Treatment Efficacy of Corticosteroids and Mycophenolate Mofetil in Patients With Immune Related Hepatitis

Hepatitis, Drug-Induced Clinical Trial

— I-HEP  

Official title:

A National Prospective Study of Patients With Hepatitis Induced by Immune Checkpoint Inhibitors; Characterization of Liver Injury, Outcome of Therapy and Randomization to Either Prednisolone or Mycophenolate Mofetil Treatment in Case of Relapse

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04810156
• Other study ID #: AA2032
• Status: Recruiting
• Phase: Phase 2
• Start date: April 7, 2021
• Est. completion date: November 7, 2025

Study information

• Verified date: December 2022
• Source: Herlev Hospital
• Contact: Inge Marie Svane, M.D. Professor
• Phone: +38683868
• Email: inge.marie.svane[@]regionh.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This clinical trial is to clarify and investigate the patterns of immune-related hepatitis and the optimal treatment choice for patients who are steroid-dependent. The project aims to prospectively characterize the various histopathological, biochemical, and phenotypical liver injury patterns induced by immune checkpoint inhibitors and the treatment responses to corticosteroids. Furthermore, the effect of adding a second-line immunosuppressive drug, either MMF in steroid-refractory or steroid-dependent cases will be explored and compared.

Description:

The number of patients treated with immune checkpoint inhibitors (ICI) is expanding worldwide due to an increasing number of indications, including additional types of cancer, combination of ICI with other antineoplastic therapies and have recently moved into the adjuvant setting. According to clinical trial material, almost all patients in ICI treatment will eventually develop any grade of an adverse event, here, estimated in up to 90 percent of treated patients. Around 10-30 percent of ICI-treated patients will show signs of liver injury related to ICI treatment and will be diagnosed with immune-related hepatitis. The treatment hereof should include observation and medium-dose steroids in low-grade asymptomatic patients (grade ≤ 2 ir-hepatitis) and high-dose steroids in higher grades according to the current European and American guidelines. However, up to 25 percent of patients with ir-hepatitis may not respond properly to steroids due to primary resistance or relapse during tapering. These patients should be offered a second-line immunosuppressive treatment. The present recommendation for patients with steroid-dependent ir-hepatitis is based on the case series and includes immunosuppressive treatment with mycophenolate mofetil (MMF). To date, no evidence exists for which second-line treatment to choose.

However, in the clinic, the initiation of MMF may be delayed, meanwhile, patients are typically treated with an increased dose of steroids. In some cases, an increased dose of steroids with prolonged tapering can be sufficient. We want to explore if increased doses of steroids or adding MMF is the best strategy for relapse of hepatitis.

In addition, patients with signs of biliary or mixed liver injury may benefit from adding ursodeoxycholic acid (UDCA).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: November 7, 2025
• Est. primary completion date: April 7, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

Cohort A:

• Abnormal liver parameters equal to = grade 3 ir-hepatitis defined as; AST/ALT/ALP >5 x ULN, INR = 2.5 x ULN, or bilirubin > 3.0 x ULN

Cohort B:

• Patients who recur during or within one months of prednisolone tapering of =2 ir-hepatitis equal to AST/ALT =3 x ULN, ALP =2.5 x ULN, INR = 1.5 x ULN, or bilirubin = 3.0 x ULN

Cohort A and Cohort B

• Histologically confirmed solid cancer

• Treatment with cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) or Programmed Cell Death-1 (PD-1)/Programmed Cell Death Ligand-1 (PD-L1) inhibitor or a combination of CTLA-4 plus PD-1 inhibitors within 6 months

• Age: = 18 years

• Women of childbearing potential: Negative serum pregnancy test and must use effective contraception. This applies from screening and until 6 months after treatment. Birth control pills, spiral, depot injection with gestagen, subdermal implantation, hormonal vaginal ring and transdermal depot patch are all considered effective contraceptives

• Men with female partner of childbearing potential must use effective contraception from screening and until 6 months after treatment. Effective contraceptives are as described above for the female partner. In addition, documented vasectomy and sterility or double barrier contraception are considered effective contraceptives

• Signed statement of consent after receiving oral and written study information

• Willingness to participate in the planned treatment and follow-up and capable of handling toxicities.

