Efficacy of Ursodeoxycholic Acid versus Corticosteroids for the Treatment of Cholestatic Hepatitis Secondary to Immunotherapy: A Multicenter, Controlled, Randomized, Open Trial

The primary objective of this study is to compare the effectiveness of ursodeoxycholic acid (UDCA) to corticosteroids in treating cholestatic hepatitis induced by immune checkpoint inhibitors (ICIs) over a 21-day period. This evaluation is clinically relevant as immune checkpoint inhibitor-induced hepatotoxicity represents a significant immune-related adverse event that may necessitate treatment discontinuation and requires prompt therapeutic intervention to prevent hepatic complications.

The secondary objectives include:

• Assessment of efficacy in terms of hepatitis resolution at 6 months stratified by treatment response groups, specifically in patients responding to UDCA at day 21, in patients responding to corticosteroids at day 21, in patients who failed UDCA after the addition of corticosteroids at day 21, and in patients who failed corticosteroids after the addition of UDCA at day 21

• Assessment of time to resolution of hepatitis by treatment response group

• Evaluation of the tolerance of UDCA, corticosteroids, and the combination of both agents

• Determination of predictive factors for response to UDCA at day 21

• Assessment of the rate of immune checkpoint inhibitor resumption by treatment response group

The sponsor did not provide information regarding the total number of participants for this clinical trial. The study population includes **adults** aged **18 years and older** of **both genders** diagnosed with **any type of cancer** except **hepatocellular carcinoma** or **cholangiocarcinoma**. Participants are patients who have developed **cholestatic hepatitis** induced by **immune checkpoint inhibitors (ICIs)** and present with specific biochemical parameters, including a ratio R≤2 (where R represents the ratio of ALT/ULN to alkaline phosphatase/ULN) and **Grade 3 or 4** severity according to **CTC-AE** criteria. The trial population includes individuals receiving any therapeutic line, whether **adjuvant** or **palliative**, who have received at least one injection of an ICI. **Women of childbearing age** enrolled in the study are required to use appropriate **contraceptive methods** throughout the entire treatment duration. The trial focuses on patients with a defined clinical condition rather than healthy volunteers.

This is a multicenter, controlled, randomized, open-label trial designed to compare the effectiveness of ursodeoxycholic acid versus corticosteroids for the treatment of cholestatic hepatitis induced by immune checkpoint inhibitors. The study is classified as a Phase IV trial evaluating the efficacy of the investigational medicinal product against standard treatment. The trial will assess adult patients aged 18 years or older with any type of cancer except hepatocellular or cholangiocarcinoma, who have received at least one injection of immune checkpoint inhibitors and developed cholestatic hepatitis with a ratio R≤2 (where R=ratio (ALT/ULN)/(PAL/ULN)), classified as Grade 3 or 4 according to CTC-AE criteria. Women of childbearing age must use appropriate contraceptive methods throughout the entire duration of treatment.

The primary endpoint is the rate of patients showing an improvement of at least 25% in liver function tests (alkaline phosphatase and/or gamma-GT) from baseline on Day 21. Secondary endpoints include the rate of patients with resolution of hepatitis (grade ≤1) at 6 months after randomization, the time to hepatitis resolution defined as the time from randomization to the date of resolution, tolerance to ursodeoxycholic acid or corticosteroids assessed according to the current NCI-CTC AE classification, factors associated with response to ursodeoxycholic acid at Day 21, and the rate of patients in whom resumption of immunotherapy was possible after hepatitis within 12 months after randomization.

The trial involves administration of prednisone (CORTANCYL 20 mg tablet) as the comparator product at a maximum daily dose of 1 mg/kg for up to 12 weeks via oral route, and ursodeoxycholic acid as the test product at a maximum daily dose of 20 mg/kg (with a maximum total dose of 1000 mg) for up to 6 months via oral route. Both products are administered orally and contain chemical active substances. The estimated recruitment start date is September 5, 2025, with an estimated end date of March 4, 2028, indicating an overall trial duration of approximately 2 years and 6 months. Participant involvement extends from the screening visit through the 6-month follow-up period, with a final assessment at 12 months after randomization to evaluate the possibility of resuming immunotherapy. Early termination from the study may occur based on adverse events, lack of efficacy, or other conditions as defined in the study protocol.

The experimental treatment consists of **ursodeoxycholic acid**, a bile acid administered for the treatment of **cholestatic hepatitis** secondary to **immunotherapy**. The **active substance** is ursodeoxycholic acid, also known as ursodiol or ursodesoxycholic acid, which is of chemical origin. The medication is administered via the **oral route**. The **maximum daily dose** is 20 mg/kg with a maximum total dose of 1000 mg. The **treatment period** extends up to 6 months. This product serves as the test intervention in the trial.

The **comparator treatment** consists of **prednisone**, a corticosteroid used for comparison with the experimental medication. The product is marketed as CORTANCYL 20 mg in **tablet** form (comprimé sécable). Prednisone is the active substance of chemical origin. The medication is administered via the **oral route**. The maximum daily dose is 1 mg/kg with a maximum total dose of 1 mg/kg. The treatment period extends up to 12 months. The **pharmaceutical form** is a divisible tablet manufactured by CHEPLAPHARM ARZNEIMITTEL GMBH. This corticosteroid serves as the control arm in this **randomized**, **open-label**, **multicenter** trial comparing the efficacy of the two treatment approaches over a 21-day evaluation period.

Efficacy will be assessed through the evaluation of liver function parameters in patients with **cholestatic hepatitis** induced by immune checkpoint inhibitors. The primary endpoint is the rate of patients demonstrating an improvement of at least 25% in liver function tests, specifically **alkaline phosphatase** and/or **gamma-GT**, from baseline on Day 21. Secondary endpoints include the rate of patients achieving resolution of hepatitis, defined as grade ≤ 1 according to the NCI CTC-AE classification, at 6 months after randomization. The time to hepatitis resolution will be measured as the interval from the date of randomization to the date when hepatitis grade reaches ≤ 1. Additional secondary endpoints encompass the assessment of adverse events according to the NCI-CTC AE classification to evaluate tolerance to **ursodeoxycholic acid** or **corticosteroids** or both. Factors associated with response to ursodeoxycholic acid at Day 21 will be analyzed, including the immunotherapy molecule used, duration of immune checkpoint inhibitor treatment, presence or absence of bile duct dilation, and tumor histology. The rate of patients in whom resumption of immunotherapy is possible after hepatitis within 12 months after randomization will also be evaluated.