Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT03898661 |
| Other study ID # |
AGO/2018/004 |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
Early Phase 1
|
| First received |
|
| Last updated |
|
| Start date |
March 29, 2019 |
| Est. completion date |
January 1, 2021 |
Study information
| Verified date |
September 2023 |
| Source |
University Hospital, Ghent |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
In this open-label pilot study we want to investigate whether intralaesional injection with
collagenase clostridium histolyticum (XiapexR) into the esophageal stricture followed by
dilation 24 hours later improves the outcome of patients with refractory esophageal
anastomotic strictures as compared to dilation alone (standard of care).
Description:
Local injection of collagenase clostridium histolyticum (XiapexR) for refractory iatrogenic
esophageal strictures: an open-label pilot study.
1. Objective of the study
To investigate whether intralaesional injection with collagenase clostridium
histolyticum (XiapexR) into the esophageal stricture followed by dilation 24 hours later
improves the outcome of patients with refractory esophageal anastomotic strictures as
compared to dilation alone (standard of care).
2. 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. Dysphagia score (0: no dysphagia, able to eat normal diet; 1: moderate passage: able to
eat some solid foods; 2: poor passage: able to eat semi-solid foods only; 3: very poor
passage: able to swallow liquids only; 4: no passage: unable to swallow anything) 5
General information
3.1 Investigator(s)
Prof Dr. Pieter Hindryckx Department of Gastro-Enterology Ghent University Hospital
Pieter.Hindryckx@uzgent.be (+3293320726)
Prof Dr. Danny De Looze Department of Gastro-Enterology Ghent University Hospital
Danny.delooze@uzgent.be
Dr. David Tate Department of Gastro-Enterology Ghent University Hospital David.tate@uzgent.be
3.2 Sponsor
Ghent University Hospital, with a grant of the Belgian Society of Gastrointestinal Endoscopy.
3.3 Departments/laboratories involved in the study
Department of Gastro-enterology Ghent University Hospital, Corneel Heymanslaan 10 9000 Ghent
4 Introduction
The main causes of benign esophageal strictures are inflammatory (reflux disease,
eosinophilic esophagitis, caustic…) or iatrogenic (post-irradiation, post endoscopic
(sub)mucosal resection, post radiofrequency ablation, anastomotic…). Most esophageal
strictures respond well to endoscopic balloon dilation. Nonetheless, more than one third of
patients develop recurrent symptoms after dilation within the first year (1).
Especially iatrogenic strictures can be difficult to treat and often require multiple
dilation sessions to obtain long-term relief of dysphagia (2, 3). According to the Kochman
criteria, a refractory stricture is defined as a cicatricial or fibrotic narrowing of the
esophageal luminal diameter resulting in clinical symptoms of dysphagia, with an inability to
successfully remediate the anatomic problem to a diameter of at least 14 mm over 5 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 once the target diameter of 14 mm has been achieved (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 esophageal iatrogenic 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 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).
5 The present study
5.1 Study design
Proof of concept open pilot study with a historical control cohort.
5.2 Medication
5.2.1 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
5.2.2 Producer
Lonza AG Lonzastrasse 3930 Visp Switzerland
5.2.3 Distributor
Swedish Orphan Biovitrum AB SE-112 76 Stockholm Sweden
5.2.4 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).
5.2.5 Administration way
Intralaesional injection.
5.2.6 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:
5.2.7 Storage conditions
Store in a refrigerator (2°C - 8°C). Do not freeze.
5.2.8 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
5.2.9 Drug accountability
Drug accountability will be documented.
5.3 The subjects
5.3.1 Number of subjects
Active group: 10 patients presenting with iatrogenic esophageal strictures. Control group: A
historical cohort that consists of 40 consecutive patients that received an endoscopic
balloon dilation 12-15mm for an iatrogenic anastomotic stricture at our centre.
5.3.2 Inclusion criteria
The patient is 18-90 years old The patient suffers from dysphagia caused by an iatrogenic
esophageal stricture The stricture is amenable for endoscopic dilation The patient has
undergone at least 1 previous endoscopic dilation for the same stricture The patient has
signed the ICF
5.3.3 Exclusion criteria The patient is not fluent in Dutch
5.3.4 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.
5.3.5 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)
5.3.6 Possible advantages and risks for the subjects
It is possible that participation to the study will result in less need for repeat dilations
for the iatrogenic esophageal strictures (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. 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).
6 Procedures
6.1 Procedures
After informed consent, patients with an iatrogenic esophageal stricture will receive a first
esophagoscopy 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
esophagoscopy 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.
6.2 Flowchart
- Between day -7 to day -1: Informed consent
- 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.
7 Randomisation / blinding
Not Applicable, as this is an open label trial.
8 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
9 Adverse event reporting
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).
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.
