Local Injection of Collagenase Clostridium Histolyticum (XiapexR) for Refractory Iatrogenic Esophageal Strictures: an Open-label Pilot Study
Phase: EARLY_PHASE1
Conditions: Stricture, Esophageal Stricture, Anastomotic, Collagenosis
Sponsor: University Hospital, Ghent

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Protocol “AGO/2018/004”, versie 2, dd 31/MAR/2020 
Part I : Trial related part of the protocol 
 
 
1 Title of the trial 
 
Local injection of collagenase clostridium histolyticum (XiapexR) for refractory 
gastrointestinal strictures: an open-label pilot study. 
2 
Trial number 
 
Protocol:AGO/2018/004 
 
EudraCT number: 2018-003637-14 
 
3 Objective of the study 
 
To investigate whether intralaesional injection with collagenase clostridium 
histolyticum (XiapexR) into the stricture followed by dilation 24 hours later improves 
the outcome of patients with refractory gastrointestinal strictures as compared to 
dilation alone (standard of care). 
 
4 End point(s) and timepoint(s) of evaluation 
 
Primary outcome measure: 
Number of repeat dilations that are required over a timespan of 6 months. 
 
Secondary outcome measures:  
1) time to first repeat dilation 
2) complication rate. 
3) For upper gastrointestinal strictures only: Dysphagia/gastric outlet obstruction 
score (0:, able to eat normal diet; 1: moderate passage: able to eat some solid foods; 

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2: poor passage: able to eat semi-solid foods only; 3: very poor passage: able to 
drink liquids only; 4: no oral intake possible 
4) For lower gastrointestinal strictures only: (Ileo)colorectal obstruction scoring 
system (0, requiring continuous decompression; 1, no oral intake; 2, liquid or enteral 
nutrition; 3, oral intake of soft solids, low-residue diet, or full diet with symptoms of 
stricture*; and 4, oral intake of soft solids, low-residue diet, or full diet without 
symptoms of stricture*. Symptoms of stricture include abdominal pain/cramps, 
abdominal distension, nausea, vomiting, constipation, and diarrhea which are related 
to gastrointestinal transit). 
 
5 General information 
 
5.1 Investigator(s) 
 
Dr. Pieter Hindryckx 
Department of Gastro-Enterology 
Ghent University Hospital 
Pieter.Hindryckx@uzgent.be (+3293320726) 
 
5.2 Sponsor 
 
Ghent University Hospital, with a grant of the Belgian Society of Gastrointestinal 
Endoscopy. 
 
5.3 Departments/laboratories involved in the study 
 
Department of Gastro-enterology 
Ghent University Hospital, 

Department of Gastro-Enterology 
 
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Corneel Heymanslaan 10 
9000 Ghent 
 
6 Introduction 
 
The main causes of benign gastrointestinal (GI) strictures are inflammatory (eg: reflux 
disease, eosinophilic esophagitis, Crohn’s disease, caustic…) or iatrogenic (post-
irradiation, post endoscopic (sub)mucosal resection, post radiofrequency ablation, 
anastomotic…). Most strictures respond well to endoscopic balloon dilation. 
Nonetheless, more than one third of patients develop recurrent symptoms after 
dilation within the first year (1). 
In some case, the stricture can be difficult to treat and require multiple dilation 
sessions to obtain long-term relief of dysphagia, eating difficulties or lower GI 
obstructive symptoms (2, 3).  A refractory stricture is defined as a cicatricial or fibrotic 
narrowing luminal diameter resulting in clinical symptoms of a) dysphagia 
(esophageal strictures), b) gastric outlet obstruction (for strictures of the stomach, 
pylorus, duodenum of gastrojejunal anastomosis) or c) lower GI obstruction 
(abdominal distension and cramps, vomiting) with an inability to successfully 
remediate the anatomic problem to a sufficient diameter over 3 dilation sessions at 
two-week intervals (4). A recurrent stricture is defined as a cicatricial or fibrotic 
narrowing with an inability to maintain a satisfactory luminal diameter for four weeks 
(4).   Several options (stenting, intralesional injection of corticosteroids, needle knife 
incision) have been proposed to manage these strictures, with a varying success rate 
(5).  A significant proportion of patients will finally need self-bougienage or surgery 
(5). 
In conclusion, the treatment of  GI strictures remains a challenge for clinicians and 
there is an unmet need for novel approaches to manage the patients suffering from 
this condition in order to avoid repeated dilations and/or invasive surgery. 
 
XiapexR is a locally injectable collagenase approved for the management of 
Dupuytren’s and Peyronie’s disease (6, 7). Xiapex is a mixture of two collagenases, 
enzymes produced by the bacterium Clostridium histolyticum that dismantle collagen. 
Approximately 24 hours after local injection, the collagen fibres have lost their 

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strength and can be easily broken by manipulation.  This therapy has been a 
breakthrough in the management of Dupuytren’s disease, avoiding surgery in the 
vast majority of patients (6).  
After local injection, the collagenases do not reach the bloodstream in significant 
amounts and are presumed to largely stay at the point of injection until they are 
broken down by proteases. As a result, side effects are uncommon and are most 
often injection site reactions including lymphadenopathy (swollen lymph nodes), 
itching, pain, oedema, and bleeding (for example in the form of bruises or 
ecchymoses). Allergic reactions are seen in less than 1% of patients (8). 
 
XiapexR has been proposed as a promising treatment for refractory urethral strictures 
but has never been evaluated in refractory GI strictures (9). 
 
7 The present study 
 
7.1 Study design 
 
Proof of concept open pilot study with a historical control cohort. 
7.2 Medication 
 
7.2.1 Composition and dosing 
 
One vial (0.9mg) xiapex in 3ml dissolvent (also provided by the company) will be 
divided over 4 quadrants within the fibrotic stricture 
 
 
7.2.2 Producer 
 
Lonza AG 
Lonzastrasse 
3930 Visp 
Switzerland 
 
7.2.3 Distributor 
 
Swedish Orphan Biovitrum AB 
SE-112 76 Stockholm 

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Sweden 
 
7.2.4 Packaging 
 
Xiapex powder is supplied in a clear glass vial (3 ml, type I glass) with rubber 
stopper, aluminium seal and flip-off cap (polypropylene). Solvent: 3 ml solution 
supplied in a clear glass vial (5 ml, type I glass) with rubber stopper, aluminium seal 
and flip-off cap (polypropylene). 
 
7.2.5 Administration way 
 
Intralaesional injection. 
 
7.2.6 Labelling 
 
Xiapex is a commercialized product and the commercially available labelling will be 
used. A study label will be applied to the medication (not obscuring the original label), 
with following information: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.2.7 Storage conditions 
 
Store in a refrigerator (2°C - 8°C). 
Do not freeze. 
 
Xiapex 0,9 mg poeder en 3 ml oplosmiddel voor 
oplossing voor injectie 
 
EudraCT N°: 2018-003637-14 
 
TRIAL subject ID nr: ________ Initialen: _______ 
Datum/ Date visite: ________ 
 
ENKEL VOOR STUDIEGEBRUIK Gebruiksaanwijzing: 
Eén vial (0.9mg) xiapex in 3 ml oplosmiddel 
intralaesioneel (verdeeld over 4 kwadranten van 
fibrotische strictuur). Buiten het zicht en bereik van 
kinderen houden - Bewaren in de koelkast (2-8°C) in de 
oorspronkelijke verpakking 
 
Contactpersoon: Prof Dr. Pieter Hindryckx, Tel: 
0485638106 
 
Sponsor: UZ Gent, Corneel Heymanslaan 10, 9000 Gent 

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7.2.8 Known side effects of the medication 
 
After local injection the collagenases do not reach the bloodstream in significant 
amounts and are presumed to largely stay at the point of injection until they are 
broken down by proteases. As a result, side effects are uncommon and are most 
often injection site reactions including lymphadenopathy (swollen lymph nodes), 
itching, pain, oedema, and bleeding (for example in the form of bruises or 
ecchymoses). Allergic reactions are seen in less than 1% of patients Drug 
accountability 
7.2.9 Drug accountability 
 
Drug accountability will be documented. 
 
7.3 The subjects 
 
7.3.1 Number of subjects 
 
Active group: 10 patients presenting with refractory GI strictures.   
Control group: A historical cohort that consists of 40 consecutive patients that 
received an endoscopic balloon dilation 12-15mm for a refractory GI stricture at our 
centre. 
7.3.2 Inclusion criteria 
 
The patient is 18-90 years old 
The patient suffers from a GI stricture  
The stricture is amenable for endoscopic dilation 
The patient has undergone at least 1 previous endoscopic dilation for the same 
stricture within the last 3 months 
The patient has signed the ICF 
 
7.3.3 Exclusion criteria 
The patient is not fluent in Dutch 
 
 
7.3.4 Replacement of subjects 
 
Patients that are not able to participate to the study will receive the standard of care, 
consisting of endoscopic dilations alone. Only 1 intralaesional administration of the 
study drug is given at the start of the experiment. Early drop-out of the study (before 
6 months) will therefore not impact further standard care of the patient. 
 

