Evaluation of Transmural Healing as a Treatment Target in Moderately to Severely Active Crohn's Disease Using Upadacitinib, Risankizumab, and Ustekinumab

The primary objective of this study is to demonstrate that treating to achieve a target of corticosteroid-free **transmural healing** (TMH) combined with intestinal ultrasound (IUS) outcomes, clinical remission, and biomarker remission is superior to a target of corticosteroid-free clinical remission and biomarker remission after 48 weeks in patients with moderately to severely active **Crohn's disease**. This objective is clinically relevant as it aims to establish a more comprehensive treatment target that could potentially lead to better long-term disease control and improved patient outcomes.

Secondary objectives include:

• Comparing composite disease outcomes, clinical outcomes, endoscopic outcomes, IUS outcomes, histologic outcomes, biomarker outcomes, and patient-reported outcomes in participants treated with different treat-to-target strategies for 48 weeks.
• Evaluating the kinetics of IUS outcomes in participants with moderate to severe Crohn's disease treated with vedolizumab, specifically in those randomized to a treatment target of IUS outcomes, clinical remission, and biomarker remission.
• Comparing longer-term outcomes and safety in participants treated with different treat-to-target strategies for 48 weeks.

The clinical trial involves a total of **117 participants** diagnosed with **moderately to severely active Crohn's Disease**. The study population includes adults aged 18 to 80 years, encompassing both male and female subjects. Participants were selected based on specific criteria, including a Crohn's Disease Activity Index (CDAI) score of 220 to 450 and a Simple Endoscopic Score for Crohn's Disease (SES-CD) of ≥6, or ≥4 for those with isolated ileal disease. Additionally, participants must have a C-reactive protein (CRP) level of ≥5 mg/L and/or fecal calprotectin (FCal) of ≥250 μg/g at screening. The trial includes individuals who are biologic-naïve or have had exposure to no more than one advanced therapeutic compound for Crohn's Disease treatment, with only 15% to 30% having prior exposure. Participants may continue a stable dose of 5-aminosalicylic acid (5-ASA) if initiated at least four weeks prior to screening. The study excludes vulnerable populations and requires participants to be capable of full participation, with written informed consent obtained. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of treating to a target of transmural healing in patients with **moderately to severely active Crohn's disease**. This is a randomized, double-blind, controlled study with a primary objective to demonstrate that achieving corticosteroid-free transmural healing plus intestinal ultrasound outcomes is superior to achieving corticosteroid-free clinical and biomarker remission after 48 weeks. The trial is expected to commence on May 31, 2024, and conclude by January 31, 2028, with a total duration of approximately 96 weeks for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, disease activity, and previous treatment exposure. The trial will include multiple follow-up visits at specified intervals, including Weeks 6, 14, 22, 30, 38, and 48, to monitor clinical and biomarker responses. The end-of-study visit will occur at Week 96, where final assessments will be conducted. The expected length of participant involvement is up to 96 weeks, with conditions for early termination including significant adverse events or failure to adhere to study protocols.

The study will involve the administration of various investigational products, including **upadacitinib**, **risankizumab**, **ustekinumab**, **adalimumab**, **infliximab**, and **vedolizumab**, through oral, intravenous, or subcutaneous routes, depending on the specific product. The trial will also utilize corticosteroids such as **prednisone** and **budesonide** as auxiliary treatments. Participants will be monitored for primary endpoints, such as corticosteroid-free endoscopic remission at Week 48, and secondary endpoints, including clinical and biomarker responses at various time points. The trial will ensure rigorous safety monitoring, with exposure-adjusted incidence rates of serious adverse events and adverse events of special interest being recorded throughout the study duration.

The clinical trial involves the administration of several **experimental medications** and non-experimental treatments to evaluate their efficacy in treating moderately to severely active Crohn's Disease. The primary experimental medication is **upadacitinib**, a chemical compound administered orally. It is provided in a pharmaceutical form identified as PHF00212MIG, with a maximum daily dose of 45 mg and a total dose of 15,120 mg over a treatment period of 66 weeks.

**Risankizumab** is another experimental medication used in the trial. It is a protein-based substance administered either intravenously (IV) or subcutaneously (SC). The pharmaceutical form is PHF00231MIG, with a maximum daily dose of 600 mg and a total dose of 23,040 mg over 66 weeks.

**Ustekinumab** is also included in the study, administered via IV or SC routes. It is a protein-based medication with a pharmaceutical form of PHF00230MIG. The maximum daily dose is 520 mg, with a total dose of 1,150 mg over the same treatment period.

**Adalimumab** is administered subcutaneously, with a pharmaceutical form of PHF00231MIG. It is a protein-based medication with a maximum daily dose of 160 mg and a total dose of 2,800 mg over 66 weeks.

**Infliximab** is administered through IV infusion, with a pharmaceutical form of PHF00230MIG. It is a protein-based medication with a maximum daily dose of 5 mg/kg and a total dose of 50 mg/kg over 66 weeks.

**Vedolizumab**, marketed as Entyvio, is administered via intravenous infusion. It is provided as a powder for concentrate for solution for infusion, with a maximum daily dose of 300 mg and a total dose of 7,200 mg over 96 weeks. The product is manufactured by Takeda Pharma A/S and is labeled for clinical trial use.

Non-experimental treatments include **prednisone** and **budesonide**, both classified as corticosteroids. Prednisone is administered orally in tablet form, with a maximum daily dose of 40 mg and a total dose of 1,295 mg over 8 weeks. Budesonide is also administered orally, with a maximum daily dose of 9 mg and a total dose of 357 mg over the same period.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. The study aims to assess the effectiveness of these treatments in achieving corticosteroid-free clinical remission and biomarker remission in patients with Crohn's Disease.

Efficacy in the clinical trial will be assessed using a range of primary and secondary endpoints. The primary endpoint is **corticosteroid-free endoscopic remission** at Week 48. Secondary endpoints include a variety of measures such as corticosteroid-free transmural healing (TMH) combined with endoscopic and clinical remission, corticosteroid-free intestinal ultrasound (IUS) response, and clinical remission at Week 48. Additional secondary endpoints involve corticosteroid-free clinical remission and response at Weeks 14, 22, and 48, as well as changes in the Crohn's Disease Activity Index (CDAI) total score from baseline during follow-up at specified weeks.

Further assessments will include the Simple Endoscopic Score for Crohn's Disease (SES-CD) and its change from baseline to Week 48, TMH, IUS response, bowel wall thickness (BWT), and the Crohn's Disease Segmental Activity Score (CDS) at various timepoints. Biomarker remission and response will be evaluated at Week 48, with C-reactive protein (CRP) and fecal calprotectin (FCal) responses monitored during follow-up. Patient-reported outcomes will be measured using the 2-item Patient-Reported Outcome (PRO 2) score, Symptoms and Impacts Questionnaire for Crohn's Disease (SIQ-CD), and the Urgency Numerical Rating Score (NRS), with changes from baseline assessed at multiple timepoints.

Histologic remission and response at Week 48, as well as time to Crohn's Disease-related complications from randomization through Week 96, will also be evaluated. The trial will monitor exposure-adjusted incidence rates of serious adverse events (SAEs), all adverse events (AEs), and AEs of special interest (AESIs). These efficacy parameters will be collected and analyzed at specified intervals throughout the trial to determine the effectiveness of the treatment strategies being tested.