Immune-Mediated Cholestasis
Conditions
Keywords
DILI, Immune checkpoint inhibitors, Cancer, Cholestatic hepatitis
Brief summary
The clinical trial aims 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. The trial presents a detailed scientific justification for comparing UDCA to corticosteroids, describing the treatment and detailing the follow-up procedures. It hypothesizes that UDCA could be superior to corticosteroids for treating ICI-related cholestatic hepatitis, based on its established use in primary biliary cholangitis and a favorable tolerance profile compared to corticosteroids.
Interventions
Ursodeoxycholic acid (UDCA) will be administered orally at an initial dose of 13-15 mg/kg/day, divided into two daily doses. After assessment of the primary endpoint at Day 21, UDCA will be continued for a total treatment duration of 6 months. In case of absence of treatment response, defined as no decrease of alkaline phosphatase and/or gamma-glutamyl transferase levels of at least 25% compared with baseline, corticosteroids which represent the reference treatment, will be added at a dose of 0.5-1 mg/kg.
DRUGCorticosteroids (Reference Treatment)
Corticosteroids will be administered orally at a dose of 0.5-1 mg/kg/day for 21 days, followed by a tapering schedule of 10 mg per week until treatment discontinuation. At Day 21, if there is no adequate response (defined as less than 25% decrease in alkaline phosphatase and/or gamma-glutamyl transferase from baseline), the corticosteroid taper will continue and ursodeoxycholic acid (UDCA) will be added at a dose of 13-15 mg/kg/day.
Sponsors
University Hospital, Montpellier
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adults ≥18 years old * Any type of cancer except hepatocellular or cholangiocarcinoma * At least one ICI injection * Cholestatic hepatitis Grade CTC-AE 3 or 4
Exclusion criteria
* Ongoing corticosteroids treatment * Other causes of hepatitis * Cirrhosis * ICI for hepatocellular carcinoma or cholangiocarcinoma * Biliary obstruction * Medical contraindication to corticosteroids or UDCA * Mixed or hepatocellular hepatitis * Total bilirubin \> 1,5 ULN, Prothrombin rate \< 70% * Medical contraindication to MRI or liver biopsy * Oher serious side effects requiring corticosteroids * Pregnant and breast-feeding patients * Patients under articles L1121-5 to 8 of the public health code * Lack of informed consent * Patients not affiliated with French social security system * Patients uncapable of understanding french
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Improvement of at least 25% in liver function tests on day 21 after randomization | 21 days after randomization | The rate of patients showing an improvement of at least 25% in liver function tests (alkaline phosphatase and/or gamma-GT) on Day 21 after randomization. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Hepatitis Resolution at 6 Months | 6 Months after randomization | Rate of patients with resolution of hepatitis, defined as hepatitis grade ≤ 1 according to the current National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), at 6 months after randomization. |
| Time to Hepatitis Resolution | From Randomization to end of follow-up at 12 months | Time to hepatitis resolution, defined as the time from the date of randomization to the date of hepatitis resolution (grade ≤ 1). Hepatitis severity will be graded according to the current National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) |
| Tolerance to UDCA and/or Corticosteroids | From treatment initiation following the randomization to end of follow-up at 12 months | Tolerance to ursodeoxycholic acid (UDCA) and/or corticosteroids will be evaluated through the assessment of adverse events. Adverse events will be collected throughout the study and graded according to the current National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) |
| Resumption of immunotherapy | Within 12 months after randomization | Rate of patients in whom resumption of immunotherapy was possible after hepatitis within 12 months after randomization |
Countries
France
Contacts
CONTACTDr. MEUNIER
PRINCIPAL_INVESTIGATORDr. Meunier
University Hospital, Montpellier
Outcome results
None listed