Precise Infliximab Exposure and Pharmacodynamic Control

Study Overview
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Brief Summary
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Approximately 3 million people in the United States are living with inflammatory bowel disease, which includes Crohn's Disease (CD). There are limited treatment options approved for use in children and adults with Crohn's disease. Physicians need better ways to inform decisions on treatment. The main reason for this research study is to determine if a computer program that calculates an individualized dose based on a patient's blood testing results (precision dosing) can better achieve the best possible response to infliximab compared to standard dosing (conventional dosing).

Detailed Description
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This is an open-label, cluster randomized clinical trial to test whether precision infliximab dosing with a targeted concentration intervention is superior in achieving deep remission (endoscopic healing and clinical remission) compared to patients receiving conventional infliximab dosing. With recognition that CD patients who achieve the target of deep remission with anti-TNF dose optimizations following pharmacodynamic monitoring had a significant reduction in CD-related adverse events, our central hypothesis is precision dosing with infliximab during induction and maintenance will achieve superior rates of deep remission vs. conventional care (control arm)

Official Title
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Precise Infliximab Exposure and Pharmacodynamic Control to Achieve Deep Remission in Pediatric Crohn's Disease

Conditions
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Crohn Disease

Intervention / Treatment
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* Device: RoadMAB
* Drug: Infliximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent from the patient (≥18 years old) or from parent/legal guardian if patient is <18 years old Written informed assent from patient when age appropriate Diagnosis of Crohn's disease within the last 90 days (luminal-only or luminal with a perianal fistula or abscess treated with antibiotics for at least 7 days) ≥6 years to ≤22 years of age, anti-TNF naïve and starting infliximab Clinical activity and luminal inflammation, defined by both (1) and (2) (1) PCDAI≥10 (<18 years old) or CDAI ≥150 (≥18 years old) in last 60 days before the decision to start infliximab (2) SES-CD>6, or SES-CD>3 for isolated ileal disease (or a report of large intestinal ulcerations)* within the last 60 days or a fecal calprotectin >250 μg/g within last 60 days before the decision to start infliximab C-reactive protein >0.5 mg/dL in last 30 days and/or fecal calprotectin >250 μg/g within last 60 days before the decision to start infliximab Negative TB (tuberculosis) interferon-gamma release test and a negative urine pregnancy test for female patients (if menstruation has started) Exclusion Criteria: Diagnosis of ulcerative colitis or inflammatory bowel disease-unspecified Prior use of anti-TNF therapy (infliximab, adalimumab, certolizumab pegol, or golimumab) Internal (abdominal/pelvic) penetrating fistula(e) in last 180 days Intra-abdominal abscess/phlegmon/inflammatory mass in the last 180 days Active perianal abscess (receiving oral antibiotics for <7 days) Intestinal stricture (luminal narrowing with pre-stenotic dilation >3 cm) and surgery planned in the next 90 days Clostridium difficile infection or other intestinal infection in the last 1-week or a severe infection in the last 90 days. Severe infection is defined as requiring hospitalization for treatment or a vancomycin taper. Current hospitalization for complications of severe Crohn's disease Planned use of methotrexate or 6-mercaptopurine (azathioprine) during the induction (first 3 doses of infliximab) phase Current ileostomy, colostomy, ileoanal pouch, and/or previous extensive small bowel resection (>35 cm) or any CD surgery planned within the next 90 days History of autoimmune hepatitis, primary sclerosing cholangitis, thyroiditis, or juvenile idiopathic arthritis Treatment with another investigational drug in the last four weeks History of malignancy (including lymphoma or leukemia) Currently receiving treatment for histoplasmosis History of TB, human immunodeficiency virus (HIV), an immunodeficiency syndrome, a central nervous system demyelinating disease, history of heart failure or receiving intravenous antibiotics in last 14 days for any infection Currently pregnant, breast feeding or plans to become pregnant in the next 1 year Inability or failure to provide informed assent/consent Any developmental disabilities that would impede providing assent/consent

