Clinical trial NCT03808506: Relationship Between Baseline Burden of Disease and TDM in Ulcerative Colitis
Official title: Relationship Between Baseline Burden of Disease and Anti-TNF Drug Trough Levels in Ulcerative Colitis.
Study type: OBSERVATIONAL
Overall status: WITHDRAWN
Conditions: Ulcerative Colitis
Keywords: Ulcerative colitis
Therapeutic drug monitoring
fecal calprotectin
adalimumab
bowel ultrasound
Lead sponsor: London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's
Sponsor class: OTHER
First posted: 2019-01-17
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

Brief 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Baseline fecal calprotectin concentration
timeFrame: Performed within 4 weeks of starting adalimumab therapy
Secondary outcomes:
measure: Post Induction fecal calprotectin concentration
timeFrame: Performed 6 weeks post induction therapy
measure: Baseline Mayo Endoscopic Score
timeFrame: Performed within 12 weeks of study entry
measure: Baseline bowel ultrasound inflammatory score
timeFrame: Performed within 12 weeks of starting adalimumab therapy
Other outcomes:
Locations:
city: London
country: Canada
facility: London Health Sciences Center
state: Ontario
Study officials:
affiliation: Western University
name: Brian Yan, H.B Sc, MD
role: PRINCIPAL_INVESTIGATOR
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