In the present study, we propose to explore whether a Systems Medicine approach can identify biomarkers that predict the clinical outcome in patients with Crohn*s disease in whom vedolizumab is started.
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To identify biomarkers predicting response to vedolizumab in patients with CD
Secondary outcome
Clinical response at 20 weeks, after induction therapy with vedolizumab defined
as a reduction in the Harvey Bradshaw Index (HBI) score of at least 3 points
-To gain insight in pathways, associated with (non)reponse to vedolizumab in
patients with CD -Remission at 20 weeks, defined as a HBI < 4 -Sustained
clinical benefit at 52 weeks, i.e. persistent clinical improvement under
vedolizumab treatment during follow-up without need for new courses of
corticosteroids or any other systemic drug (azathioprine, methotrexate,
anti-TNF or investigational drugs), or surgery -Molecular handprint defining
response to therapy -Calprotectin < 100 mg/mL at 1 year -CRP< 5 mg/mL at 1 year
-HBI at 1 year -Change in IBDQ and EQ5D
Background summary
The introduction of monoclonal antibodies (ani-TNFs) has revolutionized the
treatment of the disease. Unfortunately, the success of these agents is
hampered by loss of response in a significant proportion of patients. Since
2015, vedoliumab, an integrin α4β7 antagonist, has been registered for the
treatment of inflammatory bowel disease. This drug is well tolerated by
patients and has a very favorable safety profile. Response rates range from 31%
for patients with Crohn's disease to 47% for ulcerative colitis at week six in
the original studies. Cumulative rates after one year for clinical remission,
mucosal healing, and deep remission are 58.4%, 38.9%, and 28.3%, respectively.
Unfortunately, a large group of patients do not respond to vedolizumab. Since
the use of vedolizumab is associated with significant financial expenditures,
toolsare needed to help predict who will and who will not respond on the drug.
Systems Medicine is an approach, which exploits a multitude of *OMICS* layers
(transcriptome, genome, proteome, metabolome and epigenome of individual cells
in addition to the fecal microbiome and metabolome) and ultimately integrates
these data layers with sophisticated computational approaches to an underlying
network of nodes leading to disease. Previously, our group successfully applied
an element of this approach to reveal an important initial insight as to how
altered plasmacytoid dendritic cells function contributes to pathology in
scleroderma. In addition, using this approach we were recently able to identify
the molecular pathways that identify rheumatoid arthritis patients that could
stop anti-TNF therapy successfully
Study objective
In the present study, we propose to explore whether a Systems Medicine approach
can identify biomarkers that predict the clinical outcome in patients with
Crohn*s disease in whom vedolizumab is started.
Study design
Treatment: Vedolizumab 300 mg according to standard treatment regimen
Safety precautions: Routine screening prior to starting vedolizumab:
-Feces on bacterial pathogens using PCR and clostridium toxin, X-Thorax,
Mantoux, Quantiferon test
Research procedures: Prior to initiation of vedolizumab treatment (base line
assays): All patients undergo routine colonoscopy to objectify disease activity
as part of routine care. Eight additional biopsies will be collected during
this procedure and stored at -80C. Stool and blood samples will be taken for
Systems Medicine and the two faecal samples will be frozen for microbiome
analysis. Clinical disease activity will be determined by the HBI. Blood count,
CRP and faecal protectin will be determined in the context of routine care.
Patients will be asked to complete three questionnaires: the EuroQOL five
dimensions questionnaire (EQ5D), PRO-3 and the Inflammatory Bowel Disease
Questionnaire (IBDQ).
Follow up: At week 6, 40 mL of blood will be drawn from the infusion before the
vedolizumab is administered, and trough levels will be determined.
Fecal samples will again be requested for microbiome determination at weeks 20
and 52 after the start of treatment. 40 mL of blood will be drawn for the
study. Patients will be asked to complete three questionnaires: the EuroQOL
five dimensions questionnaire (EQ5D), the Inflammatory Bowel Disease
Questionnaire (IBDQ) and the PRO-3. Clinical disease activity will be
determined by the HBI.
After 1 year or in the event of a clinical flare-up, a further colonoscopy will
be repeated to assess disease activity. Eight additional biopsies will be taken
again.
Study burden and risks
Minimal burden, no risks Extra: Questionnaires and collecting stoolsamples
Minimal risk associated with obtaining extra biopsies during routine
colonoscopies
Heidelberglaan 100
Utrecht 3584CX
NL
Heidelberglaan 100
Utrecht 3584CX
NL
Listed location countries
Age
Inclusion criteria
- Confirmed and active Crohn*s disease defined as follows
o HBI > 4 and at least 2 of the following
* CRP > 10
* calprotectine > 150
* Endoscopic active disease
* Active disease on MRI-enterography
- Age > 18 year
- Anti-TNF naive or exposed (infliximab and/or adalimumab)
Exclusion criteria
- No consent to participate in the study
- Active perianal disease
- Prior vedolizumab or ustekinumab therapy
- Recent use of antibiotics (within 4 weeks of baseline)
- Hospitalised patients or patients in need of surgery
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| Other | NL6439 |
| CCMO | NL74279.041.20 |
| OMON | NL-OMON25264 |