The Bullseye study XL

Rationale: The introduction of monoclonal antibodies has revolutionized the treatment of Crohn’s disease (CD). Unfortunately, the efficacy of these agents is hampered by loss of response in a considerable number of patients. Since 2015, vedolizumab, an integrin α4β7 antagonist, has been licensed for the treatment of CD and UC. It’s well tolerated and has an overall favourable safety profile. (1) Response rates vary between 31% for CD and 47% for UC at week 6 in the original studies, (2;3) and 12-month cumulative rates of clinical remission, mucosal healing and deep remission are 58.4%, 38.9% and 28.3% respectively. (4) However, a considerable proportion of patients does not respond to vedolizumab. Since the use of vedolizumab is associated with substantial financial expenditures, tools to identify patients in whom the drug will be effective are warranted.
Objective: To explore whether a Systems Medicine approach can identify biomarkers that predict clinical outcomes in patients with Crohn’s disease in whom vedolizumab is started.
Study design: Observational, longitudinal, multicentre study
Study population: Adult Crohn’s disease patients with luminal disease, who are anti-TNF therapy exposed and in whom vedolizumab is initiated.
Intervention (if applicable): This is an observational study
Main study parameters/endpoints: Biomarkers associated with response will be identified, employing a System Medicine approach. Response is defined as a reduction in the Harvey Bradshaw Index (HBI) score of at least 3 points at week 20. The association between the identified biomarkers and clinical response will subsequently be validated in subgroups of patients who are in remission or did not respond to the drug at 20 weeks (HBI < 4) or have or have not a 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 other systemic drugs, such as azathioprine, methotrexate, anti-TNF, investigational drugs, or surgery).
Nature and extent of the burden and risks associated with participation, benefit and group relatedness: During colonoscopy (which is routinely performed before initiating biological therapy), six mucosal biopsies will be obtained for research purposes. At baseline, 40 mL blood, and two faecal samples will be collected. During follow-up, 5 times 20 mL blood and 3 faecal samples will be collected over one year. Follow-up endoscopy at one year will be performed (as usual) to assess mucosal healing. Patients will be asked to undergo an additional proctoscopy with biopsies at week 20 (optional). In case the patient experiences a flare within one year, the extent and severity of the flare will be assessed through endoscopy. An additional six mucosal biopsies will be obtained at each of these endoscopies for research purposes.
Blood withdrawal carries a negligible risk of complications. The risk of bleeding or perforation following the taking of biopsies during colonoscopy is very low, approximately 1 per 1000 colonoscopies. Patients will be asked to complete questionnaires assessing disease activity and quality of life at each follow-up moment (max.15 minutes, 5 times in total).

Response and non-response to vedolizumab can be predicted using biomarkers, identified through a System Medicine approach.

Week 0,6,20 and 52 after start of vedolizumab therapy

This is an observational study. Patients will be treated with vedolizumab as in regular care.