the Investigator/Participating Site before, during and following termination of the Trial.
The Sponsoris responsible for archiving Trial specific documentation (such as but notlimited to the Trial
protocol, any amendmentsthereto,the final Clinical Study Report (CSR) andthe Trial database) according
to ICH-GCP E6(R2). Source data and site-specific Trial documents (such as butnotlimited to theoriginal
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 beheld on electronic record, provided that media
back-up exists, hard copies can be obtained, if required and measuresare 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.
9
Ethical and Regulatory Considerations
9.1
Ethics Committee (EC) review & reports
Before the start of the Trial, this protocol and other related documents (e.g. ICF, advertisements,IB, etc.)
will be submitted for review to the EC andto the relevant CA for Trial authorization. The Trial shall not
commenceuntil such approvals have been obtained.
It is the responsibility of the Cl to produce the Annual Progress Report (APR) and submit to the EC/CA
within 30 days of the anniversary date on whichfavourable opinion to start the Trial was given, and annually
until the Trial is declared ended.
The Cl shall notify the EC/CA ofthe end ofthe Trial. Should the Trial be temporarily suspended or, ended
prematurely, the Cl will notify the EC/CA andinclude the reasons for suspension/premature termination
within 15 days of the decision. The Cl will submit a final report with the results of the study, including any
publications/abstracts, to the EC/CA within
| year oftrial termination or within 6 months for paediatric
Trials.
9.2
Peer review
This Trial protocol was peer reviewed by 3 number independent experts. Peer review was conducted by
expert referees to the professional and scientific standards expectedforclinical studies.
9.3
Regulatory Compliance
TheTrial will be conducted in compliance with the principles outlined in the requirements for the conduct
ofclinical Trials in the EU as providedfor in Directive 2001/20/EC or EU Regulation 536/2014,as applicable,
and any subsequent amendments,as well as 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)orthe Belgian law of May 7th 2017 onclinical
Trials with medicinal products for human use, as applicable, and with the EU General Data Protection
Regulation 2016/679 (GDPR), the relevant Belgian laws implementing the GDPR, the Belgian Law of August
22° 2002 on patient rights and all other applicable legal and regulatory requirements.
 
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9.4
Protocol / GCP compliance
The Trial 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 humanparticipants. Compliance with this standard provides public assurancethattherights,
safety, and well-being of Trial participants are protected, consistent with the principles that originated in
the most recent version of the Declaration of Helsinki, and that the Trial data are credible, reliable and
reproducible.
TheInvestigator and Trial team acknowledge and agreethat prospective, planned deviations or waivers to
the protocol are not permitted underapplicable regulations onclinical 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 Cl and Sponsor. Deviations should also be reported to the
EC aspart of the EC’s continued review ofthe 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 understoodthat “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 protectthe safety of any
participant includedin the Trial, evenif this action represents a deviation from the protocol. In such
cases, the Sponsor should benotified of this action and the EC atthe Trial site should be informed
according to local procedures and regulations.
9.5
Data protection and participant confidentiality
The Trial will be conducted in compliance with the requirements of the EU General Data Protection
Regulation 2016/679 (GDPR), 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). In case personal data is transferred outside the European
Economic Area, safeguards will be taken 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 atall 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 orloss or destruction while in its custody.
9.6
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 malpracticeliability, and (ii) generalliability.
For Belgian Participating Sites
Art 29 of the Belgian Law relating to experiments on human persons dated May 7", 2004 applies.
Prior to the start of the Trial, the Sponsor shall enter into an insurance contract in order to adequately
coverTrial participants from Belgian sites in accordancewith art. 29 of the said law.
For non-Belgian Participating Sites
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Version: 1.0_03082021
 
