MedDataX Logo

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

NCT ID: NCT04810156

Last Updated: 2022-12-14

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

Get a concise snapshot of the trial, including recruitment status, study phase, enrollment targets, and key timeline milestones.

Recruitment Status

RECRUITING

Clinical Phase

PHASE2

Total Enrollment

60 participants

Study Classification

INTERVENTIONAL

Study Start Date

2021-04-07

Study Completion Date

2025-11-07

Brief Summary

Review the sponsor-provided synopsis that highlights what the study is about and why it is being conducted.

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.

Detailed Description

Dive into the extended narrative that explains the scientific background, objectives, and procedures in greater depth.

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).

Conditions

See the medical conditions and disease areas that this research is targeting or investigating.

Hepatitis, Drug-Induced

Keywords

Explore important study keywords that can help with search, categorization, and topic discovery.

Hepatitis Immunotherapy Cancer Adverse events Immune checkpoint inhibitors Steroid-refractory Steroid-dependent

Study Design

Understand how the trial is structured, including allocation methods, masking strategies, primary purpose, and other design elements.

Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

The aim is to enroll around 40 patients in Cohort A for prospectively characterize the various patterns of liver injury histopathologically, biochemically, and phenotypically that are induced by ICI, and the response to treatment (steroids and MMF).

Cohort B: 20 patients who experienced a relapse of ir-hepatitis (grade ≥2) during prednisolone tapering or within one month after ended tapering will be randomized to either 100% dose of current steroid dose or restart of steroid 0.5-1 mg/kg versus adding MMF (if the patient received prednisolone the tapering plan hereof is continued, prednisolone up to 25 mg can be added if clinical indicated). Treatment efficacy is evaluated after seven days, if sufficient response the patients continued treatment, in case of insufficient response a cross-over will be performed
Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

Review each arm or cohort in the study, along with the interventions and objectives associated with them.

Cohort A: Steroids and MMF in grade 3-4 ir-hepatitis

Patients with ≥ 3 grade ir-hepatitis will be treated with high-dose steroids 2 mg/kg/day intravenously. A diagnostic liver biopsy will be taken. Patients with mixed or cholestatic liver injury patterns will be added UDCA. Treatment evaluation will be performed after 72 hours, patients in UDCA will be evaluated will be on day 7. Patients with sufficient steroid response defined as ≥ 20% reduction in ALT, AST, ALP or bilirubin at day 4 or day 7 will undergo steroid tapering with a transition to peroral steroids. Patients with initial insufficient treatment response, defined as less than \< 20% reduction in ALT, AST, ALP, or bilirubin, are considered as having a steroid-refractory condition and will be added MMF. In case of no response or increase of ALT, AST, ALP, or bilirubin during treatment with steroids plus MMF a third-line treatment may be introduced according to the individual treating hepatologist.

Group Type ACTIVE_COMPARATOR

Mycophenolate Mofetil

Intervention Type DRUG

Day 1: MMF 500 mg twice a day Day 2: MMF 1000 mg twice a day

Solu-Medrol

Intervention Type DRUG

2 mg/kg/day

Ursodeoxycholic acid

Intervention Type DRUG

Patients with mixed or cholestatic liver injury pattern will also be administrated peroral UDCA according to weight

Prednisone tablet

Intervention Type DRUG

Shift from solu-medrol IV to peroral prednisolon. A tapering plan will be performed.

Cohort B: Prednisolone versus MMF in steroiddependent ≥2 ir-hepatitis (randomized)

Patients who experienced relapse of ir-hepatitis of grade ≥2 during prednisolone tapering or within one months after ended tapering will be randomized to either 100% dose of current steroid dose or restart of steroid 0.5-1 mg/kg versus adding MMF (if the patient received prednisolone the tapering plan hereof is continued, prednisolone up to 25 mg can be added if clinical indicated). Treatment efficacy is evaluated after seven days, if sufficient response the patients continued treatment, in case of insufficient response a cross-over will be performed.

Group Type ACTIVE_COMPARATOR

Mycophenolate Mofetil

Intervention Type DRUG

Day 1: MMF 500 mg twice a day Day 2: MMF 1000 mg twice a day

Ursodeoxycholic acid

Intervention Type DRUG

Patients with mixed or cholestatic liver injury pattern will also be administrated peroral UDCA according to weight

Prednisone tablet

Intervention Type DRUG

Shift from solu-medrol IV to peroral prednisolon. A tapering plan will be performed.

Interventions

Learn about the drugs, procedures, or behavioral strategies being tested and how they are applied within this trial.

Mycophenolate Mofetil

Day 1: MMF 500 mg twice a day Day 2: MMF 1000 mg twice a day

Intervention Type DRUG

Solu-Medrol

2 mg/kg/day

Intervention Type DRUG

Ursodeoxycholic acid

Patients with mixed or cholestatic liver injury pattern will also be administrated peroral UDCA according to weight

Intervention Type DRUG

Prednisone tablet

Shift from solu-medrol IV to peroral prednisolon. A tapering plan will be performed.

Intervention Type DRUG

Other Intervention Names

Discover alternative or legacy names that may be used to describe the listed interventions across different sources.

Cellcept Myfenax Methylprednisolone Medrol Corticosteroids Steroid ursochol steroid Corticosteroids

Eligibility Criteria

Check the participation requirements, including inclusion and exclusion rules, age limits, and whether healthy volunteers are accepted.

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
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

Meet the organizations funding or collaborating on the study and learn about their roles.

Inge Marie Svane

OTHER

Sponsor Role lead

Responsible Party

Identify the individual or organization who holds primary responsibility for the study information submitted to regulators.

Inge Marie Svane

M.D. Professor

Responsibility Role SPONSOR_INVESTIGATOR

Principal Investigators

Learn about the lead researchers overseeing the trial and their institutional affiliations.

Inge M Svane

Role: STUDY_DIRECTOR

Study Director, National Center for Cancer Immune Therapy, Dept. of Oncology, Hospital Herlev

Rikke B Holmstrøm

Role: PRINCIPAL_INVESTIGATOR

Ph.D student, National Center for Cancer Immune Therapy, Dept. of Oncology, Hospital Herlev

Locations

Explore where the study is taking place and check the recruitment status at each participating site.

Herlev University Hospital

Herlev, Copenhagen, Denmark

Site Status RECRUITING

Aalborg University Hospital

Aalborg, , Denmark

Site Status NOT_YET_RECRUITING

Aarhus University Hospital

Aarhus, , Denmark

Site Status RECRUITING

Rigshospitalet

Copenhagen, , Denmark

Site Status RECRUITING

Odense University Hospital

Odense, , Denmark

Site Status RECRUITING

Countries

Review the countries where the study has at least one active or historical site.

Denmark

Central Contacts

Reach out to these primary contacts for questions about participation or study logistics.

Inge Marie Svane, M.D. Professor

Role: CONTACT

Phone: +38683868

Email: [email protected]

Rikke B Holmstrøm, M.D

Role: CONTACT

Phone: +4538682971

Email: [email protected]

Facility Contacts

Find local site contact details for specific facilities participating in the trial.

Rikke B Holmstrøm, MD

Role: primary

Peter Holland-Fischer, Ph.d, MD

Role: primary

Niels Kristian Aagaard, Ph.d., DMsc, MD

Role: primary

Peter N Bjerring, Ph.D. MD

Role: primary

Annette D Fialla, Ph.d, MD

Role: primary

Other Identifiers

Review additional registry numbers or institutional identifiers associated with this trial.

AA2032

Identifier Type: -

Identifier Source: org_study_id