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7.3.5 Restrictions and prohibitions for the subjects 
 
- 
Patient need fasting for at least 8 hours prior to the gastroscopies 
- 
Patients on anticoagulant medication need to interrupt the treatment according 
to the recommendations of the treating physician (Prof dr. Pieter Hindryckx or 
prof dr Danny De Looze)  
 
7.3.6 Possible advantages and risks for the subjects 
 
It is possible that participation to the study will result in less need for repeat dilations 
for a refractory upper GI stricture (unknown).  
 
Every dilation carries the risk of perforation, even in the most experiences hands. No 
additional dilations are performed in light of the study. It is unknown whether local 
injection of the study drug augments the risks of perforation. 
Every patient is carefully monitored after dilation (standard of care). Upon clinical 
suspicion of perforation, a CT scan is performed for confirmation. In case of 
confirmed perforation, endoscopic stenting is immediately performed to bridge the 
defect, allowing healing of the defect. The stent can most of the time be removed 
after 6 weeks. In some case, endoscopic clipping is the treatment of choice to close 
the iatrogenic perforation. Surgical intervention is seldomly needed 
 
Side effects of the study drug (XiapexR) are expected to be very limited, as the study 
drug does not enter the bloodstream in significant amounts and is rapidly degraded in 
the bloodstream by proteases. Local reactions (bleeding, swelling, inflammation) are 
theoretically possible.  Like all foreign substances, Xiapex can induce allergic 
reactions but these seem to be very rare (only 1 case described in literature). 
 
8 Procedures 
 
8.1 Procedures 
 
After informed consent, patients with an a refractory upper GI stricture will receive a 
first esophagogastroscopy or ileocolonoscopy with local injection of XiapexR injection 
into the stricture prior to dilatation. One vial (0.9mg) xiapex in 3ml dissolvent (also 
provided by the company) will be divided over 4 quadrants within the fibrotic stricture. 
After 24 hours, a second esophagogastroscopy or ileocolonoscopy will be performed 
to perform balloon dilation of the stricture 12-15mm (standard of care). 
The historical cohort will not undergo any procedures, but their patient file will be 
reviewed to gain outcome data. ICF will be obtained if the patient is still in follow-up 
at our department. 
8.2 Flowchart 
 
- 
Between day -7 to day -1: Informed consent  

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- 
Day 0: Endoscopy, xiapex injection into the strictures (4 quadrants, 0.75ml or 
0.25mg per quadrant) 
- 
Day +1: Endoscopy, CRE balloon dilation 12mm to max 15mm 
- 
Day +2 to month 2: clinical evaluation (by phone) every 2 weeks with a window 
of 3 days (see above for primary and secondary outcome measures) 
- 
Month 2-month 6: Clinical evaluation (by phone) every 4 weeks with a window 
of 3 days (see above for primary and secondary outcome measures) 
 
The expected total duration of the trial is 18 months. 
 
 
 
9 Randomisation / blinding 
 
Not Applicable, as this is an open label trial. 
 
10 Prior and concomitant therapy 
 
Patients on anticoagulant medication need to interrupt the treatment according to the 
recommendations of the treating physician (Prof dr. Pieter Hindryckx or prof dr Danny 
De Looze). 
All other prior or concomitant medications are allowed  
 
11 Adverse event reporting 
 

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List of abbreviations 
AE 
 
Adverse Event 
CA 
 
Competent Authority 
EC 
 
Ethics Committee 
SAE  
Serious Adverse Event 
SSAR  
Suspected Serious Adverse Reaction 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
 
Adverse events (AE) 
The following information will be recorded: 
• 
nature of adverse event 
• 
date and time of occurrence and disappearance 
• 
intensity: mild, moderate or severe 
• 
frequency: once, continuous or intermittent 
• 
decision regarding study: continuation or withdrawal 
• 
relation to the study medication (see below) 
 
AE’s will be recorded from the first drug administration until the end of the trial. 
Special attention will be given to those subjects who have discontinued the trial for an 
AE, or who experienced a severe or a serious AE. 
 