Exclusion Criteria:

• Concomitant chemotherapy treatment or tyrosine kinases or angiogenesis inhibitors

• Concomitant immunosuppressive medication except prednisolone

• Patients with hepatocellular carcinoma

• Known hypersensitivity to one of the active drugs or excipients

• Uncontrolled infection

• Acute viral hepatitis

• Any medical condition that will interfere with patient compliance or safety

• Simultaneous treatment with other experimental drugs or other anticancer drugs

• Pregnant or breastfeeding females

• Phenylketonuria

Related Conditions & MeSH terms

• Chemical and Drug Induced Liver Injury
• Hepatitis
• Hepatitis A
• Hepatitis, Drug-Induced

Intervention

Drug:
• Mycophenolate Mofetil
Day 1: MMF 500 mg twice a day Day 2: MMF 1000 mg twice a day
• Solu-Medrol
2 mg/kg/day
• Ursodeoxycholic acid
Patients with mixed or cholestatic liver injury pattern will also be administrated peroral UDCA according to weight
• Prednisone tablet
Shift from solu-medrol IV to peroral prednisolon. A tapering plan will be performed.

Locations

Country	Name	City	State
Denmark	Aalborg University Hospital	Aalborg
Denmark	Aarhus University Hospital	Aarhus
Denmark	Rigshospitalet	Copenhagen
Denmark	Herlev University Hospital	Herlev	Copenhagen
Denmark	Odense University Hospital	Odense

Sponsors (1)

Lead Sponsor	Collaborator
Inge Marie Svane

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Blood biomarkers	Correlation of the baseline immune markers, genomics and other biomarkers in blood	Until completion of the study, an average of 5 years
Other	Description of changes in the fecal microbiome	Description of changes in the fecal microbiome and characterization of the prevalence of specific bacteria e.g. Faecalibacterium and Firmicutes	Until completion of the study, an average of 5 years
Primary	Treatment-assessed hepatitis response rates	Treatment-assessed hepatitis response rates with steroids and steroids plus either mycophenolate mofetil or tacrolimus	Through study completion, an average of 5 years
Primary	Time to response or downgrading of liver injury in days	Time to response or downgrading of liver injury in patients with =grade 3 ir-hepatitis measured as; Days to =20 percent reduction in liver specific transaminases (ALT/AST) or bilirubin Days to shift to peroral prednisolone and discharge	Until completion of the study, an average of 5 years
Secondary	Relapse rate of immune related hepatitis =2 during tapering plan	Percent of patients with relapse to grade =2 hepatitis during steroid or during steroid plus either mycophenolate mofetil or tacrolimus tapering.	Through study completion, an average of 5 years
Secondary	Time to downgrading of hepatotoxicity assessed by CTCAE v5.0	Time to downgrading of hepatotoxicity from grade 4 to grade 3, to grade 2 and to grade 1, respectively, assessed by CTCAE v5.0	Through study completion, an average of 5 years
Secondary	Description of histopathological changes in liver tissue	Number of patients with hepatocellular, cholestatic and mixed liver injury respectively, assessed by histological findings of predominant injury to hepatocytes, bile ducts or combined.	Until completion of the study, an average of 5 years
Secondary	Incidence of abnormal laboratory test results	Incidence of abnormal laboratory test results in blood	Until completion of the study, an average of 5 years
Secondary	Cumulated doses of corticosteroids and MMF respectively	Cumulated doses of corticosteroids and MMF respectively, during the study period of 6 months	Until completion of the study, an average of 5 years
Secondary	Cancer progression free survival at 6 months	Cancer progression free survival at 6 months	Until completion of the study, an average of 5 years
Secondary	Overall survival rates at 6 months	Overall survival rates at 6 months	Until completion of the study, an average of 5 years