The primary objective of this study is to establish molecular profiles in lower rectal biopsies as close to the internal fistula orifice tissue and fistula scrapings based on single cell RNA sequencing, cellular protein expression by CyTOF and…
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Presence and amount of inflammatory cell subtypes, stromal cells and
identification of mucosal microbiome in rectal biopsies and fistula scrapings
that relate to prediction of response to treatment for complex perianal Crohn*s
fistulas. Response and remission will be measured by a combination of clinical
and MRI endpoints.
Secondary outcome
- The proportion of patients with a combination of clinical and radiological
remission (defined as fistula drainage assessment (FDA)-100% and remission
according to the MAGNIFI-CD index *) and response (defined as FDA-50% or
remission according to the MAGNIFI-CD index *, or FDA-50% and response
according to the MAGNIFI-CD index*. All other combinations will be scored as
non-responder.
*Cut-off values for response and remission according to the MAGNIFI-CD index
are currently under investigation.
- The proportion of patients with radiological remission defined as a
completely fibrotic tract on MRI at week 26
- The proportion of patients with clinical fistula response and remission
measured by the perianal disease activity index (PDAI; defined as PDAI<=4 for
response and PDAI-50% for remission) at week 26 compared to baseline
- Proportion of patients with symptomatic response and remission measured at
week 26 compared to baseline by resp. a 25% and 50% reduction on a 10 cm
patient scored visual analogue scale of global disease severity
- Proportion of patients with symptomatic response and remission measured by
the IBDQ-32 questionnaire (defined as IBDQ-32 <168 for remission and delta
IBDQ-32 >27 for response) at week 26 compared to baseline
- Proportion of patients with response and remission of quality-of-life
measured by the CAF-QoL questionnaire (Crohn*s Anal Fistula - Quality of Life
score) at week 26 compared to baseline
- Proportion of patients in clinical remission and response for Crohn*s disease
activity at week 0, 9 and 26 measured by the Harvey-Bradshaw Index (HBI;
defined as HBI < or = 4 for remission and HBI - 3 for response)
- Proportion of patients achieving biochemical remission at week 9 and 26
(defined as serum C-reactive protein <5.0 mg/L and fecal calprotectin < 250
mg/g)
- Time to biochemical remission (defined as serum C-reactive protein <5.0 mg/L
and fecal calprotectin < 250 mg/g)
- Proportion of patients with extraintestinal manifestations at week 26 as
compared to baseline
- Adverse events
Background summary
Complex perianal fistulizing Crohn*s disease (pCD) is a frequent and
debilitating complication of Crohn*s disease (CD) with major impact on quality
of life and morbidity. Crohn*s perianal fistulas are challenging to treat as
they are often refractory to conventional medical treatment strategies such as
antibiotics, immunomodulators and biologic drugs, such as anti-tumor necrosis
factor agents (anti-TNF). Furthermore, current fistula treatment algorithms -
in the absence of data - do not include a personalized approach of care. Here
we aim to investigate a novel biomarker assay by a multi-omics approach that
predicts treatment response for patients with complex perianal Crohn*s disease
during different treatment modalities of known efficacy (anti-TNF and
mesenchymal stem cells) and experimental strategies (hyperbaric oxygen
treatment, HBO).
Study objective
The primary objective of this study is to establish molecular profiles in lower
rectal biopsies as close to the internal fistula orifice tissue and fistula
scrapings based on single cell RNA sequencing, cellular protein expression by
CyTOF and microbiome in pCD patients which can predict response to treatment.
Identification of these profiles in peripheral blood should lead to a biomarker
panel that could allow stratification to a more personalized treatment approach
in perianal Crohn*s disease.
Study design
Prospective, monocenter observational cohort study for biomarker research with
a 26-week follow-up will be intensively followed with pelvic MRI, sigmoidoscopy
with biopsies, clinical assessment and fecal and blood sampling.
Study burden and risks
Burden: all subjects need to undergo three moments of clinical evaluation and
investigations, most of these will be scheduled during clinical necessary
hospital visits. Although additional blood and fecal sampling, and an
additional MRI and sigmoidoscopy with biopsies is an extra burden in this
study.
Benefits: patients do not directly benefit from the study procedures, but could
do indirectly if a successful biomarker panel is created in this study.
