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Value of Pharmacokinetic Assays in the Prediction of Therapeutic Response in Ulcerative Colitis (PREDIRESPUC)

Primary Purpose

Ulcerative Colitis

Status

Terminated

Phase

Not Applicable

Locations

France

Study Type

Interventional

Intervention

Blood sample

Rectosigmoidoscopy

About this trial

This is an interventional prevention trial for Ulcerative Colitis focused on measuring Ulcerative Colitis, Vedolizumab, anti-vedolizumab

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

CHU Amiens
CHU Kremlin Bicêtre
Chu L'Archet
Ch Lyon Sud
CHU Saint-Etienne

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Ulcerative Colitis patients

Arm Description

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.

Outcomes

Primary Outcome Measures

Vedolizumab concentration at week 6

Determine the optimal threshold of VDZ serum concentration measured at W6 capable to predict the clinical response at week 10 with VDZ.

Secondary Outcome Measures

Vedolizumab concentration at week 14

Determine the optimal threshold of VDZ serum concentration measured at W14 capable to predict the clinical response at week 52 with VDZ.

vedolizumab concentration and anti-vedolizumab antibodies concentrations at week 2

Investigating whether the pharmacokinetic parameters of vedolizumab (serum trough levels concentrations, specific antibody concentrations) measured at W2 are predictive of a clinical response and clinical remission at W10.

vedolizumab concentration and anti-vedolizumab antibodies concentrations at week 14

Investigating whether the pharmacokinetic parameters of vedolizumab (serum trough levels concentrations, specific antibody concentrations) measured at W14 are predictive of a clinical response and clinical remission at W52.

Vedolizumab concentration at week 6 and mucosal healing

Analyzing the value of VDZ trough levels measured at W6 to predict mucosal healing at W10 under induction therapy with VDZ in UC

Vedolizumab concentration at week 14 and mucosal healing

Analyzing the value of VDZ trough levels measured at W14 to predict mucosal healing at W52 under induction therapy with VDZ in UC

intra and inter-individual heterogeneity of VDZ levels

Investigating the intra and inter-individual heterogeneity of VDZ levels within the time-course of VDZ therapy, including the induction and maintenance phases.

Proportion of loss of clinical response

Comparing the proportion of loss of clinical response in responder UC patients as well as in primary non-responders requiring VDZ dose-intensification within one-year of follow-up

Variation of serum VDZ

Assessing the relationships between the variation of serum VDZ trough levels pre- and post-optimization (delta) and the clinical response in primary non-responder patients requiring additional infusions of VDZ.

vedolizumab concentration and anti-vedolizumab antibodies concentrations

Comparing the whole and individual pharmacokinetic parameters (vedolizumab concentration and anti-vedolizumab antibodies concentrations) between patients achieving a clinical remission or not at W52

Full Information

NCT ID

NCT03724929

First Posted

October 29, 2018

Last Updated

May 22, 2023

Sponsor

Centre Hospitalier Universitaire de Saint Etienne

Collaborators

Takeda, Theradiag

1. Study Identification

Unique Protocol Identification Number

NCT03724929

Brief Title

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

Acronym

PREDIRESPUC

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

2. Study Status

Record Verification Date

May 2023

Overall Recruitment Status

Terminated

Why Stopped

The study was stopped due to lack of inclusions

Study Start Date

March 4, 2019 (Actual)

Primary Completion Date

April 15, 2022 (Actual)

Study Completion Date

June 28, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Centre Hospitalier Universitaire de Saint Etienne

Collaborators

Takeda, Theradiag

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Ulcerative Colitis

Keywords

Ulcerative Colitis, Vedolizumab, anti-vedolizumab

7. Study Design

Primary Purpose

Prevention

Study Phase

Not Applicable

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

67 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Ulcerative Colitis patients

Arm Type

Experimental

Arm Description

Intervention Type

Procedure

Intervention Name(s)

Blood sample

Intervention Description

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

Device

Intervention Name(s)

Rectosigmoidoscopy

Intervention Description

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

Primary Outcome Measure Information:

Title

Vedolizumab concentration at week 6

Description

Determine the optimal threshold of VDZ serum concentration measured at W6 capable to predict the clinical response at week 10 with VDZ.

Time Frame

Week 6

Secondary Outcome Measure Information:

Title

Vedolizumab concentration at week 14

Description

Determine the optimal threshold of VDZ serum concentration measured at W14 capable to predict the clinical response at week 52 with VDZ.

Time Frame

Week 14

Title

vedolizumab concentration and anti-vedolizumab antibodies concentrations at week 2

Description

Time Frame

Week 2

Title

vedolizumab concentration and anti-vedolizumab antibodies concentrations at week 14

Description

Time Frame

Week 14

Title

Vedolizumab concentration at week 6 and mucosal healing

Description

Analyzing the value of VDZ trough levels measured at W6 to predict mucosal healing at W10 under induction therapy with VDZ in UC

Time Frame

Week 6

Title

Vedolizumab concentration at week 14 and mucosal healing

Description

Analyzing the value of VDZ trough levels measured at W14 to predict mucosal healing at W52 under induction therapy with VDZ in UC

Time Frame

Week 14

Title

intra and inter-individual heterogeneity of VDZ levels

Description

Investigating the intra and inter-individual heterogeneity of VDZ levels within the time-course of VDZ therapy, including the induction and maintenance phases.

Time Frame

Week 52

Title

Proportion of loss of clinical response

Description

Comparing the proportion of loss of clinical response in responder UC patients as well as in primary non-responders requiring VDZ dose-intensification within one-year of follow-up

Time Frame

Week 52

Title

Variation of serum VDZ

Description

Time Frame

Week 52

Title

vedolizumab concentration and anti-vedolizumab antibodies concentrations

Description

Comparing the whole and individual pharmacokinetic parameters (vedolizumab concentration and anti-vedolizumab antibodies concentrations) between patients achieving a clinical remission or not at W52

Time Frame

Week 52

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Xavier ROBLIN

Organizational Affiliation

CHU Saint-Etienne

Official's Role

Principal Investigator

Facility Information:

Facility Name

CHU Amiens

City

Amiens

ZIP/Postal Code

80000

Country

France

Facility Name

CHU Kremlin Bicêtre

City

Le Kremlin-Bicêtre

ZIP/Postal Code

94270

Country

France

Facility Name

Chu L'Archet

City

Nice

ZIP/Postal Code

06200

Country

France

Facility Name

Ch Lyon Sud

City

Pierre-Bénite

ZIP/Postal Code

69230

Country

France

Facility Name

CHU Saint-Etienne

City

Saint-Étienne

ZIP/Postal Code

42055

Country

France

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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