Value of Pharmacokinetic Assays in the Prediction of Induction and Maintenance Therapeutic Response in Crohn's Disease

NCT ID: NCT02768532

Last Updated: 2023-06-15

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE4
• Total Enrollment: 47 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-07-01
• Study Completion Date: 2023-01-23

Brief Summary

Vedolizumab (VDZ) is a monoclonal antibody which has shown its efficacy in Crohn's disease by inducing and maintaining clinical response/remission. The French marketing authorization was obtained for Crohn's disease in patients in failure with anti-TNF (Tumor Necrosis Factor) agents.

For Crohn's disease patients treated with vedolizumab, a strong association between vedolizumab serum levels and clinical response to induction and maintenance was demonstrated by anterior studies.

It could be of paramount interest to early identify Crohn's Disease patients under vedolizumab who will be responders to vedolizumab induction and to identify those who will achieve clinical remission under maintenance therapy with vedolizumab.

Researchers decided to assess the clinical response to vedolizumab induction at week 10. For clinically non-responders at week 10, an additional dose of 300 mg of vedolizumab will be infused at week 10 and then every four weeks.

Detailed Description

Vedolizumab (VDZ) is a monoclonal antibody that binds to the heterodimer alpha 4 beta 7 integrin and which has shown its efficacy in Crohn's disease by inducing and maintaining clinical response/remission. The French marketing authorization was obtained for Crohn's disease in patients in failure with anti-TNF (Tumor Necrosis Factor) agents.

For Crohn's disease patients treated with vedolizumab, a strong association between vedolizumab serum levels and clinical response to induction and maintenance was demonstrated by anterior studies.

It could be of paramount interest to early identify Crohn's Disease patients under vedolizumab who will be responders to vedolizumab induction and to identify those who will achieve clinical remission under maintenance therapy with vedolizumab.

Researchers decided to assess the clinical response to vedolizumab induction at week 10, as the Gemini III trial has reported, among patients who had experienced previous TNF (Tumor Necrosis Factor) antagonist failure. 15% of those given vedolizumab were in remission at week 6 (P=0.433) versus 12% under placebo. At week 10, 26% under vedolizumab were in remission versus 12% in the placebo arm.

Moreover, at week 10, the proportion of patients presenting a clinical response was significantly higher in Crohn's Disease patients treated with vedolizumab (46% vs 24%).

In this study, for clinically non-responders at week 10, an additional dose of 300 mg of vedolizumab will be infused at week 10 and then every four weeks. In a post hoc analysis of GEMINI 2, additional dose of vedolizumab in patients clinically non responders to vedolizumab obtained a clinical remission in 33% of case.

Conditions

Crohn Disease

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Crohn's disease patients

The patients will receive vedolizumab in compliance with the marketing authorization regimen (300 mg at weeks 0, 2, 6 and then every 8 weeks) in Crohn's Disease patients in clinical failure or intolerant to anti-TNF (Tumor Necrosis Factor) drugs. In case of lack of clinical response at week 10 or loss of response in the follow-up, all patients will be optimized with vedolizumab 300 mg at week 10 (additional infusion) and every following 4 weeks in contrast with responder patients at week 10 who will not have vedolizumab infusion at this time-point but will receive the next vedolizumab infusion at week 14 and then every 8 weeks, as recommended.

Group Type: EXPERIMENTAL

Vedolizumab

Intervention Type: DRUG

During each 8 visits (screening, V0, V1, V2, V3, V4, V5, V6) at weeks-1, 0, 2, 6, 10, 14, 22, 54, respectively), the following parameters will be systematically recorded: Crohn's disease Activity Index (CDAI), adverse events.

Blood and fecal samples will be systematically collected at weeks 0, 2, 6, 10, 14, 22 and 54 for routine serum ultrasensitive CRP (C-Reactive Protein) and fecal calprotectin assessments and for vedolizumab pharmacokinetic parameters, including the vedolizumab trough levels and the specific anti-Vedolizumab antibodies. In case of loss of response, an additional measurement of serum CRP (C-Reactive Protein), fecal calprotectin and Vedolizumab pharmacologic parameters will be performed.

Interventions

Vedolizumab

During each 8 visits (screening, V0, V1, V2, V3, V4, V5, V6) at weeks-1, 0, 2, 6, 10, 14, 22, 54, respectively), the following parameters will be systematically recorded: Crohn's disease Activity Index (CDAI), adverse events.

Blood and fecal samples will be systematically collected at weeks 0, 2, 6, 10, 14, 22 and 54 for routine serum ultrasensitive CRP (C-Reactive Protein) and fecal calprotectin assessments and for vedolizumab pharmacokinetic parameters, including the vedolizumab trough levels and the specific anti-Vedolizumab antibodies. In case of loss of response, an additional measurement of serum CRP (C-Reactive Protein), fecal calprotectin and Vedolizumab pharmacologic parameters will be performed.

Intervention Type: DRUG

Other Intervention Names

Entyvio

Eligibility Criteria

Inclusion Criteria

• Aged over 18 years
• Men or non-pregnant women
• Patients with a diagnosis of Crohn's disease who requires to start Vedolizumab
• Crohn's disease defined as a Crohn's disease Activity Index (CDAI) > 150 points and/or fecal calprotectin levels > 250 µg/g of stool
• Crohn's Disease patients with previous failure with TNF (Tumor Necrosis Factor) antagonist agents and unacceptable side-effects from steroids, and/or immunosuppressive agents (i.e., azathioprine, 6-mercaptopurine, or methotrexate). In France, Vedolizumab has to be prescribed only in patients in failure or intolerant to anti-TNF.
• Patient taking corticosteroids orally, concomitant immunosuppressive agents, mesalamine, and antibiotics are allowed at stable dose for at least three months before inclusion. Steroid tapering has to be set up at Week 10 after starting Vedolizumab, according to the European Crohn and Colitis Organisation (ECCO) recommendations with a progressive decrease of steroids of 5 mg/day every week until complete withdrawn.
• 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 7 days before each visit
• Presence of an ileo-/colonic stoma
• Patients with known colonic stricture and exclusive or predominant anal or perineal Crohn's disease lesions
• 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 natalizumab, efalizumab or rituximab.
• Prior extensive colonic resection, obstructive (symptomatic) intestinal stricture, abdominal abscess, active or latent tuberculosis,
• Documented 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Theradiag

OTHER

Sponsor Role: collaborator

Takeda

INDUSTRY

Sponsor Role: collaborator

Centre Hospitalier Universitaire de Saint Etienne

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Xavier Roblin, MD

Role: PRINCIPAL_INVESTIGATOR

CHU SAINT-ETIENNE

Locations

CHU Kremlin Bicetre

Paris, Le Kremlin-Bicêtre, France

CHU d'Amiens

Amiens, , France

CHU L'Archet

Nice, , France

CHU Lyon-Sud, Hospices Civils de Lyon, PIERRE-BENITE

Pierre-Bénite, , France

Chu Saint Etienne

Saint-Etienne, , France

Countries

France

Other Identifiers

2016-001587-11

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

1608051

Identifier Type: -

Identifier Source: org_study_id