Meibergdreef 9
Amsterdam 1105AZ
NL
Meibergdreef 9
Amsterdam 1105AZ
NL
Listed location countries
Age
Inclusion criteria
All patients in treatment groups:
1. Confirmed diagnosis of CD with previously or currently documented luminal
inflammation (endoscopy and histopathology)
2. Complex perianal fistula, defined as either involving the upper two-third of
the sphincter complex (i.e., high intersphincteric, high transsphincteric,
suprasphincteric or extrasphincteric course of the fistula tract), having
multiple external openings, are associated with pain or fluctuation suggesting
a perianal abscess or are associated with a rectovaginal fistula or anorectal
stricture or active rectal ulcers, with active drainage (fluid loss on gentle
compression; perianal fistulas that were previously close but that reopened can
be included).
3. Age 16 or older
4. Signed informed consent
Mesenchymal stem cell patients:
5. Failure of conventional fistula treatment (anti-TNF and at least one
surgical closure)
Hyperbaric oxygen patients:
6. Failure of conventional fistula treatment (anti-TNF)
In this observational study we will monitor three control groups at one study
point. The following inclusion criteria will be used.
Patients with cryptoglandular fistulas without CD:
• Active cryptoglandular fistula, either superficial or complex
• No previous documentation of CD activity and a fecal calprotectin <250
• Age 16 y/o or older
Patients with CD with active proctitis and without perianal CD
• Confirmed diagnosis of CD with previously documented luminal inflammation and
rectal ulcerations >5mm (endoscopy and histopathology)
• Age 16 y/o or older
• CD treatment naive patients (i.e., immunomodulators, anti-TNF, other
biologicals)
Patients with CD without proctitis and without perianal CD:
• Confirmed diagnosis of CD with previously documented luminal inflammation
(endoscopy and histopathology), no earlier documentation of rectal ulcerations
>5mm
• Age 16 y/o or older
• CD treatment naive patients (i.e., immunomodulators, anti-TNF, other
biologicals)
Exclusion criteria
1. Patients with Ulcerative Colitis or IBD-U
2. Presence of impassible anal stricture
3. Superficial fistula only
4. Rectovaginal fistulas
5. Patients with ongoing abdominal or undrained perianal abscesses after
repeated examination-under-anesthesia with drainage by incision or seton
placement
6. Patients with a seton in situ >12 months
7. Patients with an stony
8. Enteric pathogens (such as Salmonella, Shigella, Yersinia, Campylobacter and
C. difficile) etected by stool analysis within 2 weeks prior to enrollment or
at screening
9. Active or planned pregnancy
10. Absolute contra-indications to perform MRI (e.g., claustrophobia), for
relative contra-indications (e.g., metal implants) the MRI protocol could be
adjusted upon decision with the treating physicians and patient
11. Contra-indication for endoscopy
12. Active participation in another interventional trial
13. Patients who received any investigational drug in the past 30 days or 5
half-lives, whichever is longer
14. Pregnancy and lactation
15. Patients with a history of colon cancer or colonic dysplasia, unless
sporadic adenoma, which has been removed
16. A history of alcohol or illicit drug use that in the opinion of the
principal investigator (PI) would interfere with study procedures
17. Patients with psychiatric problems that in the opinion of the PI would
interfere with study procedures
18. Patients unable to attend all study visits
19. Patients with a history of non-compliance with clinical study protocols
Anti-TNF patients
20. Patients previously exposed to anti-TNF
21. Previously unacceptable side effects or intolerance to all
immunosuppressants (both thiopurines and methotrexate)
22. Treatment with vedolizumab or ustekinumab within 30 days
23. Active or latent tuberculosis (screening according to national guidelines)
24. Cardiac failure in NYHA stage III-IV
25. History of demyelinating disease
26. Recent live vaccination (<= 4 weeks)
27. Patients with ongoing acute/chronic infection (including but not limited to
HIV, hepatitis B and C) with the exception of chronic herpes labialis or
cervical HPV
28. History of cancer in the last 5 years with the exception of non-melanoma
skin cancer
29. Male patients with negative EBV serology
Mesenchymal stem cell patients:
30. Presence of rectal ulcerations according current indication registration
31. Hypersensitivity to the product, bovine serum or any of the excipients
(Dulbecco*s Modified Eagle*s Medium, containing amino acids, vitamins, salts
and carbohydrates, and human albumin)
Hyperbaric oxygen patients:
32. Unfit for hyperbaric oxygen therapy as assessed by the hyperbaric physician
33. Contraindication for hyperbaric oxygen therapy: sensitivity to barotrauma,
claustrophobia per assessment of hyperbaric oxygen specialists.
Design
Recruitment
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL76851.018.21 |