Phase III Double-Blind, Randomized, Placebo-Controlled Study of Norursodeoxycholic Acid in Primary Sclerosing Cholangitis Patients

The primary objective of this study is to demonstrate the **superiority** of norursodeoxycholic acid (norUDCA) compared to placebo in the treatment of **Primary Sclerosing Cholangitis (PSC)**, specifically in terms of preventing disease progression. This is clinically relevant as PSC is a chronic liver disease that can lead to liver failure, and effective treatments are limited. By establishing the efficacy of norUDCA, the study aims to provide a potential therapeutic option that could alter the course of the disease.

Secondary objectives include:

• To study the safety and tolerability of norUDCA, focusing on adverse events and laboratory parameters. This is crucial for understanding the risk-benefit profile of the treatment.
• To assess the quality of life of participants, which is an important measure of the treatment's impact on daily living and overall well-being.

The clinical trial for **primary sclerosing cholangitis (PSC)** involves a total of 81 participants. The study population includes both male and female subjects, with an age range that encompasses young adults to older adults. Participants were selected based on specific criteria, including a verified diagnosis of PSC and the availability of a liver biopsy. The trial includes individuals who are considered part of a vulnerable population. Lifestyle considerations, such as the use of effective birth control methods for women of child-bearing potential, are relevant to the study. The selection process ensures that participants have signed informed consent, and women of non-childbearing potential are included if they are surgically sterile or post-menopausal for at least two years. The trial aims to evaluate the efficacy of norursodeoxycholic acid (norUDCA) compared to placebo in preventing disease progression in PSC patients.

The clinical trial is designed as a **double-blind**, **randomized**, **placebo-controlled**, phase III study aimed at evaluating the efficacy of norursodeoxycholic acid (norUDCA) in the treatment of **primary sclerosing cholangitis** (PSC). The primary objective is to demonstrate the superiority of norUDCA over placebo in preventing disease progression. The trial will involve the administration of norUDCA in the form of hard capsules, with a maximum daily dose of 1500 mg, over a treatment period of up to 336 days. Participants will be randomly assigned to receive either the active treatment or a placebo, ensuring that neither the participants nor the investigators are aware of the group assignments, thus maintaining the integrity of the double-blind design.

The trial is expected to span from the estimated recruitment start date in January 2018 to the estimated end date in March 2026. Participants will be involved in the study for the duration of the treatment period, with regular study visits scheduled to monitor their health and the progression of the disease. The sequence of study visits includes an initial inclusion (screening) visit to confirm eligibility based on criteria such as verified PSC and availability of a liver biopsy. Follow-up visits will occur at regular intervals to assess primary and secondary endpoints, including partial normalization of s-ALP and no worsening of disease stage as determined by the Ludwig stage and modified Nakanuma score. The end-of-study visit will conclude the participant's involvement, with final assessments conducted to evaluate the overall outcomes of the treatment.

Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. Such conditions may include adverse events, withdrawal of consent, or failure to adhere to the study protocol. The trial's design and procedures are structured to ensure the collection of robust data while prioritizing participant safety and adherence to ethical standards.

The clinical trial involves the administration of **norucholic acid**, commercially known as NUC01, which is a synthetic C23 homologue of the 3α,7β-dihydroxy C24 bile acid ursodeoxycholic acid. The pharmaceutical form of NUC01 is a hard capsule, intended for **oral use**. The maximum daily dose of norucholic acid is 1500 mg, with a total maximum dose of 3528 g over the treatment period. The treatment duration is set for a maximum of 336 days. The active substance, norucholic acid, is chemically derived and is not a pediatric formulation. The trial aims to evaluate the efficacy of norucholic acid in the treatment of **Primary Sclerosing Cholangitis** (PSC) by preventing disease progression.

The study also includes a **placebo** group, which serves as a comparator to the experimental treatment. The placebo is designed to match the NUC01 capsules in appearance but does not contain the active substance. The placebo is administered under the same conditions as the experimental medication to maintain the double-blind nature of the trial. The use of a placebo allows for the assessment of the true efficacy of norucholic acid by comparing outcomes between the treatment and placebo groups.

Efficacy in this clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is defined as the partial normalization of serum alkaline phosphatase (s-ALP) levels and no worsening of disease stage as determined by the Ludwig stage. Secondary endpoints include the partial normalization of s-ALP and no worsening of disease stage as determined by the modified Nakanuma score at the week 96 visit compared to baseline. Additional secondary endpoints encompass liver stiffness, fibrosis stage, liver histology, dominant strictures, and quality of life.