A prospective Pilot Intervention Study:
Near-infrared fluorescence molecular endoscopy for elucidating the mechanism of action and predicting response to vedolizumab in IBD using labelled vedoLizumab-8000CW.

Crohn*s Disease (CD) and Ulcerative Colitis (UC) are chronic idiopathic
inflammatory bowel diseases (IBD). Symptoms consist of (bloody) diarrhea,
abdominal and perianal pain. Current drugs are partly effective and have major
limitations. Vedolizumab is a humanized monoclonal antibody against α4β7
integrin capable of blocking the migration of several immune cells across the
endothelium expressing MAdCAM-1. Vedolizumab is less cost effective than
Infliximab (anti-TNFα inhibitor) and therefore, this antibody is only accepted
as a second line biological therapy after anti-TNF failure. Vedolizumab is
promised to be gut specific although until today the specific binding capacity
of vedolizumab is unknown. The University Medical Center Groningen (UMCG)
developed a fluorescent tracer for labeling vedolizumab. This study aims to
gain insight into vedolizumab distribution and concentrations. The current
study has the ambition to identify the vedolizumab target cells in the inflamed
gut inflammation using near-infrared fluorescence molecular endoscopy
(NIR-FME). By gaining insight in local vedolizumab concentrations, distribution
and discovering target cells, we aim to optimize vedolizumab dosing and
predicting response in individual patients.

The primary objective of this pilot intervention study is to gain insight into
vedolizumab distribution and to identify vedolizumab target cells in the
inflamed gut, by performing in- and ex-vivo imaging using a tracer consisting
of fluorescently labeled vedolizumab. We further aim to elucidate the mechanism
of action of vedolizumab and use our findings to predict response to treatment.

The current study is a non-randomized, non-blinded, prospective, single center
phase I intervention study. Patients, with an established diagnosis of UC or CD
with active inflammation, who are scheduled to start vedolizumab therapy, will
be administered with vedolizumab-800CW before the initiation of the vedolizumab
regimen. The tracer will be administered in our study at a microdose level
(4.5mg/30 nmol of fluorescent antibody). Near-infrared (NIR) imaging will be
performed during endoscopic intervention, by the use of a NIR fiber-bundle and
spectroscopy probe, which will be inserted through the working channel of the
standard therapeutic white light endoscope (WLE). Additionally, biopsies of
non-inflamed gut mucosa, inflamed tissue and of surrounding fluorescent tissue
(if present) will be taken. Standardized fluorescence readings will be
validated against histopathology on biopsied specimen from normal mucosa,
inflamed mucosa (based on WLE conclusions) and areas exhibiting increased
fluorescence signal during FME. Ex-vivo CITE-seq will be performed to elucidate
vedolizumab which cells can bind vedolizumab. An interim analysis of the
primary endpoint results will be performed after 5 patients haven been
included, before continuing the study. In case of insufficient fluorescent
signal, the follow-up of the study will include a dose-optimization part, in
which tracer dose can be increased, and/or a non-labeled blocking dose can be
added. All groups in all arms within the dose-escalation study will contain the
same amount of patients. During the interim analysis the safety will be
evaluated, the dose escalation study will only start if the tracer has been
found safe.
After the study procedures, patients will be treated with vedolizumab following
the standard clinical care.

Negative control arm:
Five patients will not receive vedolizumab-800CW prior to the FME procedure.
These patients will be included to investigate the autofluorescent signals of
in the gut.

Therapy arm
During the interim analysis, safety and fluorescence intensity will be
evaluated. In case no adverse events are seen and the fluorescence intensity is
considered to be optimal we will continue inclusion. After the interim
analysis, 10 patients on vedolizumab therapy will be included in the study.
Patients must be treated for at least 14 weeks before they can be included in
this study-arm. Both, patients already included in the study prior to
vedolizumab therapy and patients who were not included prior to vedolizumab
therapy can be included.
According to clinical standard care an IBD patient treated with vedolizumab
will be sheduled for a follow-up endoscopic procedure between week 10 to week
30 weeks of treatment. The exact date is dependent of (clinical) response to
treatment, not the current study or the involved researchers, but the medical
doctor together with the patient will discuss the date for a follow-up
endoscopic procedure. If patients are included they receive 2-4 days prior to
the FME procedure 15mg vedolizumab, which is considerded the optimal dose.

Patients will be, 2 to 4 days prior to the endoscopic procedure, intravenously
administrerd with the tracer vedolizumab-800CW. Where after fluorescence
endocopy, MDSFR/SFF spectroscopy and confocale laser endomicroscopy (CLE) will
be perfomed endoscopically. Furthermore we will collect biopsies for research
purposes. Patients will be sedated during the endoscopic prodedure following
standard clinical care procedures.

For the participating patients, there is no diagnostic or treatment benefit
related to the study. Participation may possibly produce useful scientific data
for the future. Risks related to the administration of vedolizumab-800CW are
described in the IMPD (version 2.0 June 2020). The risks of the fluorescence
endoscopy procedure are comparable to a clinical endoscopy, and therefore found
to be minimal and negligible.The biopsies taken at fluorescence endoscopy
procedure have a small risk of causing superficial bleeding. Most bleedings
coagulate spontaneously. If not, which is very uncommon, the gastroenterologist
will coagulate the small bleeding. For an extensive structured risk analysis,
see section 13 of the protocol. The procudure will be extended due to the study
with 15 minutes. Patients included in the current study will be sedated for a
longer period compared to the clinical standard procedure. If the patient will
be completely sedated, a team of anesthesiology collegues will monitor all the
vitals during the procedure.