Evaluation of Upadacitinib Efficacy, Safety, and Pharmacokinetics in Pediatric Patients with Moderate to Severe Crohn's Disease: A Phase 3 Multicenter Study

The primary objective of this Phase 3 multicenter study is to evaluate the **efficacy** of **upadacitinib** in pediatric subjects with moderately to severely active **Crohn's Disease** who have shown an inadequate response, intolerance, or medical contraindications to corticosteroids, immunosuppressants, and/or biologic therapy. The study aims to demonstrate a higher rate of participants achieving the co-primary endpoints of clinical remission per the Pediatric Crohn's Disease Activity Index (PCDAI) and endoscopic response at Week 64. This is assessed in the modified intent-to-treat population, which includes all participants who achieved clinical response per PCDAI at Week 12 and were randomized into the maintenance phase, comparing at least the upadacitinib 30 mg adult equivalent dose to an external placebo. The clinical relevance of this objective lies in its potential to provide an effective treatment option for pediatric patients with limited therapeutic alternatives due to the failure of standard treatments.

The clinical trial involves a total of **98 participants** diagnosed with **Crohn's Disease (CD)**. The study population includes both male and female subjects, with an age range starting from 2 years old. Participants were selected based on specific criteria, including a documented diagnosis of moderate to severe CD, as defined by a Pediatric Crohn's Disease Activity Index (PCDAI) greater than 30 and endoscopic evidence of mucosal inflammation. The trial excludes vulnerable populations and focuses on individuals who have demonstrated an inadequate response, loss of response, or intolerance to corticosteroids, immunomodulators (IMMs), and/or biologic therapy, or for whom these therapies are medically contraindicated. Participants are required to have a weight of at least 10 kg at screening and baseline. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection process ensures that participants have a confirmed diagnosis of CD, with appropriate documentation of biopsy results consistent with the diagnosis, and excludes those with current infections, colonic dysplasia, or malignancy.

The clinical trial is a **Phase 3** multicenter study designed to evaluate the efficacy, safety, and pharmacokinetics of **upadacitinib** in pediatric subjects with moderately to severely active **Crohn's Disease**. The trial employs a randomized, double-blind, controlled design with an open-label induction phase, a randomized double-blind maintenance phase, and an open-label long-term extension. The estimated duration of the trial is from September 2024 to December 2034, with participant involvement expected to last up to 220 weeks, depending on the treatment phase and response.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as weight, disease severity, and previous treatment responses. The screening will include a colonoscopy to confirm the diagnosis of Crohn's Disease and exclude other conditions. Following successful screening, participants will enter the induction phase, where they will receive open-label **upadacitinib**. Those achieving a clinical response at Week 12 will be randomized into the maintenance phase, where they will receive either **upadacitinib** or placebo in a double-blind manner. The primary endpoints include achieving clinical remission and endoscopic response at Week 64.

Follow-up visits will occur at regular intervals to monitor safety, efficacy, and pharmacokinetics, with assessments including the Pediatric Crohn's Disease Activity Index (PCDAI) and endoscopic evaluations. The end-of-study visit will conclude the participant's involvement, with a comprehensive assessment of their health status and any adverse events. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study procedures. The trial aims to provide valuable data on the long-term use of **upadacitinib** in this patient population, contributing to the understanding of its therapeutic potential in pediatric Crohn's Disease.

The clinical trial involves the administration of **Upadacitinib**, a chemical compound, in various pharmaceutical forms. The primary experimental medication is a **modified-release tablet** of Upadacitinib, which is administered orally. This formulation is designed for pediatric use and is provided by AbbVie Deutschland GmbH & Co. KG. The dosage is measured in milligrams, with a maximum treatment period of 208 weeks. The specific dosage and frequency of administration are determined based on the study protocol, ensuring participant safety and compliance.

Another formulation of Upadacitinib used in the trial is an **oral solution**, also intended for pediatric use. This formulation allows for flexible dosing, particularly beneficial for younger participants who may have difficulty swallowing tablets. The oral solution is administered orally, with the dosage expressed in milligrams per milliliter. The maximum treatment period for this formulation is 52 weeks, and dosing schedules are tailored to achieve optimal therapeutic outcomes while monitoring participant compliance.

The trial also includes a **prolonged-release tablet** form of Upadacitinib, which is administered orally. This formulation is designed to release the active substance over an extended period, potentially enhancing therapeutic efficacy and reducing dosing frequency. The prolonged-release tablet is part of the pediatric formulation strategy, with a maximum treatment period of 12 weeks. The dosing regimen is carefully monitored to ensure adherence and evaluate the drug's pharmacokinetic profile.

In addition to the experimental medications, the study utilizes several non-experimental treatments. **Methotrexate**, an antineoplastic agent, is included as a comparator treatment. It is administered as an oral solution, with the dosage in milligrams. The maximum treatment period for Methotrexate is 52 weeks, and it is sourced locally by investigational sites. Participant compliance with Methotrexate administration is monitored throughout the trial.

**Ciprofloxacin**, a fluoroquinolone antibiotic, is also used in the study. It is provided as a solution for infusion, administered intravenously. The dosage is measured in milligrams, with a maximum treatment period of 52 weeks. Ciprofloxacin is locally sourced, and its administration is closely monitored to ensure participant safety and adherence to the study protocol.

**Sulfasalazine**, an aminosalicylic acid derivative, is included as an oral tablet. The dosage is expressed in milligrams, with a maximum treatment period of 52 weeks. Sulfasalazine is locally sourced, and its administration is monitored to ensure compliance and evaluate its role in the study's therapeutic strategy.

Lastly, **Dexamethasone**, a corticosteroid, is used as a solution for injection or infusion, administered intravenously. The dosage is in milligrams, with a maximum treatment period of 52 weeks. Dexamethasone is locally sourced, and its administration is monitored to ensure participant safety and adherence to the study protocol.

The efficacy of **Upadacitinib** in the clinical trial will be assessed through a series of predefined endpoints. The primary endpoints include the achievement of clinical remission per the Pediatric Crohn's Disease Activity Index (PCDAI) and endoscopic response at Week 64 in pediatric participants. These endpoints will be evaluated in participants who achieved a clinical response per PCDAI at Week 12 and were subsequently randomized into the maintenance phase. The secondary endpoints will assess the achievement of clinical remission and endoscopic response at Week 12, as well as endoscopic remission and corticosteroid-free clinical remission at Week 64 in participants who achieved a clinical response per PCDAI at Week 12.

The efficacy parameters will be measured using the PCDAI, a validated scale for assessing disease activity in pediatric Crohn's disease. The schedule for measuring these parameters includes assessments at Week 12 and Week 64. The analysis will focus on the modified intent-to-treat population, which consists of all participants who achieved a clinical response per PCDAI at Week 12. The trial aims to demonstrate the efficacy of Upadacitinib by comparing the outcomes to an external placebo group, ensuring a robust evaluation of the treatment's impact on disease activity and remission rates.