 
The Participating Site 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 other possible
damages resulting from the Trial at the Participating Site, as required by local law. Each such insurance
coverage shall be in amounts appropriate to the conduct of the services of the Participating Site under
this Trial. The Participating Site and Sponsorshall be solely responsible for any deductible or self-insured
retention under any such policies.
9.7
Amendments
Unless for urgent reasons as specified in ICH-GCP E6(R2) section 4.5.4, amendments must not be
implemented prior to EC and/or CA review and/or approval, as applicable.
In accordance with the Belgian law of May 7" 2004 regarding experiments on humans, the Sponsor may
develop a non-substantial amendmentat any time during the Trial. If a substantial amendmentto the
clinical Trial agreement or the documents that supportedtheoriginal application for the clinical Trial
authorisation is needed, the Sponsor must submit a valid substantial amendment to the Competent
Authority (CA) for consideration, and to the EC for review and approval. The CA and/or EC will provide
a responsein accordance with timelines defined by applicable regulations, It is the Sponsor’s
responsibility to assess whether an amendmentis substantial or non-substantial for the purpose of
submission to the CA and/or EC.
Amendmentsto the Trial are regarded as‘substantial’ when theyarelikely to have a significant impact on
the safety or physical or mentalintegrity of the clinical Trial participants, or the scientific value of the
Trial.
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/2010_c82_01/2010_c82_01_en.pdf
9.8
Post-Trial activities
Notapplicable asthis is a clinical study in healthy subjects.
10
Research
Registration,
Dissemination
of
Results
and
Publication Policy
The Declaration of Helsinki (latest version) and European and Belgian regulations require that every
research Trial
involving human
participants be registered
in a publicly accessible database before
recruitmentofthe first participant. The Cl is responsible for registering the Trial.
In addition, the Cl will fulfil their ethical obligation to disseminate and make the research results publicly
available. As such the Cl 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, institutionalaffiliations and conflicts of interest must be declaredin
publication.
Publications will be coordinated by the Cl. 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.
Anypublication 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 dateoffirst submission to the Sponsorin order
to enable the Sponsorto take steps to protectits intellectual property rights and know-how.
|I
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 ofthe 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
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and prepared in the performance of the Trial protocol shall be the sole property of Sponsor unless
otherwise agreed in the clinical trial agreement.
12
Joint Commission International (JCI)
In order to ensure the same quality and safety standardsin patient care for clinical research as commonly
applied by the Sponsor in its regular activities, and in accordance with JCI standards, the Sponsor shall
comply with the following obligations: (a) the Sponsor will use trained and qualified employees or
contractors to manage and coordinate the Trial; (b) the Sponsor will ensure that multi-center Trial
reporting is reliable and valid, statistically accurate, ethical, and unbiased. (c) the Sponsor will not grant
incentives, other than standard compensations and reimbursement of costs, to Trial participants or to
participating site's staff that would compromisethe integrity of the research; (d) the Sponsor is
responsible for monitoring and evaluating the quality, safety, and ethics of the Trial and will respect the
participating site's policies and processes when performing such monitoring and evaluation activities; (e)
the Sponsor will protect the privacy and confidentiality of the Trial participants in accordance with all
applicable laws.
13
References
L
Tack J, Drossman DA. What's new in Rome IV? Neurogastroenterology and motility : the official
journal of the European Gastrointestinal Motility Society. 2017;29(9).
2.
Beeckmans D, Riethorst D, Augustijns P, Vanuytsel T, Farre R, Tack J, et al. Altered duodenalbile
salt concentration and receptor expression in functional dyspepsia. United European gastroenterology
journal. 2018;6(9): 1347-55.
3,
Hofmann AF. The continuing importance of bile acids in liver and intestinal disease. Archives of
internal medicine. 1999;159(22):2647-58.
4.
Vanuytsel T, van Wanrooy S, Vanheel H, Vanormelingen C, Verschueren S, Houben E, et al.
Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a
mast cell-dependent mechanism. Gut. 2014;63(8):1293-9.
5.
Islam KB, Fukiya S, Hagio M, Fujii N, Ishizuka S, Ooka T,et al. Bile acid is a hostfactor that regulates
the composition of the cecal microbiota in rats. Gastroenterology. 201 1;141(5):1773-81.
6.
LobiondaS, Sittipo P, Kwon HY, Lee YK. The Role of Gut Microbiotain Intestinal Inflammation
with Respect to Diet and Extrinsic Stressors. Microorganisms. 2019;7(8).
7.
Carbone F, TackJ. Gastroduodenal mechanisms underlying functional gastric disorders. Digestive
diseases (Basel, Switzerland). 2014;32(3):222-9.
8.
Tack J, Piessevaux H, Coulie B, -CaenepeelP, Janssens J. Role of impaired gastric accommodation
to a mealin functional dyspepsia. Gastroenterology. 1998; 1 15(6):1346-52.
8
CarboneF, TackJ, Hoffman |. The Intragastric Pressure Measurement: A Novel Method to Assess
Gastric Accommodation in Functional Dyspepsia Children. Journal of pediatric gastroenterology and
nutrition. 2017;64(6):9 18-24.
10.
Janssen P, Verschueren S, Ly HG, Vos R, Van OudenhoveL, TackJ. Intragastric pressure during
food
intake:
a
physiological
and
minimally
invasive
method
to
assess
gastric
accommodation.
Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.
201 1;23(4):316-22, e153-4.
I.
Deloose E‚ Janssen P, Depoortere |, Tack J. The migrating motor complex: control mechanisms
andits role in health and disease. Nature reviews Gastroenterology & hepatology. 2012;9(5):271-85.
12.
Mondal A, Xie Z, Miyano Y, Tsutsui C, Sakata |, KawamotoY, et al. Coordination of motilin and
ghrelin regulates the migrating motor complex of gastrointestinal motility in Suncus murinus. American
journal of physiology Gastrointestinal and liver physiology. 2012;302(10):G1207-15.
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interventionalclinical trial with IMP

