Long-term Safety and Tolerability Evaluation of Oral Zasocitinib in Moderate to Severe Ulcerative Colitis and Crohn's Disease Patients

The primary objective of this study is to assess the long-term **safety** and tolerability of oral zasocitinib in participants with moderately to severely active Crohn's Disease (CD) or Ulcerative Colitis (UC). This evaluation is crucial as it determines the viability of zasocitinib as a long-term treatment option for these chronic inflammatory conditions, ensuring that the benefits of the medication outweigh any potential risks over an extended period.

Secondary objectives include:

• For CD: Evaluating the long-term efficacy of zasocitinib in achieving clinical remission, clinical response, endoscopic response, and endoscopic remission over time in participants who meet response criteria at Week 52 in the parent phase 2 CD trial and receive long-term treatment for up to 108 weeks.
• For UC: Assessing the long-term efficacy of zasocitinib in achieving clinical remission, clinical response, symptomatic remission, and endoscopic changes over time in participants who meet response criteria at Week 52 in the parent phase 2 UC trial and receive long-term treatment for up to 108 weeks.
• For both CD and UC: Evaluating the effect of zasocitinib on patient-reported symptoms and disease-specific health-related quality of life (HRQoL) in participants who meet response criteria at Week 52 in the parent phase 2 trials and receive long-term treatment for up to 108 weeks.

The clinical trial involves a total of **83 participants** diagnosed with **moderate to severely active ulcerative colitis** and **moderate to severely active Crohn's disease**. The study population includes both male and female subjects, with age categories ranging from young adults to older adults. Participants were selected based on their completion of Week 52 in the parent phase 2 trials, demonstrating a clinical or symptomatic response. The trial population is characterized by individuals who are nonpregnant, nonlactating, or of nonchildbearing potential, and those of reproductive potential are required to adhere to specific contraceptive measures. The study includes a vulnerable population, ensuring that all participants are willing and able to comply with trial procedures. Lifestyle considerations such as diet and physical activity are not specified, but participants must have provided informed consent and privacy authorization prior to trial initiation.

The clinical trial is designed as a **Phase 2, open-label extension** study to evaluate the long-term safety and tolerability of oral **zasocitinib** in participants with moderately to severely active **ulcerative colitis** and **Crohn's disease**. Participants who have completed Week 52 in the parent phase 2 trials and meet the response criteria will be eligible for inclusion. The trial will involve long-term treatment with zasocitinib for up to 108 weeks. The primary endpoints include the incidence of treatment-emergent adverse events, clinically significant changes in vital signs, and adverse events of special interest. Secondary endpoints focus on clinical remission and response, endoscopic assessments, and health-related quality of life measures.

The trial will commence with a screening visit to confirm eligibility, including the completion of Week 52 in the parent trials and the presence of a clinical or symptomatic response. Participants will then enter the treatment phase, with regular follow-up visits scheduled to monitor safety and efficacy outcomes. These visits will include assessments of clinical remission, response, and endoscopic evaluations at specified intervals, such as Weeks 48 and 108. The end-of-study visit will conclude the trial, ensuring all necessary data is collected and any remaining safety assessments are completed.

Participant involvement is expected to last up to 108 weeks, with conditions for early termination including withdrawal of consent, non-compliance with trial procedures, or the occurrence of significant adverse events. The trial is structured to ensure rigorous monitoring and data collection, adhering to the highest standards of clinical research methodology.

The clinical trial involves the administration of **Zasocitinib**, an experimental medication developed by Takeda Development Center Americas, Inc. Zasocitinib is a small molecule chemical compound, also known by its synonyms NDI-034858 and TAK-279. The pharmaceutical form of Zasocitinib is a capsule, designed for oral administration. Participants in the trial will receive Zasocitinib orally, with the dosing schedule determined by the study protocol. The maximum treatment period for Zasocitinib is 112 days, although the specific dosage and frequency of administration are not detailed in the provided data. The trial aims to evaluate the long-term safety and tolerability of Zasocitinib in participants with moderately to severely active **Crohn's Disease** or **Ulcerative Colitis**.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are mentioned. The focus is solely on the administration of Zasocitinib. Participant compliance with the dosing regimen will be monitored throughout the trial to ensure adherence to the study protocol. The trial is an open-label extension, allowing for the observation of long-term effects of the medication in participants who have met response criteria in previous phase 2 trials. The study does not include a pediatric formulation of the drug, and it is not classified as an orphan drug. The trial's primary objective is to assess the safety and tolerability of Zasocitinib over an extended period, contributing to the understanding of its potential therapeutic benefits for individuals with Crohn's Disease and Ulcerative Colitis.

Efficacy in this clinical trial will be assessed using a range of primary and secondary endpoints. The primary endpoints include the incidence of treatment-emergent adverse events (TEAEs) by indication, clinically significant changes in vital signs, clinical laboratory parameters, and electrocardiogram by indication, as well as the incidence of adverse events of special interest (AESIs) by indication. Secondary endpoints focus on clinical remission and response, endoscopic response and remission, and patient-reported outcomes.

For participants with **Crohn's Disease (CD)**, clinical remission will be assessed by the proportion of participants achieving a CD Activity Index (CDAI) score of less than 150. Clinical response will be evaluated by the proportion of participants achieving a reduction in CDAI from baseline by more than 100. Endoscopic response and remission will be assessed at annual assessments at Week 48 and Week 108, with specific criteria for the simplified endoscopic score for CD (SES-CD). Patient-reported outcomes will include assessments of stool frequency and abdominal pain scores.

For participants with **Ulcerative Colitis (UC)**, clinical remission will be assessed using a modified Mayo Score (mMS) with specific subscores for stool frequency, rectal bleeding, and endoscopic findings. Clinical response will be evaluated by the reduction in mMS from baseline. Endoscopic improvement and remission will also be assessed at annual assessments. Additional patient-reported outcomes will include measures of bowel urgency, abdominal pain, fatigue, and health-related quality of life (HRQoL) using the Inflammatory Bowel Disease Questionnaire (IBDQ).