Personalized Infliximab Induction Strategy With Model-informed Dosing in Patients With Crohn's Disease

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, with many of those being young children and adolescents. Physicians need better ways to inform decisions on treatment. The main reason for this research study is to determine if a computer program that formulates a dose based on a patient's blood testing results can better achieve the optimal drug level as compared to standard dosing.

Detailed Description
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This is a Pilot study to evaluate safety, feasibility and efficacy of utilizing pharmacokinetic modeling to provide an individualized infliximab induction regimen in children and young adults with moderate to severe Crohn's disease. This clinical study is designed with the hypothesis that treatment regimens that account for individual (patient) drug clearance (pharmacokinetic modeling) will not only be safe and cost-effective, but also more effective in reducing intestinal inflammation than as-labeled dosing (ALD) regimens.

Official Title
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Personalized Infliximab Induction Strategy With Model-informed Dosing in Patients With Crohn's Disease

Conditions
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Crohn Disease

Intervention / Treatment
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* Device: RoadMAB
* Drug: Precision dosing with a dashboard


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent form from the patient (≥18 years old) or from parent/legal guardian if patient is <18 years old. Written informed assent form from patient ≥11 years old. Age criteria: ≥6 years to ≤22 years of age. Diagnosis of Crohn's Disease Starting infliximab (or biosimilar) Anti-TNF naïve (never received infliximab, adalimumab, golimumab, certolizumab or anti-TNF biosimilar) Fecal calprotectin >250 µg/g or fecal lactoferrin >10 µg/g (up to 6 weeks prior to starting infliximab) or endoscopic evidence of active Crohn's disease (up to 90 days prior to starting infliximab) wPCDAI >12.5 (up to 6 weeks) prior to the first infliximab infusion Negative urine pregnancy test for ALL female subjects Negative TB (tuberculosis) blood test Exclusion Criteria: Diagnosis of ulcerative colitis or inflammatory bowel disease-unspecified Prior treatment with infliximab, adalimumab, certolizumab or golimumab (or anti-TNF biosimilar) Active or prior evidence in past 12 months of internal (abdominal/pelvic) penetrating fistula(e) Active intestinal stricture (luminal narrowing with pre-stenotic dilation >3mm), intra-abdominal abscess or perianal abscess Active Clostridium difficile infection or other known bacterial/viral gastroenteritis in last two weeks Current ileostomy, colostomy, ileoanal pouch, and/or previous extensive small bowel resection leading to short bowel syndrome History of autoimmune disease (including autoimmune hepatitis, primary sclerosing cholangitis, thyroiditis, psoriasis or juvenile idiopathic arthritis) Treatment with another investigational drug within four weeks. Treatment with intravenous antibiotics within four weeks. Planned continuation of 6-mercaptopurine or azathioprine (Imuran) during study. Planned continuation of methotrexate during study. Treatment with intravenous corticosteroids within two weeks. Currently pregnant, breast feeding or plans in next 12 months to become pregnant Inability or failure to provide informed 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: Other
Intervention Model: Single Group Assignment
Interventional Model Description: The intervention cohort includes patients, age 6-22 years old who have been diagnosed with CD, are naïve to anti-TNF medications and are scheduled to start infliximab (or infliximab biosimilar).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RoadMAB dashboard system<br>The intervention includes utilizing Clinical and Patient Decision Support Software (RoadMABTM) that will guide the selection of the first infliximab dose followed by subsequent infliximab dose and dosing interval during the maintenance phase. During induction, three infusions will occur at 0, 2 and 6 weeks, respectively. The RoadMABTM dashboard will utilize PK modeling software to provide an infliximab starting dose recommendation (range of 5-12 mg/kg) based on the patients biochemical profile. As noted, dosing frequency (weeks) during induction will not be altered during this study. Following the first three doses, the clinician will be informed of their patients PK profile within the RoadMABTM program and with a shared document (paper). RoadMABTM will provide additional dosing recommendations after each infusion (based on the latest drug concentration measures and blood biomarkers) with the final dose and interval selected by the treating physician. | 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>* Other names: Precision dosing with a dashboard;Drug: Precision dosing with a dashboard<br>* The trial is testing whether precision dosing can more reliably achieve the targeted trough concentrations compared to standard dosing<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Obtain safety data for optimal dosing strategy and sample size estimation | Number of adverse and/or serious adverse events | 2 years | 
| Enrollment feasibility | Evaluate the rate of recruitment | 2 years | 
| Completion feasibility | Number of patients that complete the study | 2 years | 
| Rate of patient adherence to stool and blood sample collections | patient adherence to stool and blood sample collections | 2 years | 
| RoadMAB Usability | Evaluate rate of physician adherence to RoadMAB dosing recommendation | 2 years | 
| RoadMAB Efficacy | Rate of achieving infus3 (Visit 4) infliximab concentration between 16-24 μg/ml as a dichotomous outcome | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate accuracy of infliximab concentration targets - Median difference infus3 | Median difference of infus3 (Visit 4) levels between cases and controls | 2 years | 
| Evaluate accuracy of infliximab concentration targets - Incidence | Incidence of achieving infus2 (Visit 3) level between target range of 26-34 μg/ml as a dichotomous outcome | 2 years | 
| Evaluate accuracy of infliximab concentration targets - Median difference infus2 | Median difference of infus2 (Visit 3) levels between cases and controls | 2 years | 
| Evaluate accuracy of infliximab concentration targets - Maintenance | Rates of achieving maintenance targets infus4-6 (Visits 5-7) between 5-10 μg/ml | 2 years | 
| Evaluate accuracy of infliximab concentration targets | Rate of development of antiinfliximab antibodies at any infusion between cases and controls | 2 years | 
| Infus4 (Visit 5) and infus6 (Visit 7): Clinical Response | Improvement in baseline wPCDAI by >17.5 or a wPCDAI<12.5 | 2 years | 
| Infus4 (Visit 5) and infus6 (Visit 7): Clinical Remission | wPCDAI <12.5 and off corticosteroids | 2 years | 
| Sustained Remission | wPCDAI <12.5 and off prednisone for all visits from infus4 (Visit 5) to infus6 (Visit 7) | 2 years | 
| Infus4 (Visit 5) and Infus6 (Visit 7): Fecal Biochemical Response | ≥50% improvement in fecal calprotectin | 2 years | 
| Infus4 (Visit 5) and Infus6 (Visit 7): Fecal Biochemical Remission | fecal calprotectin <250 μg/g | 2 years | 
| Infus6 (Visit 7): Rate of transmural ileal | ileum subscore stage 0 (score = 0) | 2 years | 
| Infus6 (Visit 7): Rate of colonic healing | all segments of colon subscore stage 0 (score = 0) | 2 years | 
| Infus6 (Visit 7): Rate of total bowel healing | total ileum and colonic subscore is not greater than stage 0 on either individual score | 2 years |