Efficacy and Safety of Upadacitinib in Maintenance and Long-Term Extension for Crohn's Disease Post-Induction Responders

The primary objective of this study is to assess the **efficacy** and **safety** of two doses of upadacitinib compared to placebo as maintenance therapy in subjects with moderately to severely active **Crohn's disease** who have responded to upadacitinib induction treatment in previous studies (M14-431 or M14-433). This evaluation is crucial for determining the long-term management potential of upadacitinib in maintaining disease remission and improving patient outcomes in Crohn's disease.

Secondary objectives include evaluating improvements in several efficacy parameters, such as steroid discontinuation, laboratory parameters, and quality of life questionnaires. These assessments aim to provide a comprehensive understanding of the therapeutic benefits and impact on patients' daily lives.

The clinical trial involves a total of **747 participants** diagnosed with **Crohn's Disease**, focusing on individuals with moderately to severely active conditions. The study population includes both male and female subjects, encompassing an age range that includes both adults and adolescents. Participants were selected based on their prior involvement in related studies, specifically those who responded to upadacitinib induction treatment in Studies M14-431 or M14-433. The trial includes a vulnerable population, indicating that special considerations are in place for their participation. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data. The selection criteria emphasize the completion of specific study procedures and achieving clinical response, with allowances for missing endoscopy due to the coronavirus SARS-CoV-2 pandemic. The trial aims to evaluate the efficacy and safety of upadacitinib as a maintenance therapy and its long-term administration.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy and safety of **upadacitinib** in subjects with moderately to severely active **Crohn's disease**. The trial consists of two sub-studies: a maintenance phase and a long-term extension phase. The maintenance phase involves subjects who have responded to upadacitinib induction treatment in previous studies, while the long-term extension phase evaluates the continued safety and efficacy of upadacitinib. The trial is expected to last until September 2027, with participant recruitment having commenced in March 2018.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on prior clinical response and completion of specific procedures in earlier studies. Follow-up visits will occur at regular intervals to monitor clinical remission, endoscopic response, and other health parameters. The primary endpoints include the proportion of subjects achieving clinical remission and endoscopic response at Week 52 for the maintenance phase, and the occurrence rate of hospitalizations and surgeries over time for the long-term extension phase. Secondary endpoints focus on various measures of clinical remission, endoscopic outcomes, and corticosteroid use.

The expected length of participant involvement is up to 292 days, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include failure to meet inclusion criteria, withdrawal of consent, or adverse events that compromise participant safety. The trial employs a **modified-release tablet** formulation of upadacitinib, administered orally, with a maximum daily dose of 30 mg or 15 mg, depending on the cohort. A matching placebo is used to maintain the double-blind design. The study is not classified as a low-intervention trial and is conducted in accordance with phase 3 trial standards.

The clinical trial involves the administration of **Upadacitinib**, a **modified-release tablet** developed by AbbVie Deutschland GmbH & Co. KG. The active substance, upadacitinib, is of chemical origin. Two dosage regimens are employed in the study: a 30 mg daily dose and a 15 mg daily dose. The **route of administration** is oral. The maximum treatment period for both dosages is 292 days. The total maximum dose for the 30 mg regimen is 61,320 mg, while for the 15 mg regimen, it is 30,660 mg. The pharmaceutical form is designed to release the active ingredient in a controlled manner over time, ensuring sustained therapeutic levels.

A **matching placebo** is also utilized in the trial to maintain the double-blind design. The placebo is identical in appearance to the investigational medicinal product (IMP) but does not contain the active substance. The placebo is administered orally, following the same schedule as the active treatment groups, to ensure blinding and maintain the integrity of the study results.

The efficacy of **Upadacitinib** in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints for Sub-study 1 include the proportion of subjects achieving clinical remission per patient-reported outcomes (PROs) and endoscopic response at Week 52. For Sub-study 2, the primary endpoint is the occurrence rate of subjects with total hospitalizations, including Crohn's Disease (CD)-related hospitalizations and surgeries over time.

Secondary endpoints for Sub-study 1 involve various measures at Week 52, such as the proportion of subjects achieving clinical remission per the Crohn's Disease Activity Index (CDAI), endoscopic remission, and changes from baseline in the Inflammatory Bowel Disease Questionnaire (IBDQ) and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). Additionally, the study will evaluate the proportion of subjects achieving CR-100, those without corticosteroid use for CD, and those with resolution of extraintestinal manifestations (EIMs). For Sub-study 2, secondary endpoints include the proportion of subjects with clinical remission, enhanced clinical response, and endoscopic remission over time, as well as the time to loss of clinical response and remission.

These efficacy parameters will be measured and collected at specified timepoints, such as Week 0, Week 52, and every 48 weeks thereafter for Sub-study 2. The assessments will utilize validated scales and patient-reported outcomes to ensure accurate and reliable data collection. The analysis will focus on comparing the efficacy of two doses of Upadacitinib versus placebo in maintaining clinical response in subjects with moderately to severely active Crohn's Disease who have previously responded to Upadacitinib induction treatment.