Evaluation of Therapeutic Escalation with Infliximab in Postoperative Recurrence of Crohn's Disease: A Randomized Controlled Trial

The primary objective of this study is to evaluate the proportion of patients with **Crohn's disease** who do not experience endoscopic postoperative recurrence (i0-i1) at 12 months. This is assessed in patients receiving therapy escalation compared to those in the status quo arm, specifically in individuals with an i2 endoscopic postoperative recurrence occurring 6-12 months after ileocolonic anastomosis with restoration of the fecal stream. This objective is clinically relevant as it aims to determine the effectiveness of therapeutic escalation in preventing disease recurrence, which is crucial for improving long-term patient outcomes.

Secondary objectives include:

• Comparing the proportions of patients with severe endoscopic recurrence (i3-i4) at 12 months between both arms.
• Comparing the proportions of patients with clinical postoperative recurrence, surgical recurrence, and the need for endoscopic dilatation at 12 months between both arms.
• Comparing the mean change in PRO2 from the inclusion visit to 12 months between both arms.
• Evaluating the safety of therapy during the 12-month study period.
• Evaluating the quality of life and work productivity impact of therapy escalation during the 12-month study period.
• Comparing the clinical, endoscopic, and surgical outcomes of i2a and i2b patients.

The clinical trial involves a total of **20 participants** diagnosed with **Crohn's disease**. The study population includes both male and female subjects, aged between 18 and 75 years. Participants were selected based on specific criteria, including a confirmed diagnosis of Crohn's disease and having undergone an intestinal resection with ileocolonic anastomosis within the last 6 to 12 months. The trial does not include a vulnerable population. Participants are required to have had a postoperative endoscopy performed between 6 and 12 months after the surgical procedure, with endoscopic recurrence classified as i2 according to the Rutgeerts score. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection process ensures that all participants meet the necessary health status and procedural criteria to evaluate the trial's main objective effectively.

The clinical trial is designed to evaluate the efficacy of therapeutic escalation in patients with **Crohn's disease** who have experienced a moderate postoperative recurrence. This study is a randomized, controlled trial with a double-blind design, ensuring that neither the participants nor the investigators are aware of the treatment allocations. The trial is set to run from December 2021 to June 2024, with the primary objective of assessing the proportion of patients without endoscopic postoperative recurrence at 12 months in the arm receiving therapy escalation compared to the status quo arm.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed based on criteria such as age (18-75 years), a diagnosis of Crohn's disease, and a history of intestinal resection with ileocolonic anastomosis. The inclusion visit will also involve a postoperative endoscopy performed between 6 and 12 months after surgery. Follow-up visits will occur at regular intervals to monitor the participants' health status and treatment response, with the primary endpoint being the proportion of patients achieving a modified Rutgeerts score of i0-i1 at 12 months. Secondary endpoints include various clinical and patient-reported outcomes, such as the proportion of patients with higher modified Rutgeerts scores, clinical postoperative recurrence, and quality of life assessments.

The expected length of participant involvement is approximately 12 months, with conditions for early termination including significant adverse events or withdrawal of consent. The study will utilize two formulations of **infliximab**: a 120 mg solution for injection in a pre-filled pen administered subcutaneously, and a 100 mg powder for concentrate for solution for infusion administered intravenously. The maximum treatment period for the subcutaneous formulation is 11 months, while the intravenous formulation is limited to 2 months. The trial aims to provide valuable insights into the management of postoperative recurrence in Crohn's disease, contributing to improved therapeutic strategies for affected patients.

The clinical trial involves the administration of **Remsima 120 mg solution for injection in pre-filled pen**, which contains the active substance **infliximab**. This pharmaceutical form is a solution for injection, specifically designed for subcutaneous administration. The maximum daily dose is 120 mg, and the treatment period extends up to 11 months. The administration frequency is determined based on the study protocol, ensuring adherence to the specified dosing schedule. Participant compliance is monitored through regular assessments and documentation of injection adherence.

Additionally, the trial includes the use of **Remsima 100 mg powder for concentrate for solution for infusion**, also containing **infliximab**. This formulation is intended for intravenous administration. The maximum dose is 5 mg/kg, with a treatment period of up to 2 months. The infusion is prepared by reconstituting the powder into a solution, which is then administered intravenously. The dosing schedule is carefully followed as per the trial protocol, with compliance monitored through infusion records and participant follow-up.

Both formulations of **infliximab** are provided by CELLTRION HEALTHCARE HUNGARY KFT and are utilized as part of the therapeutic escalation strategy in the management of moderate postoperative recurrence in Crohn's disease. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The focus is on evaluating the efficacy of the experimental medications in preventing endoscopic postoperative recurrence in the specified patient population.

Efficacy in the clinical trial titled "Management of moderate POstoperative recurrence in Crohn's disease: a randoMizEd contROLled trial of therapeutic escalation, the POMEROL trial" will be assessed using several endpoints. The primary endpoint is the proportion of patients achieving a treatment success, defined as an i0-i1 modified **Rutgeerts score** (mRS) at 12 months. This score is a measure of endoscopic postoperative recurrence in patients with Crohn's disease.

Secondary endpoints include the proportion of patients with higher modified Rutgeerts scores (i3-i4 and i2b-i3-i4) at 12 months, as well as the proportion of patients with an i0 score. Additional secondary endpoints involve patient-reported outcomes, such as the two-item Patient Reported Outcome (PRO2) at 12 months, and clinical postoperative recurrence indicators, including average daily stool frequency and abdominal pain score, along with biomarkers like C-reactive protein (CRP) and fecal calprotectin levels. Surgical recurrence, endoscopic dilatation, time to clinical postoperative recurrence, serious adverse events, quality of life assessed by the EQ5D-5L questionnaire, and work productivity measured by the Work Productivity and Activity Impairment questionnaire are also evaluated.

The efficacy parameters will be collected and analyzed at the 12-month mark following randomization. The modified Rutgeerts score will be validated by a blinded central reading to ensure accuracy and consistency in the assessment of endoscopic recurrence. The trial aims to provide insights into the effectiveness of therapeutic escalation in preventing postoperative recurrence in Crohn's disease patients.