Prevention of postoperative endoscopic recurrence with endoscopy-driven versus systematic biological therapy: a randomized, multicentre, parallel group pragmatic non-inferiority trial in adult patients with Crohn’s disease undergoing an ileocolonic resection with ileocolonic anastomosis

The primary objective of this study is to compare the postoperative **endoscopic recurrence** rate in patients with **Crohn's disease** undergoing an ileocolonic resection with ileocolonic anastomosis. Patients are randomized to receive either systematic biological therapy or endoscopy-driven biological therapy. This objective is clinically relevant as it aims to determine the most effective strategy for preventing endoscopic recurrence, which is a significant concern in the management of Crohn's disease post-surgery.

Secondary objectives include:

• Comparing the postoperative clinical, biological, and surgical recurrence rates in the same patient population, which will provide a comprehensive understanding of the recurrence patterns and the effectiveness of the treatment strategies.
• Evaluating the direct costs, quality of life, work productivity, and safety associated with the two therapeutic approaches, which are crucial for assessing the overall impact of the treatment on patients' lives and healthcare resources.

The clinical trial involves **patients with Crohn's disease** who are undergoing surgery and possess at least one risk factor for postoperative recurrence of the disease. The study population includes both male and female participants aged 18 years and older. Participants are required to have undergone an ileocolonic resection with ileocolonic anastomosis within a specified timeframe prior to the screening visit. The trial population was selected based on specific inclusion criteria, including a diagnosis of Crohn's disease confirmed by radiology, endoscopy, and/or histology. Participants must have an increased risk for postoperative recurrence due to factors such as penetrating disease, previous ileocolonic resections, active smoking, or recent advanced therapy. The trial also considers lifestyle factors, such as smoking habits, as relevant to the study. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the efficacy of systematic versus endoscopy-driven biological therapy in preventing postoperative endoscopic recurrence in patients with **Crohn's disease** who have undergone ileocolonic resection with ileocolonic anastomosis. This is a randomized, multicenter, parallel-group, pragmatic non-inferiority trial. The trial employs a double-blind methodology to ensure unbiased results, with participants randomly assigned to either systematic biological therapy or endoscopy-driven biological therapy. The trial is expected to last until June 2031, with participant involvement spanning up to 242 weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and surgical history. Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety, with assessments including endoscopic evaluations and clinical indices such as the Harvey-Bradshaw Index and Crohn's Disease Activity Index. The primary endpoint is the rate of endoscopic recurrence at week 86, with secondary endpoints including clinical recurrence, quality of life assessments, and adverse event monitoring.

The end-of-study visit will occur at the conclusion of the participant's involvement, where final assessments will be conducted to evaluate long-term outcomes. Participants may be withdrawn from the study early if they experience severe adverse reactions, require unscheduled treatment adaptations, or if they no longer meet the study criteria. The trial aims to provide valuable insights into the optimal management of postoperative Crohn's disease, potentially influencing future therapeutic strategies.

The clinical trial involves the administration of several **biological** agents, each with specific pharmaceutical forms, dosages, and routes of administration. **Vedolizumab** is utilized in two forms: a solution for injection in a pre-filled syringe and a pre-filled pen, both administered via **subcutaneous injection**. The maximum daily dose is 108 mg, with a total maximum dose of 13,068 mg over a treatment period of 242 days. Additionally, vedolizumab is available as a solution for **intravenous infusion**, with a maximum daily dose of 300 mg and a total maximum dose of 9,450 mg.

**Risankizumab** is administered as a solution for injection via subcutaneous injection. The maximum daily dose is 360 mg, with a total maximum dose of 9,450 mg over the treatment period. This agent is classified as a protein of other origin.

**Adalimumab** is provided in two forms: a solution for injection in a pre-filled pen and a pre-filled syringe, both administered subcutaneously. The maximum daily dose is 160 mg, with a total maximum dose of 5,000 mg. Adalimumab is identified as a structurally diverse substance, specifically an immunoglobulin.

**Infliximab** is available as a solution for injection and a powder for infusion, both administered via intravenous infusion. The solution form has a maximum daily dose of 120 mg and a total maximum dose of 14,520 mg, while the powder form has a maximum daily dose of 5 mg/kg and a total maximum dose of 160 mg/kg. Infliximab is categorized as a protein of other origin.

**Ustekinumab** is administered in two forms: a solution for injection in a pre-filled syringe via subcutaneous injection and a solution for infusion via intravenous infusion. The subcutaneous form has a maximum daily dose of 90 mg and a total maximum dose of 2,700 mg, while the intravenous form has a maximum daily dose of 520 mg and a total maximum dose of 520 mg. Ustekinumab is also classified as a protein of other origin.

All treatments are administered over a maximum period of 242 days, and participant compliance is monitored throughout the trial. The study aims to compare the efficacy of systematic biological therapy versus endoscopy-driven biological therapy in preventing postoperative endoscopic recurrence in patients with **Crohn's disease** undergoing ileocolonic resection with ileocolonic anastomosis.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the rate of endoscopic recurrence, defined as an updated Rutgeerts score of **≥i2b**, at week 86 or the need for unscheduled treatment adaptation prior to week 86. Secondary endpoints include various measures such as endoscopic recurrence at week 86, clinical recurrence based on the Harvey-Bradshaw Index (HBI) and Crohn's Disease Activity Index (CDAI), quality of life assessments using the EQ-5D 5L scale, and changes in biomarkers like C-reactive protein (CRP) and faecal calprotectin at specified timepoints.

Data collection will occur at multiple timepoints, including weeks 14, 30, 46, 62, 86, 138, 190, and 242, to monitor changes from baseline. The trial will utilize validated scales and patient-reported outcomes to evaluate clinical recurrence and quality of life. The analysis will also consider direct costs, the need for additional surgical interventions, and adverse reactions to biological therapy. The trial aims to provide a comprehensive assessment of the efficacy of systematic versus endoscopy-driven biological therapy in preventing postoperative recurrence in patients with Crohn's disease.