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Protocol: OCARINA
Internal Ref.: SS64643
Version: 1.0_03082021
 
13.
Tack J, Deloose E, Ang D,Scarpellini E, Vanuytsel T, Van OudenhoveL, et al. Motilin-induced
gastric contractions signal hunger in man. Gut. 2016;65(2):214-24.
14,
Tong J, D'Alessio D. Give the receptor a brake: slowing gastric emptying by GLP-1. Diabetes.
2014;63(2):407-9.
:
15.
Guan X, Shi X, Li X, Chang B, Wang Y, Li D, et al. GLP-2 receptor in POMC neurons suppresses
feeding behavior and gastric motility. American journal of physiology Endocrinology and metabolism.
2012;303(7):E853-64.
16.
Kuhre RE, WewerAlbrechtsen NJ, Larsen O,Jepsen SL, Balk-Moller E, Andersen DB,etal. Bile
acids are important direct and indirect regulators of the secretion of appetite- and metabolism-regulating
hormonesfrom the gut and pancreas. Molecular metabolism. 2018; 1:84-95.
17,
Ipharraguerre IR, Tedo G, Menoyo D, de Diego Cabero N,HolstJJ, Nofrarias M,et al. Bile acids
induce glucagon-like peptide 2 secretion with limited effects on intestinal adaptation in early weanedpigs.
The Journalof nutrition. 2013;143(12):1899-905.
18.
Appleby RN, Walters JR. The role of bile acids in functional Gl disorders. Neurogastroenterology
and motility : the official journal of the European Gastrointestinal Motility Society. 2014;26(8):1057-69.
19.
Kowdley KV, Luketic V, Chapman R, Hirschfield GM, Poupon R, Schramm C,et al. A randomized
trial of obeticholic acid monotherapy in patients with primary biliary cholangitis. Hepatology (Baltimore,
Md). 2018;67(5):1890-902.
20.
Pockros PJ, Fuchs M,Freilich B, Schiff E, Kohli A, Lawitz EJ, et al. CONTROL: A randomized phase
2 study of obeticholic acid and atorvastatin onlipoproteins in nonalcoholic steatohepatitis patients. Liver
international: official journal of the International Association for the Study of the Liver. 2019.
21.
Nevens F, AndreoneP, Mazzella G, Strasser SI, Bowlus C, Invernizzi P, et al. À Placebo-Controlled
Trial
of Obeticholic Acid
in
Primary
Biliary
Cholangitis. The New
England
journal
of medicine.
2016;375(7):63 1-43.
22.
Friedman ES, Li Y, Shen TD,Jiang J, Chau L, Adorini L, et al. FXR-Dependent Modulation of the
Human Small Intestinal Microbiome by the Bile Acid Derivative Obeticholic Acid. Gastroenterology.
2018; 155(6):1741-52.e5.
23.
PsichasA, Little T, Lal S, McLaughlin J. Colestyramine slows gastric emptyingofliquids and reduces
appetite in healthy subjects. Neurogastroenterology and motility
: the official journal of the European
Gastrointestinal Motility Society. 2012;24(12):1095-101.18
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Version: 1.0 03082021
 
APPENDICES
Possible side effects of obeticholic acid, Ocaliva®
(Ocaliva : EPAR - Product Information;https://www.ema.europa.eu/en/medicines/human/EPAR/ocaliva)
Like all medicines, this medicine can causeside effects, although not everybodygets them.
Tell your doctor or pharmacist if you experience itching of the skin (pruritus) or if the itch gets worse
while on this medicine. In generalitching of the skin is a very common(may affect more than
| in 10 people)
side effect that begins within the first month following the start of treatment with Ocaliva and usually
becomesless severe overtime.
Other possible side effects maybe:
Very commonsideeffects (mayaffect up to | in 10 to 100 people)
* stomachpain
* feeling tired
Commonside effects (may affect up to
1 in 100 to 1000 people)
+ thyroid hormoneirregularity
+ dizziness
* fast or irregular heart beat (palpitations)
* pain in the mouth and throat
* constipation
* itchy, dry and/or red skin (eczema)
* rash
* pain in your joints
+ swelling in the hands andfeet
+ fever
Risks of upper gastrointestinal endoscopy
Rareincidents of upper gastrointestinal endoscopyincludegastrointestinal bleeding and perforation. This
may require hospitalisation or emergency treatment orsurgery.
Risks associated with insertion of the manometry catheter and duodenalfluid suction catheter
* Risks of this test include:
* Slight nosebleed
* Sore throat
* Hole, or perforation, in the esophagus (this rarely happens)
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14
Appendix |: Clinical trial protocol history
Protocol: OCARINA
Version: 1.0_03082021
 
