Severe Hepatitis Intervention With Emapalumab for Liver Disease

Official title

A Phase 2 Study of Emapalumab for Prevention of Liver Failure in Pediatric Indeterminate Severe Hepatitis Associated With T-Cell Activation: Severe Hepatitis Intervention With Emapalumab for Liver Disease

Overview

The goal of this study is to see whether a medicine called emapalumab, a monoclonal antibody, is safe and works well for patients aged 1 year and older who have indeterminate severe hepatitis with T-cell activation and have not responded well to steroids or still need them. This study has a Screening Cohort and an Intervention Cohort. The Screening Cohort will enroll patients with severe hepatitis of all etiologies to observe and collect research samples. Patients enrolled on the Screening Cohort will be asked to participate on the Intervention Cohort if they develop steroid-refractory/ dependent indeterminate severe hepatitis (iSH-T). Additionally, patients may bypass the Screening Cohort and enroll directly in the Intervention Cohort if they already meet its eligibility criteria. Patients in the Intervention Cohort will be treated with emapalumab.

Detailed description

This clinical protocol evaluates the use of emapalumab, an anti-IFN-γ monoclonal antibody, in children aged ≥1 year with steroid-refractory or steroid-dependent indeterminate severe hepatitis with T cell activation (iSH-T). This study aims to establish a safe and effective treatment pathway for a previously steroid-refractory/dependent subjects with iSH-T.

Pediatric severe acute hepatitis is a rare but serious disorder that can rapidly progress to liver failure. Previously healthy children who develop severe acute hepatitis can unpredictably progress to pediatric acute liver failure (PALF) over the course of days to weeks. Importantly, as many as 30-50% of all PALF cases have no specific causal etiology for their liver failure and are termed indeterminate PALF (iPALF) and are at the highest risk for liver transplantation. Work from the PALF study group investigators has identified that iPALF is a leading indication for liver transplantation in children. Additional investigation indicates that iPALF patients have significant T cell activation and CD8+ T cell infiltration of their hepatic tissue. There are reports using immunosuppression in iPALF and PALF with favorable results and it is also the subject of a current multicenter trial in children (NCT04862221).

Interventions

• Drug Emapalumab
  Participants on the Intervention Cohort will receive a combination of immunomodulatory regimen using emapalumab and methylprednisolone (or prednisone equivalent), aimed at controlling severe immune-mediated hepatitis and preventing progression to liver failure.

Primary outcome measures

• Incidence of Liver Failure [Time frame: 30, 90, and 180 days after the start of emapalumab]

Secondary outcome measures (12)

• Complete Response (CR) [Time frame: throughout study participation/ up to 180 days]
• Cytokine and Chemokine Profiling [Time frame: through study participation/ up to 180 days]
• Emapalumab Immunologic Effects [Time frame: through study completion/ up to 180 days]
• Incidence and Severity of Adverse Events [Time frame: from first emapalumab dose through study completion, up to 180 days]
• Population Summary Measure [Time frame: throughout study participation/ up to 180 days]
• Time to First Complete Response [Time frame: throughout study participation/ up to 180 days]
• Partial Response (PR) [Time frame: throughout study participation/ up to 180 days]
• Sustained Response Off Therapy (SR) [Time frame: throughout study participation/ up to 180 days]
• Non-Response (NR) [Time frame: After 4 doses of emapalumab/ about 2 weeks after start of therapy]
• Proportion of Patients with Overall Response (CR or PR) [Time frame: from first dose of emapalumab to week 8 of therapy]
• Time to First Overall Response (OR) [Time frame: throughout study participation/ up to 180 days]
• Sustained CR Off Therapy at Day 180 [Time frame: 180 days on study therapy]

Eligibility criteria

Inclusion Criteria (Screening Cohort):

• Age: Participants must be ≥ 1 year of age at the time of screening.
• Evidence of Severe Hepatic Injury of all etiology (not just iSH/ iSH-T): Serum alanine aminotransferase (ALT) ≥ 1000 U/L documented within 7 days prior to enrollment.

Exclusion Criteria (Screening Cohort):

• Any condition impairing informed consent/assent or protocol compliance

Inclusion Criteria (Intervention Cohort; patients who meet Intervention Cohort eligibility can bypass Screening Cohort enrollment):

• Steroid-refractory, steroid-dependent, or relapse of hepatitis after stopping steroids and have an Indeterminate etiology of hepatitis based on standard of care, age appropriate evaluation
• Age: ≥ 1 year
• ALT ≥ 1000 U/L prior to initiation of any immune modulatory therapy
• Evidence of T-cell activation at initial diagnosis, as indicated by one of the following:

• sIL2R > 2× upper limit of normal (ULN)
• CXCL9 > 5× ULN
• CD8+ T-cell infiltration in the liver
• INR < 2.0 without evidence of hepatic encephalopathy

Exclusion Criteria (Intervention Cohort; patients who meet Intervention Cohort eligibility can bypass Screening Cohort enrollment):

• Patients with known Liver failure (defined as INR >2 on two consecutive occasions without hepatic encephalopathy (HE), or INR ≥1.5 with evidence of HE)
• Evidence of chronic liver disease or parenchymal nodularity as demonstrated on imaging (US, CT, or MRI)
• Evidence of hepatic encephalopathy
• Severe acquired aplastic anemia at presentation
• Organ dysfunction assessment defined below:

• Renal dysfunction: eGFR < 30 mL/min/1.73m² or
• Mechanical Ventilation
• Persistent systemic infection despite appropriate antimicrobial therapy
• Active infection with Hepatitis A, B, C, HIV, or herpes simplex virus
• Active mycobacteria (typical and atypical), Histoplasma Capsulatum, Herpes zoster infections.
• Patients with positive respiratory viral infection, including adenovirus, rhinovirus/enterovirus, SARS-CoV-2, influenza, and respiratory syncytial virus, only if they also have declining respiratory function needing positive pressure support. Suspected primary hemophagocytic lymphohistiocytosis based on patients with a history of consanguinity and/or central nervous system dysfunction or other clinical manifestations that is exaggerated compared to the degree of liver dysfunction (as judged by the site investigator and study team)
• Diagnosis of Autoimmune Hepatitis, Wilson Disease, inborn error of metabolism, acute drug or toxin-induced liver injury, or ischemic liver injury
• History of severe hypersensitivity or allergy to any component of this study regimen
• History of confirmed malignancy
• History of recreational drug use within the past 4 weeks, excluding cannabinoids
• Therapy with an immunosuppressive agent or an experimental drug within the past 6 weeks
• Pregnant, planning to become pregnant during study window, or breastfeeding at time of study entry
• Patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method (e.g. hormonal contraceptives, intrauterine device, or double-barrier method) for the duration of their study participation. Patients must maintain adequate contraception for at least 4 weeks after their last dose of emapalumab.
• Live-virus vaccination within 4 weeks of study entry or anticipated need for a live or live attenuated vaccine within 4 weeks after the last dose of emapalumab
• Peceived Bacillus Calmette-Guerin vaccine within 12 weeks prior to screening
• Patient or parent/guardian unable to give informed consent or unable to comply with the treatment protocol
• Prisoners will be excluded

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Arthur M. Blank Children's Healthcare of Atlanta — Atlanta

Identifiers

NCT: NCT07744919 · SHIELD

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