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

Overview

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.

Interventions

• Drug Adalimumab
  Administration of adalimumab with optimisation either 80 mg every 14 days by subcutaneous injection, or the same dose of 40 mg every 7 days.
• Drug Vedolizumab
  Strategy B: administration of vedolizumab 300mg by infusion at baseline, 14 days, 42 days and 60 days, followed by a dose of 108mg every fortnight by subcutaneous injection.

Primary outcome measures

• ADA optimized versus Vedolizumab as second line [Time frame: Week 24]

Secondary outcome measures (12)

• Proportion of deep remission [Time frame: Weeks 0; 24]
• Proportion of clinical remission [Time frame: Weeks 0; 24]
• faecal calprotectin (microG / g) [Time frame: Week 24]
• serum C-reactive protein (CRP) mg/l [Time frame: Week 24]
• Proportion of endoscopic remissions according to Crohn's Disease Endoscopic Index score (CDEIS) [Time frame: Week 24]
• Proportion of endoscopic remissions according to Lewis score [Time frame: Week 24]
• Proportion of endoscopic remissions according to the number of ulcerations [Time frame: Week 24]
• Proportion of endoscopic remissions according to the Magnetic Resonance Imaging (MRI) activity [Time frame: Week 24]
• Proportion of endoscopic remissions according to bowel thickness [Time frame: Week 24]
• Treatment failure [Time frame: Weeks : 24; 52]
• Adverse events [Time frame: Week 24]
• Symptomatic remission at week 24 [Time frame: Week 24]

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).
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

France · 12 centers

• APHP - Hôpital Bicêtre — Le Kremlin-Bicêtre
• CHU Amiens — Amiens
• CHRU Lille — Lille
• Chu Limoges — Limoges
• APHM — Marseille
• CHU Montpellier — Montpellier
• Hôpital de l'Archet II — Nice
• Assistance Publique - Hôpitaux de Paris — Paris
• … and 4 more centers

Identifiers

NCT: NCT06180382 · 23CH134 · 2023-508154-25-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