Efficacy, Safety, and Pharmacokinetics of Ustekinumab in Pediatric Patients with Moderate to Severe Crohn's Disease: A Phase 3 Randomized Controlled Trial

The primary objective of this Phase 3 study is to evaluate the **efficacy** of ustekinumab dosing in inducing clinical remission in pediatric participants with moderately to severely active Crohn's disease. This is clinically relevant as achieving remission can significantly improve the quality of life and long-term health outcomes for pediatric patients suffering from this chronic inflammatory condition. Additionally, the study aims to assess the **safety profile** of ustekinumab in this population, which is crucial for understanding the risk-benefit ratio of the treatment. Furthermore, the study will evaluate ustekinumab **exposure** (pharmacokinetics) to ensure appropriate dosing and therapeutic levels are achieved in pediatric patients.

The clinical trial involves a total of **30 participants** diagnosed with **moderately to severely active Crohn's disease**. The study population includes both male and female pediatric subjects, with an age range starting from 2 years old. Participants were selected based on their confirmed diagnosis of Crohn's disease or fistulizing Crohn's disease with active colitis, ileitis, or ileocolitis, verified through endoscopy and histology. The trial includes individuals with a baseline Pediatric Crohn's Disease Activity Index (PCDAI) score greater than 30, indicating moderate to severe disease activity. Participants may be on a stable regimen of enteral nutrition for at least two weeks prior to the induction period. The study also requires females of childbearing potential to have a negative highly sensitive urine pregnancy test at screening and prior to study intervention administration. The trial population is considered vulnerable, given the pediatric nature of the participants. The sponsor has not provided specific information regarding lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the **efficacy**, safety, and pharmacokinetics of **ustekinumab** in pediatric participants with moderately to severely active **Crohn's disease**. This is a Phase 3 study that involves an open-label intravenous induction treatment followed by a randomized, double-blind, subcutaneous maintenance phase. The trial is expected to last until June 2025, with recruitment having started in January 2021. Participants will be involved in the study for a maximum treatment period of 40 weeks.

The trial begins with a screening visit to confirm eligibility, which includes verifying the presence of active Crohn's disease through endoscopy and histology, and ensuring a Pediatric Crohn's Disease Activity Index score greater than 30. Participants must also meet other inclusion criteria, such as having a negative pregnancy test for females of childbearing potential. The induction phase involves intravenous administration of ustekinumab, followed by subcutaneous maintenance dosing. The primary endpoint is achieving clinical remission by Week 8 of the induction phase.

Study visits are scheduled at regular intervals to monitor the participants' health and response to treatment. These visits include assessments of disease activity, safety evaluations, and pharmacokinetic sampling. The end-of-study visit will occur after the completion of the maintenance phase, where final assessments will be conducted. Participants may be withdrawn from the study early if they experience significant adverse effects, fail to comply with study procedures, or if the investigator deems it necessary for their safety.

The clinical trial involves the administration of **ustekinumab**, a monoclonal antibody, as the experimental medication. Ustekinumab is provided in three different pharmaceutical forms for this study. The first form is **STELARA 130 mg concentrate for solution for infusion**, which is administered intravenously. The maximum daily dose for this form is 520 mg, with a total dose not exceeding 520 mg over a treatment period of 1 day. This formulation is intended for the induction phase of the study.

The second form of ustekinumab used in the trial is **STELARA 90 mg solution for injection in pre-filled syringe**, administered subcutaneously. The maximum daily dose for this form is 90 mg, with a total dose not exceeding 450 mg over a treatment period of 40 weeks. This formulation is used during the maintenance phase of the study. The administration of this form is facilitated by the UltraSafe Passive Delivery System, a needle guard system that ensures safe and accurate delivery of the medication.

The third form is **STELARA 45 mg solution for injection**, also administered subcutaneously. The maximum daily dose for this form is 60 mg/m², with a total dose not exceeding 300 mg/m² over a treatment period of 40 weeks. This formulation is also used during the maintenance phase of the study.

In addition to the experimental treatments, the study includes the use of placebo controls, identified as PL1 and PL2. These are non-active substances used to compare the effects of the experimental medication. The placebo is administered in a manner consistent with the active treatments to maintain the study's double-blind design.

The efficacy of **ustekinumab** in the clinical trial will be assessed primarily through the endpoint of clinical remission at Induction Week 8. This trial involves pediatric participants with moderately to severely active Crohn's disease. The primary endpoint is defined as achieving clinical remission, which will be evaluated using the Pediatric Crohn's Disease Activity Index (PCDAI). Participants must have a baseline PCDAI score greater than 30 to be eligible for the study, indicating moderately to severely active disease.

The assessment of efficacy will be conducted at specific timepoints, with the primary evaluation occurring at Week 8 of the induction period. The trial will utilize ileocolonoscopy to confirm active Crohn's disease, defined by the presence of ulceration with a Simple Endoscopic Score for Crohn's Disease (SES-CD) score of 3 or higher. In cases where ulceration cannot be evaluated due to stricture or inadequate bowel preparation, alternative criteria such as elevated C-reactive protein (CRP) levels or fecal calprotectin levels will be used to confirm disease activity.

Data collection will involve validated scales and laboratory tests to ensure accurate measurement of the efficacy parameters. The trial is designed to provide a comprehensive evaluation of the efficacy of ustekinumab in inducing clinical remission in the target population, with the aim of improving treatment outcomes for pediatric patients with Crohn's disease.