Orismilast for the treatment of moderate to severe ulcerative colitis

The primary objective of this study is to explore evidence of **efficacy** of orismilast in the oral treatment of patients with moderate to severe **ulcerative colitis** (UC) when dosed twice daily for up to 12 weeks. This is clinically relevant as it aims to determine the therapeutic potential of orismilast in managing UC, a chronic inflammatory bowel disease that significantly impacts patient quality of life.

Secondary objectives include:

• To add depth and detail to the primary objective using Total Mayo score and validated biomarker measures.
• To explore the impact of orismilast on patient-reported quality of life.
• To investigate the safety and tolerability of orismilast in the oral treatment of patients with UC when applied twice daily for up to 12 weeks.

The clinical trial involves **adult patients** diagnosed with **ulcerative colitis**, aged 18 years and older, including both male and female participants. The sponsor has not provided the total number of participants. The study population was selected based on specific criteria, including a confirmed diagnosis of ulcerative colitis with a minimum of three months of disease history and a Mayo endoscopic subscore of 2 or 3 at screening. Participants are required to be on a stable medication regimen for at least three months, which may include treatments such as 5-ASA, mercaptopurine, methotrexate, or azathioprine, and now require intensification of their treatment. Women of childbearing potential must adhere to highly effective birth control methods throughout the trial and for 16 weeks after the last administration. The trial does not include a vulnerable population, and participants are expected to have provided informed consent in accordance with GCP and local legislation.

The clinical trial is designed to evaluate the efficacy of **orismilast** in the treatment of moderate to severe **ulcerative colitis**. This is a Phase 4, randomized, double-blind, controlled study with a primary objective to assess the proportion of patients achieving clinical remission on the Total Mayo score at Week 12. The trial will involve the administration of orismilast in a modified-release tablet form, dosed orally twice daily for a period of up to 12 weeks. The study is expected to commence recruitment on October 2, 2023, and conclude by September 30, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of ulcerative colitis, and current treatment regimen. The inclusion criteria specify that participants must be adults aged 18 years or older, with a minimum of three months of disease history and a Mayo endoscopic subscore of 2 or 3 at screening. Women of childbearing potential must adhere to highly effective birth control methods throughout the trial and for 16 weeks post-treatment. Following the screening, participants will attend follow-up visits at Weeks 2, 4, 6, and 12 to monitor changes in clinical parameters, including high-sensitivity C-reactive protein levels, fecal calprotectin levels, and the Total Mayo score. The end-of-study visit will occur at Week 12, where the primary and secondary endpoints will be assessed.

The expected duration of participant involvement is approximately 12 weeks, with conditions for early termination including the occurrence of treatment-emergent adverse events, serious adverse events, or adverse events of special interest. Participants may also be withdrawn if they fail to comply with the study protocol or if their condition necessitates a change in treatment. The trial will ensure adherence to Good Clinical Practice (GCP) and local legislation, with informed consent obtained from all participants prior to any screening procedures.

The clinical trial involves the use of **Orismilast**, a **modified-release tablet** developed by UNION THERAPEUTICS A/S. The active substance in this medication is **orismilast**, which is of chemical origin. The trial includes two different dosing regimens of Orismilast. The first regimen involves a maximum daily dose of 20 mg, with a total maximum dose of 7300 mg over a treatment period of up to 52 weeks. The second regimen allows for a higher maximum daily dose of 60 mg, with a total maximum dose of 21900 mg over the same treatment period. Both regimens are administered orally, and the medication is not formulated for pediatric use. The trial aims to evaluate the efficacy of Orismilast in the treatment of moderate to severe **ulcerative colitis**.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data. The dosing schedule for Orismilast involves twice-daily administration, and participant compliance will be monitored throughout the study to ensure adherence to the prescribed regimen. The trial's main objective is to explore the evidence of efficacy of Orismilast in achieving clinically relevant endpoints in patients with ulcerative colitis over a 12-week period.

The efficacy of Orismilast in the treatment of moderate to severe **ulcerative colitis** will be assessed through a series of primary and secondary endpoints. The primary endpoint is the proportion of patients achieving clinical remission, defined as a Total Mayo score of 2 points or lower, with no individual sub-score exceeding 1 point, at Week 12. Secondary endpoints include the percent change in levels of high-sensitivity C-reactive protein and fecal calprotectin from baseline at Weeks 2, 4, 6, and 12. Additionally, the proportion of patients with endoscopic improvement at Week 12, defined by a Mayo endoscopic subscore of 0 or 1 without friability, will be evaluated.

Further secondary endpoints involve changes from baseline in specific items of the Total Mayo score, known as PRO2, at Week 12, and clinical response at Week 12, defined as a decrease from baseline in the Total Mayo score by at least 3 points and 30%, with a decrease in the rectal bleeding subscore by at least 1. Patient-reported outcomes will be measured using the Short Inflammatory Bowel Disease Questionnaire (sIBDQ) and the Hospital Anxiety and Depression Scale (HADS), with changes from baseline assessed at Weeks 2, 4, 6, and 12. The occurrence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events of special interest (AESIs) will be monitored throughout the study.