Predicting Response to Vedolizumab in Pediatric Inflammatory Bowel Diseases

Study Overview
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Brief Summary
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Vedolizumab (VDZ) is a humanized immunoglobulin G1 monoclonal antibody acting against α4β7 integrin which modulates lymphocyte trafficking in the gut. Results from the adult GEMINI-1 and GEMINI-2 trials demonstrated clinical efficacy in induction and maintenance of remission in both ulcerative colitis (UC) and Crohn's disease (CD), respectively. Recent real life cohorts in adults support the effectiveness of VDZ in inducing and maintaining remission, both in CD and UC. In pediatrics, there are very limited data on the use of VDZ besides two retrospective case series. Data on immunogenicity and therapeutic drug monitoring (TDM) of VDZ is conflicting in adults and practically non-existent in children. The investigators aim to prospectively explore the real life short and longer term outcomes of VDZ in pediatric IBD (including growth) and to develop a prediction model for treatment success based on VDZ trough levels and other clinical and laboratory variables.

Detailed Description
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This is a multi-center prospective cohort study in which the investigators are aim to enroll 140 children under the age of 18 years, diagnosed with CD, inflammatory bowel disease unclassified (IBDU) or UC (approximately 70 in UC/IBDU and 70 in the CD group) who commenced on Vedolizumab for any reason at the discretion of the treating physician. Patients will be followed up to 3 years at 8 different time points: week 0, week 2, week 6, week 14, week 30, week 54 (1 year), week 108 (2 years) and week 162 (3 years). Blood work will be collected at each visit during the time of venous access insertion for the drug infusion for serum and stool sample will be collected at visits 0, 14, 30, and 54. In addition, at week 0 and 14 whole blood will be collected into a PaxGene tube for gene expression analysis.

Official Title
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Predicting Response to Vedolizumab in Pediatric Inflammatory Bowel Diseases (IBD) Including Drug Levels: a Multi-center Prospective Cohort Study, From the Pediatric IBD Porto Group of European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN)

Conditions
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Crohn's Disease, Ulcerative Colitis, Inflammatory Bowel Disease

Intervention / Treatment
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* Drug: Vedolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children under the age of 18 years. IBD Diagnosis Initiating Vedolizumab therapy Exclusion Criteria: 1. Starting Vedolizumab to prevent post operative recurrence

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vedolizumab<br>IV Vedolizumab 177mg/m2 Body Surface Area (BSA), max. 300mg Induction regimen: 0,2,6 and then every 8 weeks | Drug: Vedolizumab<br> <br> * Other names: Entyvio;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete remission at week 14 | As defined by all three criteria: i. Steroids and Exclusive enteral nutrition (EEN) (defined as >50% of daily calories with enteral nutrition)- free ii. Clinical remission (i.e. weighted Pediatric Crohn's Disease Activity Index (wPCDAI) <12.5 points in CD, and Paediatric Ulcerative Colitis Activity Index (PUCAI) <10 in UC) iii. CRP lower than 1.5 times upper normal limit (UNL) (may be substituted by Erythocytes Sedimentation Rate (ESR) if CRP missing) | weeks 14 | 
| Complete remission at week 30 | As defined by all three criteria: i. Steroids and Exclusive enteral nutrition (EEN) (defined as >50% of daily calories with enteral nutrition)- free ii. Clinical remission (i.e. weighted Pediatric Crohn's Disease Activity Index (wPCDAI) <12.5 points in CD, and Paediatric Ulcerative Colitis Activity Index (PUCAI) <10 in UC) iii. CRP lower than 1.5 times upper normal limit (UNL) (may be substituted by Erythocytes Sedimentation Rate (ESR) if CRP missing) | weeks 30 | 
| Complete remission at week 54 | As defined by all three criteria: i. Steroids and Exclusive enteral nutrition (EEN) (defined as >50% of daily calories with enteral nutrition)- free ii. Clinical remission (i.e. weighted Pediatric Crohn's Disease Activity Index (wPCDAI) <12.5 points in CD, and Paediatric Ulcerative Colitis Activity Index (PUCAI) <10 in UC) iii. CRP lower than 1.5 times upper normal limit (UNL) (may be substituted by Erythocytes Sedimentation Rate (ESR) if CRP missing) | weeks 54 | 
| Complete remission at week 108 | As defined by all three criteria: i. Steroids and Exclusive enteral nutrition (EEN) (defined as >50% of daily calories with enteral nutrition)- free ii. Clinical remission (i.e. weighted Pediatric Crohn's Disease Activity Index (wPCDAI) <12.5 points in CD, and Paediatric Ulcerative Colitis Activity Index (PUCAI) <10 in UC) iii. CRP lower than 1.5 times upper normal limit (UNL) (may be substituted by Erythocytes Sedimentation Rate (ESR) if CRP missing) | weeks 108 | 
| Complete remission at week 162 | As defined by all three criteria: i. Steroids and Exclusive enteral nutrition (EEN) (defined as >50% of daily calories with enteral nutrition)- free ii. Clinical remission (i.e. weighted Pediatric Crohn's Disease Activity Index (wPCDAI) <12.5 points in CD, and Paediatric Ulcerative Colitis Activity Index (PUCAI) <10 in UC) iii. CRP lower than 1.5 times upper normal limit (UNL) (may be substituted by Erythocytes Sedimentation Rate (ESR) if CRP missing) | weeks 162 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Steroid and EEN free clinical remission (without the need for normal CRP) using PCDAI or PUCAI score and concomitant medication list. |  | week 30, week 54, week 108, week 162 | 
| Steroid and EEN free clinical response (without the need for normal CRP) using PCDAI or PUCAI score and concomitant medication list. |  | week 30, week 54, week 108, week 162 | 
| Fecal calprotectin levels | Levels of calprotectin will be measured in the lab using calprotectin kit. | week 30, week 54, week 108, week 162 | 
| serum CRP levels | CRP levels will be measured in the lab | week 30, week 54, week 108, week 162 | 
| Rate of loss of response including drug levels |  | week 30, week 54, week 108, week 162 | 
| Steroid dependency (defined as cumulative use of >4 months in a year with at least one need to increase dose while weaning) |  | week 30, week 54, week 108, week 162 | 
| Adverse events |  | week 30, week 54, week 108, week 162 | 
| Measures of mucosal inflammation as available as part of clinical care using endoscopy, imaging or capsule endoscopy. |  | week 30, week 54, week 108, week 162 | 
| Time to induction of remission |  | week 30, week 54, week 108, week 162 | 
| Longitudinal Physician Global Assessment (PGA) | PGA will be measured using Visual analogue scale (VAS) | week 30, week 54, week 108, week 162 | 
| Height velocity as compared with the year prior to commencing VDZ |  | week 30, week 54, week 108, week 162 | 
| Need for surgical interventions (including resections, colectomy, and dilatations) |  | week 30, week 54, week 108, week 162 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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UC: Ulcerative colitis, VDZ: Vedolizumab, CD: Crohn's disease, TDM: Therapeutic drug monitoring