Clinical trial NCT03724929: Value of Pharmacokinetic Assays in the Prediction of Therapeutic Response in Ulcerative Colitis
Official title: Value of Pharmacokinetic Assays (Vedolizumab and Anti-vedolizumab Antibody) in the Prediction of Induction and Maintenance Therapeutic Response in Ulcerative Colitis
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Ulcerative Colitis
Keywords: Ulcerative Colitis
Vedolizumab
anti-vedolizumab
Lead sponsor: Centre Hospitalier Universitaire de Saint Etienne
Sponsor class: OTHER
Collaborators: name: Takeda
name: Theradiag
First posted: 2018-10-30
Enrollment: 67
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: Vedolizumab (VDZ) is a monoclonal antibody that binds to the heterodimer α4β7 integrin and which has shown its efficacy in Ulcerative Colitis (UC) by inducing and maintaining clinical response/remission. The French marketing authorization was obtained for Ulcerative Colitis in patients in failure with anti-Tumor Necrosis Factor (anti-TNF) agents. In the pivotal study, correlation between drug levels and clinical response during induction and maintenance therapy were reported. Moreover, in 3.7% of cases, anti-vedolizumab antibodies were reported during the time-course and 1% had samples that were persistently positive. Up to now, data on the pharmacologic VDZ parameters are scarce and the relationships as well as the predictive value of the measurement of VDZ concentrations and VDZ monoclonal antibodies (mAbs) during the induction and maintenance phases remains unknown. It could be of paramount interest to early identify UC patients under VDZ who will be responders to VDZ induction and to identify those who will achieve clinical remission under maintenance therapy with VDZ.

Detailed description: The contribution of the pharmacokinetic studies of monoclonal antibodies (anti-TNF antibodies currently) has assumed increasing importance of its use in clinical practice. Therapeutic algorithms for both Infliximab (IFX) and Adalimumab (ADA) have been published and are used by many expert teams in the event of loss of therapeutic response. Similarly, the concentrations are assuming important in the indication of therapeutic de-escalation. Lastly, the assays may predict medium-term therapeutic response to treatment and thus enable proposal of preventive therapeutic changes (5). The Gemini 1 study (phase 3 vedolizumab vs. placebo in Ulcerative Colitis) showed a correlation between drug levels and clinical response during induction and maintenance therapy. Moreover, in 3.7% of cases, anti-vedolizumab antibodies were reported during the time-course and 1% had samples that were persistently positive. (1). In addition, we have decided to assess the clinical response to VDZ induction at W10 (Week 10), as the Gemini III trial for Crohn Disease (Crohn Disease) have reported, among patients who had experienced previous Tumor Necrosis Factor (TNF) antagonist failure, that 15% of those given vedolizumab versus 12% under placebo were in remission at W6 (P=0.433) whereas a higher proportion of them were in remission (26%) under VDZ when compared with the placebo arm (12%) at week 10. Therefore, in clinically non-responders at W10, an additional dose of 300 mg of VDZ will be infused at W10 and every four weeks.

Eligibility criteria: Inclusion Criteria:

* Aged over 18 years
* Men or non-pregnant women
* Patients with a diagnosis of ulcerative colitis who requires to start VDZ
* Moderate to severe active ulcerative colitis defined as a total mayo score ranging from 6 to 12 and endoscopic Mayo score above 1
* UC patients with previous failure with TNF antagonist agents and unacceptable side-effects from steroids, and/or immunosuppressive agents (i.e., azathioprine, 6-mercaptopurine, or methotrexate).
* oral prednisone, are allowed at stable dose for at least 4 weeks-before inclusion. Concomitant immunosuppressive agents, mesalamine, are allowed at stable dose for at least three months before inclusion. Steroid tapering has to be set up at Week 6 after starting VDZ, according to the European Crohn's and Colitis Organisation (ECCO) recommendations.
* Informed written consent given.

Exclusion Criteria:

* Existing pregnancy, lactation, or intended pregnancy within the next 15 months
* Minors or History of disease, including mental/emotional disorder that might interfere with their participation in the study
* Serious secondary illnesses of an acute or chronic nature, which in the opinion of the investigator renders the patient unsuitable for inclusion into the study
* Inability to comply with the protocol requirements
* Inability to fill in the diary cards during the last 3 days before each visit
* Severe Acute UC needed hospitalisation
* Known previous or concurrent malignancy (other than that considered surgically cured, with no evidence for recurrence for 5 years)
* Short bowel syndrome
* Previous treatments with vedolizumab, natalizumab, efalizumab or rituximab.
* Previous treatment with adalimumab within 30 days prior enrollment or infliximab and certolizumab pegol within 60 days before enrollment (This period may be shortened in the opinion of the investigator.)
* Prior extensive colonic resection, obstructive (symptomatic) intestinal stricture, abdominal abscess, active or latent tuberculosis,
* Clostridium difficile superinfection;
* Indeterminate colitis
* Concomitant leukocyte apheresis.
* Any contraindication to vedolizumab therapy
* Patients who denied the protocol, not ability to accept or sign consent of the protocol
* Subject involved in another interventional clinical trial

Primary outcomes:
measure: Vedolizumab concentration at week 6
timeFrame: Week 6
Secondary outcomes:
measure: Vedolizumab concentration at week 14
timeFrame: Week 14
measure: vedolizumab concentration and anti-vedolizumab antibodies concentrations at week 2
timeFrame: Week 2
measure: vedolizumab concentration and anti-vedolizumab antibodies concentrations at week 14
timeFrame: Week 14
measure: Vedolizumab concentration at week 6 and mucosal healing
timeFrame: Week 6
measure: Vedolizumab concentration at week 14 and mucosal healing
timeFrame: Week 14
measure: intra and inter-individual heterogeneity of VDZ levels
timeFrame: Week 52
measure: Proportion of loss of clinical response
timeFrame: Week 52
measure: Variation of serum VDZ
timeFrame: Week 52
measure: vedolizumab concentration and anti-vedolizumab antibodies concentrations
timeFrame: Week 52
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHU Amiens
city: Le Kremlin-Bicêtre
country: France
facility: CHU Kremlin Bicêtre
city: Nice
country: France
facility: Chu L'Archet
city: Pierre-Bénite
country: France
facility: Ch Lyon Sud
city: Saint-Étienne
country: France
facility: CHU Saint-Etienne
Study officials:
affiliation: CHU SAINT-ETIENNE
name: Xavier ROBLIN
role: PRINCIPAL_INVESTIGATOR
References: