Lead Investigator: Sebastian Zundler, University Hospital Erlangen
Title of Proposal Research: Evaluation of the relationship between vedolizumab peripheral blood serum level at week 6 and binary clinical outcomes at week 10/14 – a meta-analysis
Vivli Data Request: 5074
Funding Source: None
Potential Conflicts of Interest: Unrelated from the proposed research, S.Z. received research funding from Takeda, Roche and Shire as well as honoraria from Takeda and Roche. Since this might be perceived as potential conflict of interest, it will be disclosed in any publications.
Summary of the Proposed Research:
Inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis are still medically incurable diseases. Despite therapeutic advances many patients do not respond to available treatments or lose response over time, which causes considerable morbidity. One of the current options for IBD therapy is the anti-a4b7 integrin antibody vedolizumab, which is given in a fixed dose of 300mg iv. Recent studies have shown that the actual vedolizumab exposure that is achieved in patients varies widely. Moreover, many studies have also reported that higher serum concentrations are associated with a higher probability of clinical, endoscopic and/or histological response to vedolizumab. However, some evidence also suggests that very high exposure leads to decreased efficacy of the antibody. Thus, for individualized and optimized patient care, it seems important to determine the optimal range of exposure to vedolizumab. By using therapeutic drug monitoring to increase the exposure to vedolizumab up to optimal therapeutic levels, this might substantially help to improve patient care in the field of IBD.
Statistical Analysis Plan
Endpoints and Covariates
• Primary interest:
Prognostic factor (continuous): Peripheral blood serum level at week 6
Primary Endpoint (binary): Clinical remission at week 10
Secondary Endpoints (binary): Clinical response at week 10, Steroid-free remission at week 10, clinical remission at week 14, clinical response at week 14, steroid-free remission at week 14
• Secondary interest:
Subset: patients with high peripheral blood serum level at week 6
Potential prognostic factors: available baseline variables
Dependent Variable: Serum level at week 6 (categorized)
The following steps will be performed separately for each of the requested studies:
Regard all serum level groups and calculate remission rates at week 10 with 95% confidence interval.
Model-based analysis: Use a generalized additive model with integrated smoothness estimation for the binary outcome “clinical remission at week 14” considering the independent variable “serum level at week 6” by the R-package mgcv and the function gam(). Use bootstrap to achieve a 95% confidence interval for the serum level at which highest remission rates are observed.
Perform analogue analyses for secondary endpoints.
Define serum level groups: Serum level groups are defined dependent on the serum level at week 6 with the highest remission rate at week 14 given by the generalized additive model – denoted by SLbest in the following.
Serum level groups include all patients with
– SLbest ± 5 μg/ml
– (SLbest + 10 μg/ml) ± 5 μg/ml
– (SLbest – 10 μg/ml) ± 5 μg/ml
– (SLbest – 20 μg/ml) ± 5 μg/ml
If there are not enough patients in the groups or if there is a wide range of serum level with equally high remission rates, the planned width of 10 μg/ml is extended.
To explore the potential effect of prognostic factors on serum level at week 6, regard only the two highest serum level groups and use multivariable logistic regression with binary outcome “serum level group” and available baseline variables as independent variables.
Phase III, Multicenter, Randomized, Double-blinded, Placebo-controlled, Parallel-group Study to Examine the Efficacy, Safety, and Pharmacokinetics of Intravenous MLN0002 (300 mg) Infusion in Induction and Maintenance Therapy in Japanese Patients With Moderately or Severely Active Ulcerative Colitis
Study ID: NCT02039505
Sponsor ID: MLN0002/CCT-101
A Phase 3, Randomized, Placebo-Controlled, Blinded, Multicenter Study of the Induction of Clinical Response and Remission by Vedolizumab in Patients With Moderate to Severe Crohn’s Disease
Study ID: NCT01224171
Sponsor ID: C13011
A Phase 3, Randomized, Placebo-Controlled, Blinded, Multicenter Study of the Induction and Maintenance of Clinical Response and Remission by MLN0002 in Patients With Moderate to Severe Ulcerative Colitis
Study ID: NCT00783718
Sponsor ID: C13006
A Phase 3, Randomized, Placebo-Controlled, Blinded, Multicenter Study of the Induction and Maintenance of Clinical Response and Remission by Vedolizumab (MLN0002) in Patients With Moderate to Severe Crohn’s Disease
Study ID: NCT00783692
Sponsor ID: C13007
Becker E, Dedden M, Gall C, et al. Residual homing of α4β7-expressing β1+PI16+ regulatory T cells with potent suppressive activity correlates with exposure-efficacy of vedolizumab. Gut Published Online First: 30 August 2021.