A Phase 3 Multicenter Study to Evaluate Efficacy, Safety, and Pharmacokinetics of Upadacitinib with Open-Label Induction, Randomized, Double-Blind Maintenance and Open-Label Long-Term Extension in Pediatric Subjects with Moderately to Severely Active Ulcerative Colitis and Inadequate Response, Intolerance, or Medical Contraindications to Corticosteroids, Immunosuppressants, and/or Biologic Therapy

The primary objective of this Phase 3 multicenter study is to evaluate the **efficacy** of **Upadacitinib** in pediatric subjects with moderately to severely active **ulcerative colitis**. The study aims to demonstrate efficacy by assessing the rate of subjects achieving Adapted Mayo Score (AMS) clinical remission at Week 8 during the open-label induction phase and at Week 52 among Week 8 responders during the double-blind maintenance phase. This is based on the intent-to-treat (ITT) population for the induction endpoint and the modified ITT (mITT) population for the maintenance endpoint, compared to an external placebo. The clinical relevance of this objective lies in its potential to provide a new therapeutic option for pediatric patients who have an inadequate response, intolerance, or medical contraindications to corticosteroids, immunosuppressants, and/or biologic therapy.

Secondary objectives include demonstrating efficacy based on a higher rate of subjects achieving ranked secondary endpoints in the specified pediatric subjects, using the ITT population for induction efficacy and the mITT population for maintenance efficacy, compared to an external placebo.

The clinical trial involves a total of **74 participants** diagnosed with **Ulcerative Colitis**. The study population comprises pediatric subjects, both male and female, aged between 2 to 17 years. Participants are required to have a documented diagnosis of moderately to severely active Ulcerative Colitis, characterized by an Adapted Mayo Score (AMS) of 5 to 9 points and an endoscopy subscore of 2 or 3. The trial includes individuals who have shown an inadequate response, loss of response, intolerance, or medical contraindications to corticosteroids, immunosuppressants, and/or biologic therapy. All subjects must weigh at least 10 kg at the time of screening and baseline. The selection process ensures the exclusion of current infections, colonic dysplasia, and malignancy, confirmed by colonoscopy during the screening period. Participants must have discontinued specific biologic agents, such as infliximab and adalimumab, two half-lives prior to baseline, and any other biologic agent or procedure within 30 days or five half-lives prior to baseline, whichever is longer. The trial does not require a minimum washout period for biologic therapy if there is proper documentation of an undetectable drug level. The study population is considered vulnerable, given the pediatric nature of the participants.

The clinical trial is designed to evaluate the **efficacy**, safety, and pharmacokinetics of **Upadacitinib** in pediatric subjects with moderately to severely active **ulcerative colitis**. This is a Phase 3, multicenter study that includes an open-label induction phase, a randomized, double-blind maintenance phase, and an open-label long-term extension. The trial aims to demonstrate the efficacy of Upadacitinib by achieving a higher rate of subjects with Adapted Mayo Score (AMS) clinical remission at Week 8 and Week 52 among Week 8 responders, compared to an external placebo. The study is expected to conclude by August 2028, with recruitment having commenced in August 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease severity, and previous treatment history. The primary inclusion criteria require pediatric subjects aged 2 to 17 years with a documented diagnosis of ulcerative colitis, confirmed by colonoscopy, and an inadequate response or intolerance to corticosteroids, immunosuppressants, or biologic therapy. The study will exclude subjects with current infections, colonic dysplasia, or malignancy. Following the screening, eligible participants will enter the induction phase, where they will receive open-label Upadacitinib for 8 weeks. Those who achieve clinical remission will be randomized into the double-blind maintenance phase for an additional 44 weeks, with the possibility of continuing into the open-label long-term extension.

The expected length of participant involvement is up to 304 weeks, depending on their response and continuation into the long-term extension phase. Study visits will be scheduled at regular intervals to monitor safety, efficacy, and pharmacokinetics, with assessments including clinical evaluations, laboratory tests, and endoscopic procedures. The end-of-study visit will occur at the conclusion of the participant's involvement, where final assessments will be conducted. Conditions that may lead to early termination from the study include adverse events, withdrawal of consent, or non-compliance with study procedures. The trial is structured to ensure rigorous monitoring and adherence to ethical standards, with the primary and secondary endpoints focused on achieving clinical remission and endoscopic improvement.

The clinical trial involves the administration of **Upadacitinib**, a Janus kinase (Jak) inhibitor, in various pharmaceutical forms. The first form is a **prolonged-release tablet**. This formulation is designed for oral administration and is not a pediatric formulation. The maximum treatment period for this form is 16 weeks. The dosage and frequency of administration are determined based on the study protocol, with compliance monitored throughout the trial.

Another form of **Upadacitinib** used in the trial is an **oral solution**. This formulation is specifically designed as a pediatric formulation, allowing for easier administration in younger participants. The maximum treatment period for this form is 304 weeks. The oral solution is administered according to the dosing schedule outlined in the study protocol, with participant compliance closely monitored.

The trial also includes a **modified-release tablet** form of **Upadacitinib**. This formulation is intended for oral administration and is not a pediatric formulation. The maximum treatment period for this form is 304 weeks. The dosing schedule is specified in the study protocol, and adherence to the regimen is monitored to ensure participant compliance.

In addition to the experimental treatments, the study may involve the use of standard-of-care therapies, placebos, or comparator treatments as outlined in the study protocol. These non-experimental treatments are administered according to the guidelines provided, and participant adherence is monitored to ensure the integrity of the trial data.

The efficacy of **Upadacitinib** in the treatment of moderately to severely active ulcerative colitis in pediatric subjects will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoints include the achievement of Adapted Mayo Score (AMS) clinical remission at Week 8 during the induction phase and at Week 52 during the maintenance phase among Week 8 responders. These assessments will be conducted on the intent-to-treat (ITT) population for the induction phase and the modified ITT (mITT) population for the maintenance phase, comparing the results to an external placebo group.

Secondary efficacy endpoints will evaluate additional clinical outcomes, such as endoscopic improvement, defined as a Mayo Endoscopic Score (MES) of 1 or less, and Partial Mayo Score (PMS) clinical remission, defined as a PMS of 2 or less with no individual subscore greater than 1, both at Week 8. Further assessments at Week 52 among Week 8 responders will include endoscopic improvement, PMS clinical remission, AMS clinical response, and the ability to discontinue corticosteroids while achieving AMS clinical remission. The AMS clinical response is characterized by a decrease in AMS by at least 2 points and 30% from baseline, with a decrease in Rectal Bleeding Subscore (RBS) of at least 1 or an absolute RBS of 0 or 1.