Long-term Efficacy and Safety of Ustekinumab in Crohn's Disease Patients with Secondary Loss of Response: An Open-Label Extension Study

The primary objective of this study is to evaluate the long-term **clinical efficacy** of a ustekinumab 90mg subcutaneous (SC) every 4 weeks (Q4w) regimen in patients with **Crohn's disease** (CD) who were previously enrolled in the REScUE study due to a secondary loss of response to a ustekinumab 90mg SC every 8 weeks (Q8w) regimen. This objective is clinically relevant as it aims to determine the sustained effectiveness of a more frequent dosing schedule in managing CD, which is crucial for optimizing treatment strategies and improving patient outcomes.

The secondary objectives include:

• Assessing the long-term safety of the ustekinumab 90mg SC Q4w regimen in the same patient population, which is essential for understanding the risk-benefit profile of the treatment.
• Evaluating the long-term biochemical effect of the regimen, providing insights into the biological response and potential biomarkers of efficacy.
• Assessing the long-term endoscopic effect, which is important for visualizing mucosal healing and disease progression.
• Determining the additional benefit of dose optimization to a ustekinumab 90mg SC Q4w regimen in patients experiencing worsening of CD during treatment with a ustekinumab 90mg SC Q8w regimen, which could inform personalized treatment adjustments.

The clinical trial involves participants diagnosed with **Crohn's disease**, focusing on individuals who have previously been enrolled in the REScUE study. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. The trial does not involve a vulnerable population. Participants were selected based on their prior inclusion in the REScUE study and their completion of the study at week 48. The sponsor has not provided the total number of participants. Key lifestyle considerations include the requirement for adequate contraception for females of reproductive age and males with partners of reproductive age. Participants must have the capacity to understand and sign an informed consent form and be able to adhere to the study visit schedule and other protocol requirements.

The clinical trial is designed to evaluate the long-term clinical efficacy and safety of **ustekinumab** in patients with **Crohn's disease** who were previously enrolled in a study due to secondary loss of response to a ustekinumab 90 mg subcutaneous injection every 8 weeks regimen. This trial is an open-label extension study, integrating Phase III and Phase IV elements, and is not classified as a low-intervention trial. The trial aims to assess the efficacy of a 90 mg subcutaneous injection of ustekinumab administered every 4 weeks. The primary endpoint is the proportion of patients achieving steroid-free clinical remission at both week 56 and week 112. Secondary endpoints include the incidence and severity of adverse events, time to disease worsening, and various remission metrics at specified intervals.

The trial is expected to run until December 31, 2026, with recruitment having commenced on September 10, 2021. Participants will be involved in the study for a maximum treatment period of 112 weeks. The study visits are structured to include an initial screening visit to confirm eligibility, followed by regular follow-up visits to monitor treatment efficacy and safety. The end-of-study visit will conclude the participant's involvement, assessing the final outcomes and any long-term effects of the treatment. Participants must have completed the previous study and meet specific inclusion criteria, such as the ability to adhere to the study schedule and provide informed consent. Conditions for early termination from the study include non-compliance with the protocol or the occurrence of significant adverse events. The study employs a subcutaneous route of administration for the investigational product, which is provided in a pre-filled syringe formulation.

The clinical trial involves the administration of **STELARA** (ustekinumab), a biologic medication formulated as a **solution for injection in a pre-filled syringe**. The active substance, ustekinumab, is a protein-based therapeutic agent. The pharmaceutical form is specifically designed for **subcutaneous injection**. Each pre-filled syringe contains a dosage of 90 mg of ustekinumab. The administration schedule for the trial is set at a frequency of every four weeks (Q4w), with a maximum treatment period of 112 weeks. The total maximum dose over the course of the study is 2520 mg. The medication is manufactured by Janssen-Cilag International NV and is not a pediatric formulation.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the long-term efficacy and safety of the ustekinumab regimen in patients with Crohn's disease who have previously experienced a secondary loss of response to a different dosing schedule of the same medication. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol.

The clinical trial aims to assess the long-term efficacy of a **ustekinumab** 90 mg subcutaneous injection administered every four weeks in patients with Crohn's disease who previously experienced a secondary loss of response to a regimen of ustekinumab 90 mg every eight weeks. Efficacy will be primarily evaluated by the proportion of patients achieving steroid-free clinical remission at both week 56 and week 112. This is defined as achieving PRO-2 remission, characterized by an average abdominal pain score (AP) of ≤1 and an average stool frequency (SF) of ≤3, without any steroid use in the preceding 28 days.

Secondary endpoints include the incidence and severity of adverse events, time to Crohn's disease worsening, and various remission rates at specified time points. These include clinical remission, biomarker remission (CRP <5 mg/L and fecal calprotectin ≤250 µg/g), and endoscopic remission (total SES-CD <5 or <4 for isolated ileitis) at weeks 56 and 112. Complete endoscopic remission, defined as a total SES-CD <3, will also be assessed. The trial will utilize validated scales and laboratory tests to measure these parameters at the designated time points.