REMODEL-CD: Precise Infliximab Exposure and Pharmacodynamic Control
Study Details
Study Description
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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2/Phase 3 |
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)
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Conventional dosing 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
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.
Other Names:
|
| Experimental: 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. |
Device: RoadMAB
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.
Drug: Infliximab
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.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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
- 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<150 (adult) and off prednisone/budesonide for ≥4 weeks
- Rate of Clinical Response [Week 14 and Week 52]
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)
- Rate of Primary Clinical Nonresponse [Week 16]
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
- 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 Sustained Steroid-free Remission [Week 22 - Week 52]
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
- Rate of Steroid-free Remission -biomarker composite [Week 14 and Week 52]
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
- Rate of Endoscopic Healing [Week 52]
Simple endoscopic score-Crohn's disease ≤2
- Rate of Complete Endoscopic Healing [Week 52]
Simple endoscopic score-Crohn's disease=0
- Rate of Endoscopic Remission [Week 52]
Simple endoscopic score-Crohn's disease<4
- Rate of Mucosal Healing [Week 52]
Simple endoscopic score-Crohn's disease ≤2 and Ileal Global Histologic Activity Score (GHAS)/ Colon Global Histologic Activity Score (CGHAS) ≤2
- PK Model Bias [Week 0 - Week 84]
Model predicted vs. actual infliximab concentration Bias: mean predictive error (MPE)
- PK Model Precision [Week 0 - Week 84]
Model predicted vs. actual infliximab concentration Precision: root mean squared error (RMSE)
- Rate of IBD related event - Fistula [Week 0 - Week 52]
Occurrence of fistula and presence of antibody to infliximab >200 ng/mL
- 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 - 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 IBD related event - Antibodies to infliximab [Week 0 - Week 52]
Occurrence of antibodies to infliximab defined as >200 ng/mL
- 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
- Rate of Growth Restoration- Height velocity [Week 14 - Week 52]
In Tanner stage I-III subjects: change in height velocity (zscore) by gender
- PK of infliximab in pediatric patients [Week 0 - Week 52]
Measured infliximab clearance at baseline and at week52
- Correlation between infliximab induction exposure and endoscopic remission [Exposure Week 0 - Week 14, Efficacy Week 54]
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.
- Correlation between infliximab induction exposure and deep remission [Exposure Week 0 - Week 14, Efficacy Week 54]
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.
- Patient Reported Outcome-2 (PRO2) Response [Week 6, Week 14, Week 26, Week 52]
defined as a >50% improvement in total score from baseline
- Patient Reported Outcome-2 (PRO2) Remission [Week 6, Week 14, Week 26, Week 52]
defined as a stool frequency ≤3.0 and abdominal pain ≤1.0 (from baseline)
- Quality of Life & Disability -IMPACT-III score [Week 52]
Total IMPACT-III (child) score
- Quality of Life & Disability - Inflammatory Bowel Disease Disk score [Week 52]
Total Inflammatory Bowel Disease Disk (without sexual function assessment) 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
- Rate of Adverse events [Week 0 - Week 52]
Number of Adverse Events
- Rate of Serious Adverse events [Week 0 - Week 52]
Number of Serious Adverse Events
Eligibility Criteria
Criteria
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
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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)
-
≥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
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Intra-abdominal abscess/phlegmon/inflammatory mass in the last 180 days
-
Active perianal abscess (receiving oral antibiotics for <7 days)
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Intestinal stricture (luminal narrowing with pre-stenotic dilation >3 cm) and surgery planned in the next 90 days
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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.
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Current hospitalization for complications of severe Crohn's disease
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Planned use of methotrexate or 6-mercaptopurine (azathioprine) during the induction (first 3 doses of infliximab) phase
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Current ileostomy, colostomy, ileoanal pouch, and/or previous extensive small bowel resection (>35 cm) or any CD surgery planned within the next 90 days
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History of autoimmune hepatitis, primary sclerosing cholangitis, thyroiditis, or juvenile idiopathic arthritis
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Treatment with another investigational drug in the last four weeks
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History of malignancy (including lymphoma or leukemia)
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Currently receiving treatment for histoplasmosis
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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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Children's Hospital of Los Angeles | Los Angeles | California | United States | 90027 |
| 2 | Lucile Packard Children's Hospital Stanford | Palo Alto | California | United States | 94304 |
| 3 | Rady Children's Hospital San Diego | San Diego | California | United States | 92123 |
| 4 | Nemours Children's Health System-Wilmington | Wilmington | Delaware | United States | 19803 |
| 5 | Nemours Children's Health System-Jacksonville | Jacksonville | Florida | United States | 32207 |
| 6 | Riley Hospital for Children | Indianapolis | Indiana | United States | 46202 |
| 7 | Cincinnati Children's Hospital | Cincinnati | Ohio | United States | 45229 |
| 8 | Cleveland Clinic Children's Hospital | Cleveland | Ohio | United States | 44106 |
| 9 | Nationwide Children's Hospital | Columbus | Ohio | United States | 43205 |
| 10 | Medical College of Wisconsin, Children's of Wisconsin | Milwaukee | Wisconsin | United States | 53226 |
Sponsors and Collaborators
- Children's Hospital Medical Center, Cincinnati
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
- Principal Investigator: Phillip Minar, MD,MS, Children's Hospital Medical Center, Cincinnati
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 2022-0071
- R01DK132408-01