 Original CTP version:
1.0 dated 30/08/2021
 
 
Amendment #1:
dated
 
Modifications made / Reason for amendment:
 
 
 
 
 
 
 
 
Amendment #2:
dated
 
Modifications made / Reason for amendment:
 
 
 
 
 
 
 
 
 
 
 
 
 
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15
Appendix 2: Data Processing Annex (DPA)
Definitions:
e
“Protocol” means the documententitled The effect of obeticholic acid on gut microbiota, gastric
motility, accommodation, gastrointestinal peptide in healthy volunteers
containing the details of
the academic Trial as developed by the Sponsor and approvedbythe relevant Ethics Committee.
e
“Sponsor” means University Hospitals Leuven (UZ Leuven).
e
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 underarticle
4, 7) of the Regulation (EU) 2016/679 (“Data Controller”).
e
“Applicable Law” meansanyapplicable data protection orprivacy laws, including:
a)
the Regulation (EU) 2016/679 also referred as the General Data Protection Regulation
("GDPR'");
b)
other applicable laws that are similar or equivalent to or that are intended to or implement
the lawsthat are identified in (a) of this definition;
e
"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:
|.
The Data Processoris instructed to process the Personal Data for the term ofthe Trial and only
for the purposesof 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 Trial protocol, including with regard to
transfers of personal data to a third country or an international organization, unless the Data
Processoris required to do so according to Union or MemberState 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 Processorconsiders 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 aboutthis.
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 Processorshall implement appropriate technical and organizational measures to prevent
that the Personal Data processedis:
(i)
accidentally or unlawfully destroyed,lost or altered,
(ii) disclosed or madeavailable without authorization, or
(iii) otherwise processedin violation of Applicable Law.
5.
The appropriate technical and organizational security measures must be determined with due
regard for:
(i)
the currentstate of the art,
(ii) the cost of their implementation, and
(iii) the nature, scope, context and purposesof processing as well as the risk of varyinglikelihood
and severity for the rights and freedomsof natural persons.
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
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and regulations in the area of privacy and data protection (such as, the right of access, the right to
rectification, theright to erasure, the right to restrict the processing, theright to data portability
and the right to object)
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.
The Data Controller is entitled to appoint at its own cost an independent expert, reasonably
acceptable to the Data Processor, whoshall have access to the Data Processor's data processing
facilities and receive the necessary information for the sole purposeof 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.
The Data Processor mustgive authorities who by Union or MemberState 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 physicalfacilities against proper proof of identity
and mandate, during normal business hours and upon reasonable prior written notice.
. 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 MemberState 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 underthe Protocol, or (b) otherfailure 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 Processoris considered data controller) received directly from the Data Participants
or from third parties.
. 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
numberof Data Participants concerned, and stating the categories and (by approximation) the
numberofthe personaldata registers affected (datasets);
(ii)
the likely consequencesof 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 adverseeffects of such breach.
. The Data Processor shall document (and shall keep such documentationavailable for the Data
Controller) any Personal Data breaches, including the facts related to the Personal Data breach,
its effects and the corrective measurestaken. After consulting with the Data Controller, the Data
Processorshall take any measures needed tolimit the (possible) adverse effects of Personal Data
breaches (unless such consultation cannot be awaited due to the nature of the Personal Data
breach).
. The Data Processor must promptly and reasonablyassist the Data Controller (with the handling
of (a) responsesto any breach ofsecurity as describedin 10)(ii) above and (b) any requests from
Data Participants under ChapterIll of the GDPR, including requests for access, rectification,
blocking or deletion. The Data Processor must also reasonably assist the Data Controller by
implementing appropriate technical and organizational measures for the fulfilment of the Data
Controller's obligation to respond to such requests.
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14.
Version: 1.0_03082021
 
 
 
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 Processoris implied, and where the assistance of the Data Processoris
necessary for the Data Controller to comply with its obligations. This includes, butis notlimited
to, at the requestto 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.
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.
. The Data Controller has the right to receive a copy of the relevant provisions of Data Processor's
agreement with the subprocessorrelated to data protection obligations. The Data Processor shall
remain fully liable to the Data Controller for the performance of the subprocessor obligations
underthis DPA. The fact that the Data Controller has given consent to the Data Processor's use
of a subprocessoris without prejudice for the Data Processor's duty to comply with this DPA.
 
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