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

Sponsor

Alimentiv Inc. (Other)

Overall Status

Recruiting

CT.gov ID

NCT03765450

Collaborator

(none)

Enrollment

Locations

35.4

Anticipated Duration (Months)

7.5

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Ulcerative Colitis	Drug: Infliximab

Detailed Description

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.

Study Design

Study Type:

Observational

Anticipated Enrollment :

30 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

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

Actual Study Start Date :

Dec 21, 2018

Anticipated Primary Completion Date :

Dec 1, 2021

Anticipated Study Completion Date :

Dec 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Single Group Study 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 Patients will receive infliximab at the discretion of their physician as part of standard of care.

Arm

Intervention/Treatment

Single Group Study

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

Patients will receive infliximab at the discretion of their physician as part of standard of care.

Outcome Measures

Primary Outcome Measures

Inter-compartmental Difference in Infliximab Concentration [22 weeks]
Infliximab population pharmacokinetics

Secondary Outcome Measures

Change in Proteome [22 weeks]
Change in Proteomics before and after therapy
Change in Transcriptome [22 weeks]
Change in Transcriptomics before and after therapy
Change in Robarts Histopathologic Index [22 weeks]
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).
Change in Mayo Clinic Endoscopic Score [22 weeks]
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSD	San Diego	California	United States	92037
2	Cornell University	New York	New York	United States	10065
3	London Health Sciences Center	London	Ontario	Canada	N6A 5A5
4	Mount Sinai Hospital	Toronto	Ontario	Canada	M5G 1X5