Clinical trial NCT03679546: EFFICACI : EFFicacy of Intravenous Infliximab Versus Vedolizumab After Failure of subCutaneous Anti-TNF in Patients With UlCerative Colitis
Official title: EFFICACI : EFFicacy of Intravenous Infliximab Versus Vedolizumab After Failure of subCutaneous Anti-TNF in Patients With UlCerative Colitis : A Double Blinded Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Ulcerative Colitis
Lead sponsor: Rennes University Hospital
Sponsor class: OTHER
First posted: 2018-09-20
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A prospective, multicenter, randomized, double blind clinical trial
Primary purpose: TREATMENT

Brief summary: Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) that results from immune dysregulation. Arguably, the development of Tumor Necrosis Factor (TNF) antagonists (including infliximab, adalimumab and golimumab) revolutionized the management of immune-mediated chronic diseases in the past two decades.

However, about one third of patients will not respond to a first anti-TNF treatment and 10% to 30% will loose response to anti-TNF during the follow-up.

Historically, a switch between anti-TNF was performed to recapture remission and response to anti-TNF. Recently, a new biologic therapy blocking another target has been approved and is now reimbursed during ulcerative colitis, namely vedolizumab. Vedolizumab is an anti-integrin agent avoiding the recruitment of lymphocytes specifically in inflamed gut tissue.

Emerging data suggest that a switch of therapeutic class (meaning a change of biologic target with Non-TNF-targeted biologic) in case of clinical failure or insufficient response to anti-TNF may be the best choice. This idea of a switch out of the anti-TNF class is also supported by data on drug monitoring that may help physician decision making in case of loss of response. However, no trial is currently available and ongoing to assess the best therapeutic strategy. The aim of the proposed study is to assess the best biological based strategy in patient losing response to a first subcutaneous anti-TNF (golimumab and/or adalimumab).

Detailed description: Design :

A prospective, multicenter, randomized, double blind clinical trial

Primary objective :

To determine whether a non-TNF-targeted biologic (vedolizumab) is superior to infliximab to treat patient with UC losing response or with a primary failure to a first subcutaneous anti-TNF drug at week 14.

Secondary objective :

* To assess the rate of clinical response and remission at Week 54 in each group of treatments and the time to clinical response and remission from baseline ;
* To assess the changes in faecal calprotectin levels from baseline to week 14 and 54 according to treatment ;
* To assess the rate of colectomy and hospitalization in each treatment group ;
* To assess the rate of mucosal healing at week 14 and 54 in each group of treatments ;
* To assess the rate of loss of response in each group of treatments for patients responder after induction phase ;
* To assess the changes of quality of life indexes and the disability index from baseline to week 14 and 54 ;
* To determine the safety profile of each group of treatments ;
* To characterize the response in each group of treatments according to drug monitoring of the first anti-TNF agent ;
* To describe the pharmacokinetics of infliximab and vedolizumab as second-line treatment of UC and explore the sources of pharmacokinetic inter-individual variability ;
* To identify predictive factors of response to the treatment, including pharmacokinetic features

Expected findings and impact:

The patients include in the clinical will not lose any benefit since both treatments are actually indicated and effective in this condition. In both arm of treatment, patients will receive an effective treatment.

The study will optimize physician decision making to decrease the disease activity period in UC patients with known consequence such as hospitalisation, surgery, work cessations with related cost effects.

Eligibility criteria: Inclusion Criteria:

* Male or non-pregnant female, non-lactating female;
* 18 years of age or older and less than 75 years ;
* Documented diagnosis of UC for at least 6 months ;
* Left side colitis or pancolitis ;
* Moderate to severe disease according to a Mayo score equal or above 6 with a Mayo endoscopic sub-score of 2 or 3 ;
* Active disease despite ongoing treatment with adalimumab or golimumab for at least 12 weeks (inadequate response, failure, loss of response or intolerance) ;
* Ability of the subject to participate fully in all aspects of this clinical trial ;
* Written informed consent must be obtained and documented ;
* Naïve to Janus kinase inhibitor (JAK inhibitor) ;
* Affiliation to the national health insurance.

