Pharmacokinetics of IFX and TNF Concentrations in Serum, Stool, and Colonic Mucosa in Acute Severe Ulcerative Colitis

Study Overview
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Brief Summary
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This is an open-label, prospective, observational study with the primary objective to characterize the pharmacokinetics of infliximab in patients with Acute Severe Ulcerative Colitis.

Detailed Description
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In Acute Severe Ulcerative Colitis (ASUC), drug exposure may be affected by intestinal protein loss leading to hypoalbuminemia and rapid clearance of infliximab (IFX). Importantly, 2 studies have associated the loss of IFX in stool with poor outcomes. Multiple observational studies have identified that patients with faster IFX clearance have worse clinical outcomes and higher rates of antidrug antibody formation. To better understand optimal dosing of IFX in ASUC, the pharmacokinetics of IFX in association with outcomes must be better defined in this setting.

Official Title
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Pharmacokinetics of Infliximab and Tumor Necrosis Factor Concentrations in Serum, Stool, and Colonic Mucosa in Acute Severe Ulcerative Colitis

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Drug: Infliximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Present to hospital with ASUC based on Truelove and Witts criteria,33 defined as the presence of more than 6 bloody stools per day along with any 1 of the following: tachycardia > 90 beats per minute, fever > 37.8 °C, hemoglobin < 10.5 g/dL, and erythrocyte sedimentation rate (ESR) > 30 mm/h (or CRP > 30 mg/L [high-sensitivity CRP > 300 mg/L]) is a suitable surrogate if ESR is not available1). Have a partial MCS > 7. Have a Mayo Clinic ES ≥ 2 with disease extending 15 cm or more beyond the anal verge. Require rescue inpatient IFX infusion as part of routine care. Note, the IFX treatment regimen is not defined by this protocol and any dosage regimen is acceptable for the purposes of this study, such as standard or accelerated induction regimens. Be able to speak English and participate fully in all aspects of this clinical trial. Provide written informed consent. Exclusion Criteria: A known history of being positive for anti-IFX antibodies. Have a serious active infection, active malignancy, or any other known condition contraindicated with infliximab therapy, according to current prescribing information. Serious underlying disease other than ASUC, or other physical or psychosocial condition that, in the opinion of the investigator, may interfere with the subject's ability to participate fully in the study. Prior enrollment in the current study.

Ages Eligible for Study
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Minimum 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Single Group Study<br>Patients with Acute Severe Ulcerative Colitis who are either a) biologic-naïve or b) biologic-experienced without a known history of anti-infliximab antibodies requiring infliximab infusion therapy as a part of standard of care. | Drug: Infliximab<br>* Patients will receive infliximab at the discretion of their physician as part of standard of care.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Inter-compartmental Difference in Infliximab Concentration | Infliximab population pharmacokinetics | 22 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Proteome | Change in Proteomics before and after therapy | 22 weeks | 
| Change in Transcriptome | Change in Transcriptomics before and after therapy | 22 weeks | 
| Change in Robarts Histopathologic Index | Change in Robarts Histopathologic Index before and after therapy The RHI consists of 4 histological items (extent of chronic inflammatory cell infiltration, neutrophils in the lamina propria, neutrophils in the epithelium, and erosions and ulceration) scored from 0 to 3 and multiplied by a weighting factor. The total RHI score is calculated by summing the weighted scores of the histological items, with total scores ranging from 0 (no disease activity) to 33 (severe disease activity). | 22 weeks | 
| Change in Mayo Clinic Endoscopic Score | Change in Mayo Clinic Endoscopic Score before and after therapy The Mayo Clinic score (MCS) scores 4 variables (stool frequency, rectal bleeding, a physician's global assessment and endoscopic findings with flexible sigmoidoscopy). The endoscopic component of the MCS assesses disease activity on a 4-point scale (0-3 points), with higher scores representing more severe disease activity. Mucosal healing is often defined as an endoscopy score of 0 or 1. Normal or inactive disease = 0 Mild disease (erythema, decreased vascular pattern, mild friability) = 1 Moderate disease (marked erythema, absent vascular pattern, friability, erosions) = 2 Severe (spontaneous bleeding, ulceration) = 3 | 22 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ASUC, Infliximab, Optimal Dose, Optimal Frequency, Theraputic Drug Monitoring