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 22 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients newly diagnosed with Crohn's disease (ages 6-22 years inclusive) within the last 90 days AND starting infliximab
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Conventional dosing<br>Induction Phase: 5-7.5 mg/kg at 0, 2, and 6 weeks. Maintenance Phase : 5-10 mg/kg at every 4-8 weeks based on results of drug concentration monitoring for a flat target of 5-10 μg/mL. | Drug: Infliximab<br>* Conventional dosing. Induction: 5-7.5 mg/kg at 0, 2, and 6 weeks. Maintenance: 5-10 mg/kg at every 4-8 weeks based on results of drug concentration monitoring for a flat target of 5-10 μg/mL. Precision dosing. Induction: 5-12.5 mg/kg at 0, 2, and 6 weeks to target a week6 concentration of 18-24 μg/mL with dosing support provided by the RoadMABTM clinical decision support tool. Maintenance: 5-15 mg/kg every 4-8 weeks to achieve apriori pharmacokinetic and pharmacodynamic targets (CRP, disease activity scores and fecal calprotectin) with dosing support provided by the RoadMABTM clinical decision support tool.<br>* Other names: Renflexis;|
| Experimental: Precision dosing<br>Induction: 5-12.5 mg/kg at 0, 2, and 6 weeks to target a week6 concentration of 18-24 μg/mL with dosing support provided by the RoadMABTM clinical decision support tool. Maintenance: 5-15 mg/kg every 4-8 weeks to achieve apriori pharmacokinetic and pharmacodynamic targets (CRP, disease activity scores and fecal calprotectin) with dosing support provided by the RoadMABTM clinical decision support tool. | Device: RoadMAB<br>* The RoadMAB Dashboard is a real-time decision support system that incorporates PK model-informed Bayesian estimation to provide precision dosing at the point of care.<br>Drug: Infliximab<br>* Conventional dosing. Induction: 5-7.5 mg/kg at 0, 2, and 6 weeks. Maintenance: 5-10 mg/kg at every 4-8 weeks based on results of drug concentration monitoring for a flat target of 5-10 μg/mL. Precision dosing. Induction: 5-12.5 mg/kg at 0, 2, and 6 weeks to target a week6 concentration of 18-24 μg/mL with dosing support provided by the RoadMABTM clinical decision support tool. Maintenance: 5-15 mg/kg every 4-8 weeks to achieve apriori pharmacokinetic and pharmacodynamic targets (CRP, disease activity scores and fecal calprotectin) with dosing support provided by the RoadMABTM clinical decision support tool.<br>* Other names: Renflexis;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Deep Remission | Pediatric Crohn's disease activity index (PCDAI) <10 (child) or Crohn's disease activity index<150 (adult), off prednisone/budesonide for >8 weeks and Simple Endoscopic Scorer Crohn's Disease (SES-CD) SES-CD≤2 | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Steroid-free Clinical Remission | Pediatric Crohn's disease activity index (PCDAI) <10 (child) or Crohn's disease activity index<150 (adult) and off prednisone/budesonide for ≥4 weeks | Week 14 and Week 52 | 
| Rate of Clinical Response | Decrease from baseline pediatric Crohn's disease activity index (PCDAI) of at least 12.5 points & total PCDAI<30 or a PCDAI<10 (child) or a reduction of Crohn's disease activity index>70 from baseline or CDAI<150 (adult) | Week 14 and Week 52 | 
| Rate of Primary Clinical Nonresponse | On prednisone >16 consecutive weeks from start of infliximab or a pediatric Crohn's disease activity index>30 or CDAI>220 for first four infusions | Week 16 | 
| Rate of Primary Biologic Nonresponse | Failure to improve baseline fecal calprotectin by >100 μg/g (limited to patients with a baseline fecal calprotectin >250 μg/g) or Failure to improve baseline c-reactive protein ≥0.5 mg/dL (limited to patients with a baseline c-reactive protein >1.0 mg/dL) | Week 16 | 
| Rate of Sustained Steroid-free Remission | Pediatric Crohn's disease activity index (PCDAI)<10 (child) or Crohn's disease activity index<150 (adult) at dose5 to week52 and off prednisone/budesonide from week 22-52 | Week 22 - Week 52 | 
