Relationship Between Baseline Burden of Disease and TDM in Ulcerative Colitis

March 7, 2023 updated by: Brian Yan, Lawson Health Research Institute

Relationship Between Baseline Burden of Disease and Anti-TNF Drug Trough Levels in Ulcerative Colitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease which often follows a relapsing/remitting course. Anti-TNF therapies are proven to be effective in UC and studies indicate that having adequate drug levels correlate with improved patient outcomes. It is unknown, however, if a high burden of disease at baseline impacts drug utilization or loss. In this study, we investigate whether measures of high burden of disease (fecal calprotectin, bowel ultrasound, and colonoscopy) at baseline predicts low drug levels after standard anti-TNF induction therapy.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

Biologic therapy has revolutionized the treatment of IBD. Over the past 20 years, a significant amount of research has been done to optimize biologic therapy using therapeutic drug monitoring (TDM). Evidence is accumulating suggesting that insufficient anti-TNF drug levels +/- development of anti-drug antibodies result in lower clinical efficacy, reduced mucosal healing, and loss of response. The pharmacokinetics of anti-TNF drug clearance leading to sub-therapeutic or absent drug levels can vary between and within any given patient. Clearance may be dependent on many factors such as severity of inflammation, total burden of disease, body weight, serum albumin levels, loss of drug through leaking into the stool, and immune mediated pathways with the development of anti-drug antibodies. Standard induction dosing does not take into account the severity and total burden of disease, which may have significant effects on the elimination of circulating drug.

Most data surrounding TDM pertain to maintenance of remission, during a relatively stable state of low burden of disease. Much less is known surrounding active drug levels during or immediately after induction therapy, at which point disease burden is relatively high and fluctuating. Some studies suggest improved response rates in those with higher anti-TNF drug levels during this phase of therapy. A retrospective study by Gibson et al assessed inpatients with acute severe ulcerative colitis and demonstrated reduction in colectomy rates in those who received accelerated and intensified infliximab induction therapy. Although trough levels were not provided in this study, the results suggest that standard induction dosing may be suboptimal in a setting of high burden of disease.

Colonoscopy is considered the gold standard in regards to determining burden of active disease in ulcerative colitis. However, it is invasive, requires endoscopy time, and carries risk. Non-invasive methods to determine the presence and extent of inflammation is of clinical and research interest. Fecal calprotectin (FC) is a promising tool which has now been incorporated into standard clinical care of IBD patients. It is used to monitor disease activity, assess response to therapy, and prognosticate future clinical relapse. Several meta-analyses demonstrate the correlation between FC with endoscopic disease scores in both Crohn's disease (CD) and Ulcerative Colitis (UC) with a pooled sensitivity of 85-92% and specificity of 75-88%.

Bowel Ultrasound (US) is another non-invasive method to assess inflammatory activity in UC, and is used in routine clinical practice. Bowel US correlates to inflammatory activity on colonoscopy and can be used to assess response to therapy and prognosticate future relapse. A benefit of sonography, as compared to colonoscopy and FC, is its ability to identify inflammatory changes deep to the superficial mucosa. This may provide additional information for burden of disease not recognized by other modalities. It is currently unknown if the burden of disease as found on sonography influences drug elimination and the resultant trough levels after induction therapy.

It is unknown if a high burden of disease at baseline impacts drug utilization or loss. In this study, measures of burden of disease (FC, bowel US, and colonoscopy) at baseline will be correlated to drug levels after standard anti-TNF induction therapy. It is hypothesized that a high burden of disease leads to low drug levels after standard induction dosing.

Study Type

Observational

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Canada
    • Ontario
      • London, Ontario, Canada, N6A5W9
        • London Health Sciences Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Adult patients with documented ulcerative colitis with active inflammation who are starting adalimumab therapy. All other concomittant therapies are allowed.

Description

Inclusion Criteria:

  1. Adult outpatients >=18 y of age with a confirmed diagnosis of ulcerative colitis
  2. Patients beginning adalimumab for active disease as clinically indicated according to the treating physician's discretion, either biologic naïve or switching biologic due to failure of prior biologic therapy
  3. Have had a colonoscopy or flexible sigmoidoscopy within 12 weeks of study entry
  4. Any other concomitant therapies are allowed (including 5'ASA, corticosteroids, azathioprine, and methotrexate).

Exclusion Criteria:

  1. Inability to provide informed consent
  2. Inability to provide a fecal calprotectin
  3. Contraindication to starting anti-TNF therapy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Ulcerative colitis patients
Patients with documented ulcerative colitis who are initiating adalimumab therapy will have baseline bowel ultrasound and fecal calprotectin completed.
Diagnostic test: Fecal calprotectin
Stool test to look at baseline burden of inflammation

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Baseline fecal calprotectin concentration
Time Frame: Performed within 4 weeks of starting adalimumab therapy
Fecal calprotectin concentration at baseline prior to starting adalimumab therapy. Fecal Calprotectin will be used as the primary outcome measure to determine burden of inflammation
Performed within 4 weeks of starting adalimumab therapy

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Post Induction fecal calprotectin concentration
Time Frame: Performed 6 weeks post induction therapy
Fecal calprotectin concentration will be re-assessed at week 6 after starting adalimumab therapy
Performed 6 weeks post induction therapy
Baseline Mayo Endoscopic Score
Time Frame: Performed within 12 weeks of study entry
Baseline endoscopic score (as assessed by colonoscopy or flexible sigmoidoscopy) to grade the severity of mucosal inflammation. The Mayo Endoscopic score is a standard, validated, and accepted grading systems which grades inflammation from 0-3.
Performed within 12 weeks of study entry
Baseline bowel ultrasound inflammatory score
Time Frame: Performed within 12 weeks of starting adalimumab therapy
Baseline severity of inflammation based on sonographic features including bowel wall thickness, depth of mural inflammation, and degree of hypervascularity. Each component will be scored from 0-3 resulting in an ultrasound severity score of 0-9 for the segment assessed. Three segments of the colon (right colon, transverse, left colon) will be assessed and scores combined to give a total inflammatory score.
Performed within 12 weeks of starting adalimumab therapy

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Lawson Health Research Institute

Investigators

  • Principal Investigator: Brian Yan, H.B Sc, MD, Western University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 1, 2019

Primary Completion (Actual)

June 19, 2022

Study Completion (Actual)

July 19, 2022

Study Registration Dates

First Submitted

January 14, 2019

First Submitted That Met QC Criteria

January 15, 2019

First Posted (Actual)

January 17, 2019

Study Record Updates

Last Update Posted (Estimate)

March 9, 2023

Last Update Submitted That Met QC Criteria

March 7, 2023

Last Verified

March 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 113446

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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