Definitions of Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a 
causal relationship with this treatment. An adverse event (AE) can therefore be any 
unfavorable and unintended sign (including an abnormal finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, 
whether or not related to the medicinal (investigational) product. 
 
Serious Adverse Avent (SAE) 
Any untoward medical occurrence that at any dose: 
- results in death 
- is life-threatening 
- requires inpatient hospitalization or prolongation of existing hospitalization, 
- results in persistent or significant disability/incapacity, 
or 
- is a congenital anomaly/birth defect. 
 
Note: Medical and scientific judgment should be exercised in deciding whether 
expedited reporting is appropriate in other situations, such as important medical 
events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject or may require intervention to prevent 
one of the outcomes listed in the definition above. 
 
Unexpected adverse event 
An adverse event, the nature or severity of which is not consistent with the applicable 
product information (e.g., Investigator's Brochure for an unapproved investigational 
product or package insert/summary of product characteristics for an approved 
product). 
 

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Life-threatening 
Any event in which the subject was at risk of death at the time of the event; it does 
not refer to an event which hypothetically might have caused death if it were more 
severe. 
 
Associated with the use of the drug 
An adverse event is considered associated with the use of the drug if the attribution is 
possible, probable or definitive. 
 

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Attribution definitions 
Not related 
An adverse event which is not related to the use of the drug. 
 
Unlikely 
An adverse event for which an alternative explanation is more likely - e.g. 
concomitant drug(s), concomitant disease(s), and/or the relationship in time suggests 
that a causal relationship is unlikely. 
 
Possible 
An adverse event which might be due to the use of the drug. An alternative 
explanation - e.g. concomitant drug(s), concomitant disease(s), - is inconclusive. The 
relationship in time is reasonable; therefore the causal relationship cannot be 
excluded. 
 
Probable 
An adverse event which might be due to the use of the drug. The relationship in time 
is suggestive (e.g. confirmed by dechallenge). An alternative explanation is less likely 
- e.g. concomitant drug(s), concomitant disease(s). 
 
Definitely 
An adverse event which is listed as a possible adverse reaction and cannot be 
reasonably explained by an alternative explanation - e.g. concomitant drug(s), 
concomitant disease(s). The relationship in time is very suggestive (e.g. it is 
confirmed by dechallenge and rechallenge). 
 
Reporting of adverse events 
 
Adverse events will be reported between the first dose administration of trial 
medication and the last trial related activity. 
All AEs and SAE’s will be recorded in the patient’s file and in the CRF. All SAE’s will 
be reported as described below. 
Medical events that occur between signing of the Informed Consent and the first 
intake of trial medication will be documented on the medical and surgical history 
section and concomitant diseases page of the CRF. 
SAE’s occurring within a period of 30 days following the last intake of trial medication 
will also be handled as such if spontaneously reported to the investigator. 
 
All serious adverse events (SAE) and pregnancies occurring during clinical trials 
must be reported by the Principal Investigator within 2 working days after becoming 
aware of the SAE to: 
- 
HIRUZ of the University Hospital Ghent. HIRUZ will submit the finalized report 
to the Central Ethics Committee. 
 
 
This reporting is done by using the appropriate SAE form. For the contact details, see 
below. 
 

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It is the responsibility of the local Principal Investigator to report the local SAE’s  to 
the local EC. 
 
In case the investigator decides the SAE is a SUSAR (Suspected Unexpected 
Serious Adverse Reaction), HIRUZ will report the SUSAR to the Central EC and the 
CA within the timelines as defined in national legislation. The National Coordinating 
Investigator reports the SUSAR to all local Principal Investigators. 
 
In case of a life-threatening SUSAR the entire reporting process must be completed 
within 7 calendar days.  In case of a non life-threatening SUSAR the reporting 
process must  completed within 15 calendar days. 
 
The first report of a serious adverse event may be made by telephone, e-mail or 
facsimile (FAX).  
 
Contact details of the Health, innovation and research institute (HIRUZ): 
e-mail: hiruz.ctu@uzgent.be  
tel.: 09/332 05 00 
fax: 09/332 05 20 
 
Contact details of the Principal Investigator: 
e-mail: Pieter.hindryckx@uzgent.be 
tel.: In hospital: 093320726; cellphone 0485638106 
fax: 093324984 
 
  
 
The investigator must provide the minimal information: i.e. trial number, subject's 
initials and date of birth, medication code number, period of intake, nature of the 
adverse event and investigator's attribution. 
This report of a serious adverse event by telephone must always be confirmed by a 
written, more detailed report. For this purpose the appropriate SAE form will be used. 
Pregnancies occurring during clinical trials are considered immediately reportable 
events. They must be reported as soon as possible using the same SAE form. The 
outcome of the pregnancy must also be reported. 
 
