Precise Infliximab Exposure and Pharmacodynamic Control
- Registration Number
- NCT05660746
- Lead Sponsor
- Children's Hospital Medical Center, Cincinnati
- Brief Summary
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
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)
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 180
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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
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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)
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≥6 years to ≤22 years of age, anti-TNF naïve and starting infliximab
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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 75 days prior to screening
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C-reactive protein >1.0 mg/dL in last 30 days and/or fecal calprotectin >250 μg/g within last 75 days prior to screening
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Negative TB (tuberculosis) interferon-gamma release test and a negative urine pregnancy test for female patients (if menstruation has started)
- 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
- Have tested positive for Clostridium difficile toxin (stool assay) or other intestinal pathogens within 14 days of screening unless a repeat examination is negative and there are no signs of ongoing infection with that pathogen.
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Conventional dosing Infliximab 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. Precision dosing RoadMAB 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. Precision dosing Infliximab 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.
- Primary Outcome Measures
Name Time Method Rate of Deep Remission Week 52 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
- Secondary Outcome Measures
Name Time Method Rate of Complete Endoscopic Healing Week 52 SES-CD=0
Rate of Endoscopic Remission Week 52 SES-CD\<4
Rate of IBD related event - Fistula Week 0 - Week 52 Occurrence of fistula and presence of antibody to infliximab \>200 ng/mL
Rate of Endoscopic Healing Week 52 Simple endoscopic score-Crohn's disease (SES-CD) ≤2
Rate of Clinical Response Week 14 and Week 52 Decrease from baseline PCDAI of at least 12.5 points \& total PCDAI\<30 or a PCDAI\<10 (child) or a reduction of CDAI\>70 from baseline or CDAI\<150 (adult)
Rate of Primary Biologic Nonresponse Week 16 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)
Rate of Steroid-free Clinical Remission Week 14 and Week 52 Pediatric Crohn's disease activity index (PCDAI) \<10 (child) or Crohn's disease activity index(CDAI)\<150 (adult) and off prednisone/budesonide for ≥4 weeks
Rate of Mucosal Healing Week 52 SES-CD≤2 and Ileal Global Histologic Activity Score (GHAS)/ Colon Global Histologic Activity Score (CGHAS) ≤2
PK Model Bias Week 0 - Week 52 Model predicted vs. actual infliximab concentration. Bias: mean predictive error (MPE)
Rate of IBD related event - Intestinal stricture Week 0 - Week 52 Occurrence of Crohn's disease related intestinal stricture
Rate of IBD related event - Starting corticosteroids Week 0 - Week 52 Occurrence of subjects starting a corticosteroid after week20
Rate of Primary Clinical Nonresponse Week 16 On prednisone \>16 consecutive weeks from start of infliximab or a PCDAI\>30 or CDAI\>220 for first four infusions
Rate of Sustained Steroid-free Remission Week 22 - Week 52 PCDAI\<10 (child) or CDAI\<150 (adult) at dose5 to week52 and off prednisone/budesonide from week 22-52
Rate of Steroid-free Remission -biomarker composite Week 14 and Week 52 PCDAI\<10 (child) or CDAI\<150 (adult), off prednisone/budesonide for ≥4 weeks, CRP≤0.5 mg/dL and fecal calprotectin \<250 μg/g
Rate of Growth Restoration - Weight change Week 14 - Week 52 In Tanner stage I-III subjects: change in baseline weight (kg) by gender and age group
PK Model Precision Week 0 - Week 52 Model predicted vs. actual infliximab concentration. Precision: root mean squared error (RMSE)
Rate of IBD related - Hospitalization Week 0 - Week 52 Occurrence of Crohn's disease related hospitalization
Rate of IBD related event - Surgery Week 0 - Week 52 Occurrence of Crohn's disease related surgery
Rate of IBD related event - Antibodies to infliximab Week 0 - Week 52 Occurrence of antibodies to infliximab defined as \>200 ng/mL
Correlation between infliximab induction exposure and endoscopic remission Exposure Week 0 - Week 14, Efficacy Week 52 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 SES-CD≤2.
Correlation between infliximab induction exposure and deep remission Exposure Week 0 - Week 14, Efficacy Week 52 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 PCDAI\<10 (child) or CDAI\<150 (adult), off prednisone/budesonide for \>8 weeks and a SES-CD≤2.
Rate of Serious Adverse events Week 0 - Week 52 Number of Serious Adverse Events
Rate of Growth Restoration- Height velocity Week 14 - Week 52 In Tanner stage I-III subjects: change in height velocity (z-score) by gender
PK of infliximab in pediatric patients Week 0 - Week 52 Measured infliximab clearance at baseline and at week52
Patient Reported Outcome-2 (PRO2) Response Week 6, Week 14, Week 26, Week 52 \>50% improvement in total score from baseline
Quality of Life & Disability -IMPACT-III score Week 52 Total IMPACT-III (child) score
Quality of Life & Disability - Short Inflammatory Bowel Disease score Week 52 Total Short IBD Questionnaire (adult) score
Process Evaluation -Usability of Decision Support Tool Week 0 - Week 52 Total System Usability Scale score
Patient Reported Outcome-2 (PRO2) Remission Week 6, Week 14, Week 26, Week 52 Stool frequency ≤3.0 and abdominal pain ≤1.0 (from baseline)
Rate of Adverse events Week 0 - Week 52 Number of Adverse Events
Quality of Life & Disability - Inflammatory Bowel Disease Disk score Week 52 Total Inflammatory Bowel Disease Disk (without sexual function assessment) score
Trial Locations
- Locations (11)
Children's Specialty Group
🇺🇸Norfolk, Virginia, United States
Children's Hospital of Los Angeles
🇺🇸Los Angeles, California, United States
Lucile Packard Children's Hospital Stanford
🇺🇸Palo Alto, California, United States
Rady Children's Hospital San Diego
🇺🇸San Diego, California, United States
Nemours Children's Health System-Wilmington
🇺🇸Wilmington, Delaware, United States
Nemours Children's Health System-Jacksonville
🇺🇸Jacksonville, Florida, United States
Riley Hospital for Children
🇺🇸Indianapolis, Indiana, United States
Cincinnati Children's Hospital
🇺🇸Cincinnati, Ohio, United States
Cleveland Clinic Children's Hospital
🇺🇸Cleveland, Ohio, United States
Medical College of Wisconsin, Children's of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
Nationwide Children's Hospital
🇺🇸Columbus, Ohio, United States