| Rate of Steroid-free Remission -biomarker composite | Pediatric Crohn's disease activity index (PCDAI)<10 (child) or Crohn's disease activity index<150 (adult), off prednisone/budesonide for ≥4 weeks, CRP≤0.5 mg/dL and fecal calprotectin <250 μg/g3 | Week 14 and Week 52 | 
| Rate of Endoscopic Healing | Simple endoscopic score-Crohn's disease ≤2 | Week 52 | 
| Rate of Complete Endoscopic Healing | Simple endoscopic score-Crohn's disease=0 | Week 52 | 
| Rate of Endoscopic Remission | Simple endoscopic score-Crohn's disease<4 | Week 52 | 
| Rate of Mucosal Healing | Simple endoscopic score-Crohn's disease ≤2 and Ileal Global Histologic Activity Score (GHAS)/ Colon Global Histologic Activity Score (CGHAS) ≤2 | Week 52 | 
| PK Model Bias | Model predicted vs. actual infliximab concentration Bias: mean predictive error (MPE) | Week 0 - Week 84 | 
| PK Model Precision | Model predicted vs. actual infliximab concentration Precision: root mean squared error (RMSE) | Week 0 - Week 84 | 
| Rate of IBD related event - Fistula | Occurrence of fistula and presence of antibody to infliximab >200 ng/mL | Week 0 - Week 52 | 
| Rate of IBD related - Hospitalization | Occurrence of Crohn's disease related hospitalization | Week 0 - Week 52 | 
| Rate of IBD related event - Surgery | Occurrence of Crohn's disease related Surgery | Week 0 - Week 52 | 
| Rate of IBD related event - Intestinal stricture | Occurrence of Crohn's disease related intestinal stricture | Week 0 - Week 52 | 
| Rate of IBD related event - Starting corticosteroids | Occurrence of subjects starting a corticosteroid after week20 | Week 0 - Week 52 | 
| Rate of IBD related event - Antibodies to infliximab | Occurrence of antibodies to infliximab defined as >200 ng/mL | Week 0 - Week 52 | 
| Rate of Growth Restoration - Weight change | In Tanner stage I-III subjects: change in baseline weight (kg) by gender and age group | Week 14 - Week 52 | 
| Rate of Growth Restoration- Height velocity | In Tanner stage I-III subjects: change in height velocity (zscore) by gender | Week 14 - Week 52 | 
| PK of infliximab in pediatric patients | Measured infliximab clearance at baseline and at week52 | Week 0 - Week 52 | 
| Correlation between infliximab induction exposure and endoscopic remission | The correlation analysis to be performed for the total area under the curve (infliximab exposure, μg*h/mL from week0-week14) and patients achieving endoscopic remission. Endoscopic remission is defined as a Simple Endoscopic Scorer Crohn's Disease (SES-CD) ≤2. | Exposure Week 0 - Week 14, Efficacy Week 54 | 
| Correlation between infliximab induction exposure and deep remission | The correlation analysis to be performed for the total area under the curve (infliximab exposure, μg*h/mL from week0-week14) and patients in deep remission. Deep remission is defined as a Pediatric Crohn's disease activity index (PCDAI) <10 (child) or Crohn's disease activity index<150 (adult), off prednisone/budesonide for >8 weeks and Simple Endoscopic Scorer Crohn's Disease (SES-CD) ≤2. | Exposure Week 0 - Week 14, Efficacy Week 54 | 
| Patient Reported Outcome-2 (PRO2) Response | defined as a >50% improvement in total score from baseline | Week 6, Week 14, Week 26, Week 52 | 
| Patient Reported Outcome-2 (PRO2) Remission | defined as a stool frequency ≤3.0 and abdominal pain ≤1.0 (from baseline) | Week 6, Week 14, Week 26, Week 52 | 
| Quality of Life & Disability -IMPACT-III score | Total IMPACT-III (child) score | Week 52 | 
| Quality of Life & Disability - Inflammatory Bowel Disease Disk score | Total Inflammatory Bowel Disease Disk (without sexual function assessment) score | Week 52 | 
| Quality of Life & Disability - Short Inflammatory Bowel Disease score | Total Short IBD Questionnaire (adult) score | Week 52 | 
| Process Evaluation -Usability of Decision Support Tool | Total System Usability Scale score | Week 0 - Week 52 | 
| Rate of Adverse events | Number of Adverse Events | Week 0 - Week 52 | 
| Rate of Serious Adverse events | Number of Serious Adverse Events | Week 0 - Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Crohn's