All subjects will receive a "trial card" indicating the name of the investigational 
product, the trial number, the investigator's name and a 24-hour emergency contact 
number. 
 
    
 
12 Study analysis 
 
12.1 Sample size calculation 
 
No sample size calculation, proof of concept open label study. 
 

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12.2 Analysis of the samples 
 
Not applicable (no sample taking) 
 
12.3 Statistical analysis 
 
This is a proof of concept open label study that will compare outcome data with a 
historical control group. Only descriptive analyses will be performed, the sample size 
will be too low for any meaningful statistical analysis. 
13 Quality control and quality assurance 
 
The principal investigator will prospectively collect the pseudonymized data and 
ensure the quality of the study procedures and study data (see also section 17 up to 
21).  
 
14 Indemnity insurance 
 
A No Fault Insurance (of the Ghent University Hospital) will be provided for this trial. 
 
15 Publication policy 
 
All data are owned by the principal investigator (Prof Dr. Pieter Hindryckx) who will 
set up the author list and author ranking of any abstract or manuscript with regard to 
the study. 

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Part II : General part of the protocol 
 
 
 
16 Independent Ethics Committee (IEC) / Institutional 
Review Board (IRB) 
 
This trial can only be undertaken after full approval of the protocol and addenda has 
been obtained from the IEC/IRB. This document must be dated and clearly identify 
the protocol, amendments (if any), the informed consent form and any applicable 
recruiting materials and subject compensation programs approved. 
During the trial, the following documents will be sent to the IEC/IRB for their review: 
• reports of adverse events as described in section 11. 
• all protocol amendments and revised informed consent form (if any). 
Amendments should not be implemented without prior review and documented 
approval / favorable opinion form the IEC/IRB except when necessary to eliminate an 
immediate hazard to trial subjects or when the change involves only logistical or 
administrative aspects of the trial. 
Reports on, and reviews of the trial and its progress will be submitted to the IEC/IRB 
by the investigator at intervals stipulated in their guidelines. 
At the end of the trial, the investigator will notify the IEC/IRB about the trial 
completion. 
 
17 ICH/GCP guidelines 
 
This trial will be conducted in accordance with the protocol, current ICH-GCP 
guidelines and applicable law(s). 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard 
for designing, conducting, recording and reporting trials that involve the participation 
of human subjects. Compliance with this standard provides public assurance that the 
rights, safety and well-being of trial subjects are protected, consistent with the 
principles that have their origin in the Declaration of Helsinki, and that the clinical trial 
data are credible. 
 
18 Subject information and informed consent 
 
Prior to entry in the trial, the investigator must explain to potential subjects or their 
legal representatives the trial and the implication of participation. Subjects will be 
informed that their participation is voluntary and that they may withdraw consent to 
participate at any time. Participating subjects will be told that their records may be 
accessed by competent authorities and by authorized persons without violating the 
confidentiality of the subject, to the extent permitted by the applicable law(s) and/or 
regulations. By signing the Informed Consent Form (ICF), the subjects or legally 
acceptable representatives are authorizing such access. 

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

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22 Signature page 
 
 
Investigator: 
 
 
 
Name:  
________________________________________________ 
 
 
 
 
Title:  
________________________________________________ 
 
 
 
 
Signature: 
________________________________________________ 
 
 
 
 
Date:  
________________________________________________ 
 
 
 
Investigator: 
 
 
 
Name:  
________________________________________________ 
 
 
 
 
Title:  
________________________________________________ 
 
 
 
 
Signature: 
________________________________________________ 
 
 
 
 
Date:  
________________________________________________ 
 
 

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2017 24;19:50. 
6: Degreef I. Collagenase Treatment in Dupuytren Contractures: A Review of the Current State Versus 
Future Needs. Rheumatol Ther. 2016;3:43-51.  
7: Dhillon S. Collagenase Clostridium Histolyticum: A Review in Peyronie's Disease. Drugs. 
2015;75:1405-12. 
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histolyticum and fasciectomy for Dupuytren's contracture. J Hand Surg Eur Vol. 2015;40:141-9. 
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Treatment of Urologic Disease: Current and Future Impact. Sex Med Rev.  2018;6:143-156.