Evaluation of Vedolizumab and Upadacitinib Efficacy and Safety in Adults with Moderate to Severe Crohn's Disease: A Randomized, Double-Blind, Phase 3b Study

The primary objective of this study is to evaluate whether **dual targeted therapy** (DTT) with vedolizumab and upadacitinib during induction improves clinical and endoscopic outcomes by Week 12, compared with vedolizumab monotherapy, in participants with moderately to severely active **Crohn's disease**. This is clinically relevant as it aims to determine the potential enhanced efficacy of combining these therapies in achieving better disease control and symptom relief in a population with significant disease activity.

Secondary objectives include:

• To evaluate further the short-term clinical and endoscopic benefits of DTT during induction, compared with vedolizumab monotherapy, in participants with moderately to severely active Crohn's disease.
• To evaluate the efficacy of vedolizumab maintenance therapy after DTT during induction, compared with vedolizumab monotherapy throughout the study, in participants with moderately to severely active Crohn's disease.

The clinical trial involves a total of **172 participants** diagnosed with **Crohn's Disease**. The study population includes both male and female subjects, aged between 18 and 64 years, who have been diagnosed with moderately to severely active Crohn's Disease. Participants were selected based on their confirmed diagnosis established at least three months prior to screening, with clinical and endoscopic evidence corroborated by a histopathology report. The trial includes individuals who have demonstrated an inadequate response to, loss of response to, or intolerance to corticosteroids, immunomodulators, or biologic therapy. The study population is characterized by a vulnerable group, indicating that special considerations may be necessary for their participation. Lifestyle factors such as diet, physical activity, and habits were not specified in the provided data.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy and safety of dual targeted therapy with intravenous **vedolizumab** and oral **upadacitinib** compared to intravenous vedolizumab and oral placebo in adults with moderately to severely active **Crohn's disease**. The trial is structured in two phases: an induction phase followed by a maintenance phase. The primary objective is to assess whether the combination therapy improves clinical and endoscopic outcomes by Week 12 compared to vedolizumab monotherapy. The trial is expected to commence recruitment in March 2025 and conclude by August 2028, with a maximum treatment period of 52 weeks for participants.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a confirmed diagnosis of Crohn's disease, evidence of mucosal inflammation, and previous inadequate response to certain therapies. Following successful screening, participants will be randomized to receive either the combination therapy or the control regimen. Study visits will occur at regular intervals to monitor safety, efficacy, and adherence to the treatment protocol. The primary endpoints include achieving clinical remission and endoscopic response by Week 12, with secondary endpoints extending to Week 52.

The expected duration of participant involvement is up to 52 weeks, with conditions for early termination including adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial will ensure blinding by using a placebo to match the blinded upadacitinib, maintaining the integrity of the study design. Participants will conclude their involvement with an end-of-study visit, where final assessments will be conducted to evaluate the long-term outcomes of the treatment. The trial's methodology and design are aligned with rigorous scientific standards to ensure the reliability and validity of the results.

The clinical trial involves the administration of **Entyvio**, a 300 mg powder for concentrate for solution for infusion, containing the active substance **vedolizumab**. Vedolizumab is a protein-based therapeutic agent classified under the ATC code L04AG05. The pharmaceutical form is a solution for infusion, and it is administered intravenously. The maximum daily dose is 300 mg, with a total maximum dose of 4350 mg over a treatment period of up to 52 weeks. The product is manufactured by Takeda Pharma A/S and is not a pediatric formulation. Participant compliance with the dosing schedule will be monitored throughout the trial.

Another treatment used in the study is **RINVOQ**, which consists of 45 mg prolonged-release tablets containing the active substance **upadacitinib**. Upadacitinib is a chemical entity with the ATC code L04AF03. The tablets are administered orally, with a maximum daily dose of 45 mg and a total maximum dose of 7560 mg over a 52-week treatment period. For blinding purposes, the tablets are over-encapsulated, although this does not alter the characteristics of upadacitinib. The product is manufactured by AbbVie Deutschland GmbH & Co. KG and is not intended for pediatric use. Compliance with the oral dosing regimen will be closely monitored during the trial.

The study also includes a **placebo** designed to match the blinded upadacitinib. The placebo is used as a comparator treatment to evaluate the efficacy and safety of the experimental medications. The placebo does not contain any active substance and is administered in a manner consistent with the experimental oral treatment to maintain the study's double-blind design. Participant adherence to the placebo regimen will be monitored to ensure the integrity of the trial results.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints include **CDAI-defined clinical remission** at Week 12, characterized by a Crohn's Disease Activity Index (CDAI) score of less than 150, and an endoscopic response at Week 12, defined as a greater than 50% decrease in the Simple Endoscopic Score for Crohn's Disease (SES-CD) from baseline, as evaluated by a central reviewer. Secondary endpoints will include PRO2-defined clinical remission at Week 12, which is determined by a 7-day average of very soft or liquid stool frequency of 2.8 or less, a 7-day average abdominal pain score of 1.0 or less, with neither being worse than baseline. Additionally, assessments at Week 52 will include CDAI-defined clinical remission, endoscopic response, and PRO2-defined clinical remission.

The efficacy parameters will be measured and collected at specified timepoints, including Week 12 and Week 52. The CDAI and SES-CD scores will be utilized as validated scales for evaluating clinical and endoscopic outcomes. The PRO2 criteria will be used to assess patient-reported outcomes related to stool frequency and abdominal pain. These assessments will be conducted in a double-blind manner to ensure unbiased results. The data collected will be analyzed to determine the efficacy of the dual targeted therapy with intravenous vedolizumab and oral upadacitinib compared to vedolizumab monotherapy in participants with moderately to severely active Crohn's Disease.