Relationship Between Baseline Burden of Disease and TDM in Ulcerative Colitis

Ulcerative Colitis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT03808506
• Other study ID #: 113446
• Status: Withdrawn
• Start date: September 1, 2019
• Est. completion date: July 19, 2022

Study information

• Verified date: March 2023
• Source: Lawson Health Research Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: July 19, 2022
• Est. primary completion date: June 19, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Colitis
• Colitis, Ulcerative
• Ulcer
• Ulcerative Colitis

Intervention

Diagnostic Test:
• Fecal calprotectin
Stool test to look at baseline burden of inflammation

Locations

Country	Name	City	State
Canada	London Health Sciences Center	London	Ontario

Sponsors (1)

Lead Sponsor	Collaborator
Lawson Health Research Institute

Country where clinical trial is conducted

Canada, 

References & Publications (24)

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Brandse JF, van den Brink GR, Wildenberg ME, van der Kleij D, Rispens T, Jansen JM, Mathot RA, Ponsioen CY, Lowenberg M, D'Haens GR. Loss of Infliximab Into Feces Is Associated With Lack of Response to Therapy in Patients With Severe Ulcerative Colitis. Gastroenterology. 2015 Aug;149(2):350-5.e2. doi: 10.1053/j.gastro.2015.04.016. Epub 2015 Apr 25. — View Citation

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* Note: There are 24 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Baseline fecal calprotectin concentration	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	Post Induction fecal calprotectin concentration	Fecal calprotectin concentration will be re-assessed at week 6 after starting adalimumab therapy	Performed 6 weeks post induction therapy
Secondary	Baseline Mayo Endoscopic Score	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
Secondary	Baseline bowel ultrasound inflammatory score	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