Evaluation of BI 706321 and Ustekinumab Combination Therapy in Patients with Moderately to Severely Active Crohn's Disease: A Randomized, Double-Blind, Placebo-Controlled Phase IIa Trial

The primary objective of this Phase IIa, randomized, double-blind, placebo-controlled trial is to evaluate the **efficacy**, safety, and tolerability of BI 706321 in combination with **ustekinumab** compared to placebo with ustekinumab in patients with moderately to severely active **Crohn's Disease** (CD) over a 12-week period. The primary endpoint is the estimation of the difference in change from baseline in the Simple Endoscopic Score for Crohn's Disease (SES-CD) after 12 weeks. This measure is clinically relevant as it provides an objective assessment of mucosal healing, which is a critical therapeutic goal in the management of CD. No secondary objectives are specified for this study.

The clinical trial involves a total of **16 participants** diagnosed with **Crohn's Disease (CD)**, characterized by moderate to severe activity. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including a confirmed diagnosis of CD for at least three months, elevated C-reactive protein (CRP) or fecal calprotectin levels, and symptomatic CD with a Crohn's Disease Activity Index (CDAI) of 150 or higher. Additionally, the presence of mucosal ulcers and a Simple Endoscopic Score for Crohn's Disease (SES-CD) of 7 or more were required. The trial includes individuals who have prior experience with at least one tumor necrosis factor (TNF) antagonist. Participants may be on a therapeutic dose of oral 5-ASA compounds, oral corticosteroids, or immunosuppressants such as azathioprine (AZA), mercaptopurine (MP), thioguanine (6-TG), or methotrexate (MTX). Women of childbearing potential are required to use highly effective birth control methods. The trial population is considered vulnerable, and the selection process ensures a comprehensive representation of individuals affected by CD.

The clinical trial is a **Phase IIa**, randomized, double-blind, placebo-controlled study designed to evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of **BI 706321** when administered orally for 12 weeks in patients with **Crohn's Disease** receiving **ustekinumab** induction treatment. The trial aims to investigate the first signal of efficacy, safety, and tolerability of BI 706321 in combination with ustekinumab compared to placebo with ustekinumab in patients with moderately to severely active Crohn's Disease over a 12-week period. The primary endpoint is the absolute change from baseline in the Simple Endoscopic Score for Crohn's Disease (SES-CD) at week 12. Secondary endpoints include percent change in SES-CD, endoscopic response and remission, biological remission, and clinical remission and response at weeks 12 and 48.

The trial will involve several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of Crohn's Disease for at least three months, elevated C-reactive protein (CRP) or fecal calprotectin, and symptomatic disease. Participants will be randomized to receive either BI 706321 or placebo, both in combination with ustekinumab. Follow-up visits will occur throughout the 12-week treatment period to monitor safety, efficacy, and any adverse events. The end-of-study visit will assess the primary and secondary endpoints and gather final safety data.

Participant involvement is expected to last approximately 12 weeks, with conditions for early termination including significant adverse events or withdrawal of consent. The trial is estimated to conclude by March 2025, with recruitment having started in October 2021. The study is not classified as low intervention and is conducted to investigate the safety and efficacy of a new therapy in patients with Crohn's Disease.

The clinical trial involves the administration of **BI 706321**, an experimental medication, in the form of a **film-coated tablet**. The active substance, BI 706321, is of chemical origin and is provided by Boehringer Ingelheim International. The medication is administered orally. The trial is designed to evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of BI 706321 over a 12-week period in patients with Crohn's Disease. The dosing schedule and specific dosage amounts are not detailed in the provided data.

In addition to the experimental medication, the trial includes the use of **matching placebo tablets** without an active substance. These placebo tablets are used to maintain the double-blind nature of the study, ensuring that neither the participants nor the investigators know who is receiving the active treatment or the placebo. The placebo is administered in the same manner as the experimental medication, orally, to ensure consistency in the administration process.

The trial also incorporates the use of **ustekinumab**, marketed under the name Stelara, which is a standard-of-care therapy for Crohn's Disease. Ustekinumab is available in two formulations: a 130 mg concentrate for solution for infusion and a 90 mg solution for injection in a pre-filled pen. Both formulations are provided by Janssen-Cilag International NV. The concentrate for infusion is administered intravenously, while the solution in the pre-filled pen is administered subcutaneously. The administration of ustekinumab is part of the induction treatment for patients in the trial, and it is used in combination with either the experimental medication or the placebo.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The trial's primary objective is to assess the difference in change from baseline in the Simple Endoscopic Score for Crohn's Disease (SES-CD) after 12 weeks of treatment. The trial is conducted under a randomized, double-blind, placebo-controlled design to ensure the reliability and validity of the results.

The efficacy of the clinical trial will be assessed primarily through the **Simple Endoscopic Score for Crohn's Disease (SES-CD)**. The primary endpoint is the absolute change from baseline in SES-CD at week 12. Secondary endpoints include the percent change in SES-CD from baseline at week 12, endoscopic response defined as a ≥50% reduction in SES-CD from baseline or at least a 2-point reduction for an induction baseline SES-CD of 4 at week 12 and week 48, and endoscopic remission defined as an SES-CD score of ≤2 at week 12 and week 48.

Additional secondary endpoints involve biological remission, characterized by C-reactive protein (CRP) levels of <5 mg/L and fecal calprotectin (FCP) levels of <250 µg/g at week 12 and week 48. Clinical remission is defined as a Crohn's Disease Activity Index (CDAI) score of <150 at week 12 and week 48. Clinical response at week 12 is defined by a CDAI reduction from baseline of at least 100 points or a CDAI score of <150. The number of patients with treatment-emergent adverse events (TEAEs) will also be monitored through the end of treatment and the residual effect period.