Clinical trial NCT06180382: Comparison of Vedolizumab Treatment to Adalimumab Dose Intensification in Crohn's Disease Patients With Loss of Response or Biomarker Activity to Adalimumab on First Line With Therapeutic Drug Concentration.
Official title: Comparison of Vedolizumab Treatment to Adalimumab Dose Intensification in Crohn's Disease Patients With Loss of Response or Biomarker Activity to Adalimumab on First Line With Therapeutic Drug Concentration: A Randomized, Multicentre, Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Crohn's Disease
Keywords: Crohn's disease
Adalimumab
Vedolizumab
therapeutic strategy
Efficacy
biomarker
Lead sponsor: Centre Hospitalier Universitaire de Saint Etienne
Sponsor class: OTHER
Collaborators: name: Takeda France
First posted: 2023-12-22
Enrollment: 220
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomization comparing 2 therapeutic strategies
Primary purpose: TREATMENT

Brief summary: A substantial fraction of IBD patients with an initial response to infliximab or adalimumab later experience re-emerging active disease despite ongoing anti-Tumour Necrosis Factor (TNF) agents maintenance therapy. The optimal intervention in patients with secondary loss-of-response (LOR) is still poorly defined, as there are still scant data on how best to choose the next intervention from among dose-intensification, switch to another anti-TNF or switch out of the anti-TNF class. Moreover, according to STRIDE 2 recommendations and CALM study, optimize patients based solely on lack of biological remission (CRP, calprotectin) can be discuss. If CALM study has showed that the intervention arm based on regular monitoring fecal calprotectin, CRP and/or CDAI to optimize patients under adalimumab was significantly associated to an increase rate of mucosal healing that the standard of care strategy based on only clinical activity, TDM was not available to guide drug optimization strategy.

Detailed description: To address these issues, for IFX or ADA therapy, several studies have proposed some algorithms according to which interventions are based on a combined assessment of IFX or ADA drug level and antibodies-to-IFX or ADA (ATI or AAA) levels at the time of therapeutic failure. Thus, IFX or ADA levels, classified as therapeutic or sub-therapeutic, and detectable or undetectable antibodies, are used to assess if LOR is likely due to immunogenicity, to non-immune-mediated pharmacokinetic problems or due to pharmacodynamic issues, and to guide interventions accordingly.

In the last AGA recommendations, the authors suggested that in case of secondary LOR under anti TNF drug with therapeutic levels to switch to another class (such as vedolizumab). However, recent studies showed that optimization of dose regimen of the same anti-TNF in these patients may still be associated with clinical response in 25% of patients. Indeed, in a recent bicentric, retrospective and non-randomized study, the investigators showed that IBD patients under ADA maintenance therapy who experience a secondary loss of response and in whom trough levels are \>4.9µg/mL, swapping to another class was significantly better than optimizing ADA, in term of time without discontinuation of treatment.

Eligibility criteria: Inclusion Criteria:

* Major patient and having given consent to participate in the study
* Patients with Crohn's disease who have responded primary to Adalimumab princeps or similar bio with loss of response to Adalimumab (40 mg every two weeks) with therapeutically adequate levels of ADA (\> 7.5 μg/mL).
* Patient affiliated to or entitled under a social security scheme

Exclusion Criteria:

* Pregnant woman
* Patient unable to perform MRI or VCE or ileocolonoscopy or ultrasound less than one month before inclusion
* Previous or current use of vedolizumab or ustekinumab for Crohn's disease or participation in a biological study
* Concomitant use of immunomodulators
* Patients on corticosteroid therapy
* History of cancer
* History of human immunodeficiency virus (HIV), immunodeficiency syndrome, central nervous system (CNS) demyelinating disease (including myelitis), neurological symptoms suggestive of demyelinating disease, chronic recurrent infection, active tuberculosis (received or untreated), severe infections such as sepsis and opportunistic infections
* Patient with ileoanal pouchitis or ileorectal anastomosis
* Patient with short small bowel syndrome as determined by investigator
* Patients receiving total parenteral nutrition (TPN)
* Patients receiving enteral nutrition
* Patient under legal protection or unable to give consent
* Hemorrhagic rectocolitis or indeterminate colitis
* Patients treated with concomitant immunosuppressive agents
* Patient treated with an optimized dose of adalimumab
* Primary non-responder to Adalimumab
* Patient previously treated with infliximab or ustekinumab before adalimumab
* Severe relapse defined by CDAI \> 330
* Patient with anoperineal Crohn's disease
* Crohn's disease patient with transient or permanent stoma.

Primary outcomes:
measure: ADA optimized versus Vedolizumab as second line
timeFrame: Week 24
Secondary outcomes:
measure: Proportion of deep remission
timeFrame: Weeks 0; 24
measure: Proportion of clinical remission
timeFrame: Weeks 0; 24
measure: faecal calprotectin (microG / g)
timeFrame: Week 24
measure: serum C-reactive protein (CRP) mg/l
timeFrame: Week 24
measure: Proportion of endoscopic remissions according to Crohn's Disease Endoscopic Index score (CDEIS)
timeFrame: Week 24
measure: Proportion of endoscopic remissions according to Lewis score
timeFrame: Week 24
measure: Proportion of endoscopic remissions according to the number of ulcerations
timeFrame: Week 24
measure: Proportion of endoscopic remissions according to the Magnetic Resonance Imaging (MRI) activity
timeFrame: Week 24
measure: Proportion of endoscopic remissions according to bowel thickness
timeFrame: Week 24
measure: Treatment failure
timeFrame: Weeks : 24; 52
measure: Adverse events
timeFrame: Week 24
measure: Symptomatic remission at week 24
timeFrame: Week 24
measure: Changes in quality of life score (Inflammatory Bowel Disease Questionnaire (IBDQ)-32
timeFrame: Weeks : 0; 24
measure: Clinical and biomarker remission
timeFrame: Weeks : 12; 52
measure: Mucosal remission
timeFrame: Week 24
measure: Clinical Decision Support Tool (CDST) score
timeFrame: Week 52
Other outcomes:
Locations:
city: Le Kremlin-Bicêtre
country: France
facility: APHP - Hôpital Bicêtre
state: Paris
city: Amiens
country: France
facility: CHU Amiens
city: Lille
country: France
facility: CHRU Lille
city: Limoges
country: France
facility: Chu Limoges
city: Marseille
country: France
facility: APHM
city: Montpellier
country: France
facility: CHU Montpellier
city: Nice
country: France
facility: Hôpital de l'Archet II
city: Paris
country: France
facility: Assistance Publique - Hôpitaux de Paris
city: Pessac
country: France
facility: CHU Bordeaux
city: Pierre-Bénite
country: France
facility: Ch Lyon Sud
city: Rennes
country: France
facility: CHU Rennes
city: Saint-Etienne
country: France
facility: CHU de Saint-Etienne
Study officials:
affiliation: CHU de Saint-Etienne
name: Mathilde BARRAU, MD
role: PRINCIPAL_INVESTIGATOR
References: