Value of Pharmacokinetic Assays in the Prediction of Therapeutic Response in Ulcerative Colitis

NCT ID: NCT03724929

Last Updated: 2023-05-23

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: NA
• Total Enrollment: 67 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-03-04
• Study Completion Date: 2022-06-28

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.

Conditions

Ulcerative Colitis

Study Design

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

Study Groups

Ulcerative Colitis patients

To determine if the best cut-off points of vedolizumab (VDZ) trough levels measured at W6 capable to identify UC patients who will achieve a clinical response at week 10 with VDZ and also the best cut-off points of VDZ trough levels measured at W14 capable to identify UC patients who will achieve a clinical remission to maintenance therapy with VDZ :

Blood samples will be systematically collected at W0, W2, W6, W14 and W52 for vedolizumab pharmacokinetic parameters, including the vedolizumab trough levels and the specific anti-vedolizumab antibody. A supplementary blood sample will be collected at W10 which is the point where a significant greater number of patients were in remission.

Rectosigmoidoscopy will be performed in each center at time points W0, W10 and W52, to evaluate treatment efficacy.

In cases of loss of response, rectosigmoidoscopy will be performed before and four weeks after optimization.

Group Type: EXPERIMENTAL

Blood sample

Intervention Type: PROCEDURE

Blood samples will be systematically collected at W0, W2, W6, W14 and W52 for vedolizumab pharmacokinetic parameters, including the vedolizumab trough levels and the specific anti-vedolizumab antibody. A supplementary blood sample will be collected at W10 which is the point where a significant greater number of patients were in remission.

Rectosigmoidoscopy

Intervention Type: DEVICE

Rectosigmoidoscopy will be performed in each center at time points W0, W10 and W52.

Interventions

Blood sample

Blood samples will be systematically collected at W0, W2, W6, W14 and W52 for vedolizumab pharmacokinetic parameters, including the vedolizumab trough levels and the specific anti-vedolizumab antibody. A supplementary blood sample will be collected at W10 which is the point where a significant greater number of patients were in remission.

Intervention Type: PROCEDURE

Rectosigmoidoscopy

Rectosigmoidoscopy will be performed in each center at time points W0, W10 and W52.

Intervention Type: DEVICE

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

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

Sponsors

Takeda

INDUSTRY

Sponsor Role: collaborator

Theradiag

OTHER

Sponsor Role: collaborator

Centre Hospitalier Universitaire de Saint Etienne

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Xavier ROBLIN

Role: PRINCIPAL_INVESTIGATOR

CHU SAINT-ETIENNE

Locations

CHU Amiens

Amiens, , France

CHU Kremlin Bicêtre

Le Kremlin-Bicêtre, , France

Chu L'Archet

Nice, , France

Ch Lyon Sud

Pierre-Bénite, , France

CHU Saint-Etienne

Saint-Etienne, , France

Countries

France

Other Identifiers

2018-001051-12

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

1708213

Identifier Type: -

Identifier Source: org_study_id