Non inclusion Criteria:

* Contraindication to continue TNF antagonist (ongoing abscess(es), clinical suspicion of tuberculosis, past allergic reaction) ;
* Contraindication to vedolizumab treatment ;
* Steroid treatment \> 20 mg/day for at least two weeks before baseline ;
* Proctitis ;
* Stoma ;
* Proctocolectomy or subtotal colectomy ;
* Planned surgery within the year of the trial ;
* Previous exposure to vedolizumab or infliximab ;
* History of cancer during the past 5 years ;
* Pregnancy or breastfeeding
* Adults legally protected (under judicial protection, guardianship, or supervision), persons deprived of their liberty.
* Ongoing participation to another interventional study

Primary outcomes:
measure: Remission
timeFrame: Week 14
Secondary outcomes:
measure: Mayo score
timeFrame: Week 54
measure: Faecal calprotectin level
timeFrame: At week 14 and 54
measure: Colectomy or hospitalization for disease flare
timeFrame: through study completion, an average of 1 year
measure: Endoscopic subscore of the mayo Score
timeFrame: at week 14 and 54
measure: Partial Mayo score
timeFrame: at week 2, 6, 14, 54
measure: Inflammatory Bowel Disease Questionnaire (IBDQ) index
timeFrame: at baseline week 14 and 54
measure: Inflammatory Bowel Disease-Disk (IBD-Disk)
timeFrame: at baseline week 14 and 54
measure: Inflammatory Bowel Disease-Disability Index (IBD-DI)
timeFrame: at baseline week 14 and 54
measure: Adverse events
timeFrame: through study completion, an average of 1 year
measure: Last trough concentration of the first subcutaneous agent
timeFrame: baseline
measure: anti-drug antibodies concentration
timeFrame: baseline
measure: Blood trough concentration of infliximab or vedolizumab
timeFrame: at baseline, weeks 0, 2, 6, 14 and 54
measure: Fecal trough concentration of infliximab or vedolizumab
timeFrame: at baseline, weeks 0, 2, 6, 14 and 54
Other outcomes:
Locations:
city: Amiens
country: France
facility: Centre Hospitalier Universitaire d'Amiens-Picardie
city: Besançon
country: France
facility: Centre Hospitalier Universitaire de Besançon
city: Bordeaux
country: France
facility: Centre Hospitalier Universitaire de Bordeaux
city: Caen
country: France
facility: Centre Hospitalier Universitaire de Caen
city: Clermont-Ferrand
country: France
facility: Centre Hospitalier Universitaire de Clermont-Ferrand
city: Clichy
country: France
facility: Assistance Publique des Hôpitaux de Paris - Hôpital Beaujon
city: Créteil
country: France
facility: Assistance Publique des Hôpitaux de Paris - Hôpital Henri Mondor
city: Lille
country: France
facility: Centre Hospitalier Universitaire de Lille
city: Lyon
country: France
facility: Hospices Civils de Lyon
city: Montpellier
country: France
facility: Centre Hospitalier Universitaire de Montpellier
city: Nancy
country: France
facility: Centre Hospitalier Universitaire de Nancy
city: Nantes
country: France
facility: Centre Hospitalier Universitaire de Nantes
city: Nice
country: France
facility: Centre Hospitalier Universitaire de Nice
city: Nîmes
country: France
facility: Centre Hospitalier Universitaire de Nîmes
city: Paris
country: France
facility: Assistance Publique des Hôpitaux de Paris - Hôpital Saint-Louis
city: Saint-Brieuc
country: France
facility: Centre Hospitalier de Saint-Brieuc
city: Saint-Étienne
country: France
facility: Centre Hospitalier Universitaire de Saint-Etienne
city: Toulouse
country: France
facility: Centre Hospitalier Universitaire de Toulouse
Study officials:
affiliation: Rennes University Hospital
name: Guillaume BOUGUEN, MD
role: PRINCIPAL_INVESTIGATOR
References: