Evaluation of Anti-TNF Therapy De-escalation Using Adalimumab and Infliximab in Adolescents and Young Adults with Inflammatory Bowel Disease

The primary objective of the study is to evaluate whether a **faecal calprotectin** (FC) guided strategy of anti-TNF dosing interval lengthening is non-inferior in maintaining remission in patients with inflammatory bowel disease (IBD), specifically **Crohn's disease** and **ulcerative colitis**, compared with an unchanged dosing interval. This is clinically relevant as it may offer a strategy to reduce medication exposure while maintaining disease control, potentially minimizing long-term adverse effects and healthcare costs.

Secondary objectives include:

• To evaluate the effectiveness of anti-TNF re-escalation after failure of dosing interval lengthening in patients with IBD in sustained remission.
• To estimate the cumulative incidence of anti-TNF associated adverse effects after dosing interval lengthening compared with an unchanged dosing interval.

The clinical trial involves participants diagnosed with **Crohn's disease** or **ulcerative colitis**, aged between 12 and 25 years. Both male and female subjects are included, and the study does not focus on a vulnerable population. Participants are required to have been treated with either 8-weekly infliximab or 2-weekly adalimumab, with the current anti-TNF agent being their first ever or having discontinued a prior agent for reasons other than primary non-response or secondary loss-of-response. The trial population was selected based on specific criteria, including the absence of symptoms associated with active inflammatory bowel disease (IBD) and having three consecutive faecal calprotectin results within the target range or confirmed endoscopic remission shortly before study entry. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of a **faecal calprotectin** (FC) guided strategy for adjusting the dosing interval of anti-TNF therapy in adolescents and young adults diagnosed with **Crohn's disease** or **ulcerative colitis**. This study is a randomized, double-blind, controlled trial with an estimated duration from March 2021 to September 2026. Participants will be randomly assigned to either maintain their current dosing interval or to have their dosing interval lengthened based on FC levels. The primary objective is to determine if the adjusted dosing strategy is non-inferior in maintaining remission compared to the standard dosing interval.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility criteria are confirmed. Key inclusion criteria include being aged 12-25 years, having a diagnosis of luminal Crohn's disease or ulcerative colitis, and being treated with either 8-weekly **infliximab** or 2-weekly **adalimumab**. Participants must have stable FC results or confirmed endoscopic remission prior to study entry. Follow-up visits will occur regularly to monitor FC levels, anti-TNF trough levels, and any adverse effects. The primary endpoint is the cumulative incidence of out-of-range FC results at 48 weeks. Secondary endpoints include the time to out-of-range FC results and the incidence of anti-TNF-associated adverse effects.

The expected length of participant involvement is approximately 48 weeks, with conditions for early termination including the development of symptoms associated with active inflammatory bowel disease or significant adverse effects. The end-of-study visit will assess the overall health status of participants and collect final data on FC levels and anti-TNF therapy outcomes. This trial aims to provide insights into the potential for personalized dosing strategies in maintaining remission in young patients with inflammatory bowel disease.

The clinical trial involves the use of **adalimumab**, a biologic medication classified under the ATC code L04AB04. Adalimumab is administered in the form of a subcutaneous injection. The pharmaceutical form is identified as PHF00231MIG. The maximum daily dose is 90 mg, with the same amount being the maximum total dose. The treatment period is set to a maximum of 9999 days. Adalimumab is a protein-based therapeutic agent, and its administration is monitored to ensure compliance with the dosing schedule.

Another experimental medication used in the trial is **infliximab**, which is also a biologic agent, categorized under the ATC code L04AB02. Infliximab is administered via intravenous infusion, with the pharmaceutical form designated as PHF00230MIG. The dosing regimen allows for a maximum daily and total dose of 15 mg/kg. Similar to adalimumab, the maximum treatment period is 9999 days. Infliximab is a protein-based medication, and its administration is carefully monitored to ensure adherence to the prescribed dosing intervals.

Both adalimumab and infliximab are utilized as test treatments in the study, with no additional non-experimental treatments such as placebo or standard-of-care therapy being employed. The trial aims to evaluate the efficacy of a fecal calprotectin-guided strategy for adjusting the dosing intervals of these anti-TNF therapies in maintaining remission in patients with inflammatory bowel disease (IBD). Participant compliance with the treatment regimen is closely monitored throughout the study to ensure accurate assessment of the therapeutic outcomes.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the cumulative incidence of out-of-range **faecal calprotectin (FC)** results at 48 weeks follow-up. Secondary endpoints include the time to first out-of-range FC results from the study baseline, the cumulative incidence of anti-TNF-associated respiratory infections and dermatological adverse effects at 48 weeks, and the evolution of FC and anti-TNF trough levels in the first 16 weeks after reverting to the previous dosing interval. Additionally, the proportion of patients developing loss-of-response in the first 16 weeks after reverting to the previous dosing interval and the identification of predictors of successful de-escalation will be evaluated.

Measurements will be collected at specified intervals, with FC levels being a critical biomarker for assessing disease activity and treatment efficacy. The trial will monitor these parameters to determine the non-inferiority of an FC-guided strategy of anti-TNF dosing interval lengthening in maintaining remission in patients with inflammatory bowel disease (IBD) compared to an unchanged dosing interval. The trial is designed to provide comprehensive data on the efficacy of the treatment strategy over a 48-week period, with specific attention to maintaining remission and minimizing adverse effects.