Severe Hepatitis Intervention With Emapalumab for Liver Disease

Phase 2Not Yet RecruitingNCT07744919

Children's Healthcare of Atlanta28 enrolled

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.

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).

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Eligibility

Sex: ALLMin age: 1 YearMax age: 30 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

Incidence of Liver Failure

INR \>2 on two consecutive occasions without hepatic encephalopathy (HE), or INR ≥1.5 with evidence of HE

Time frame: 30, 90, and 180 days after the start of emapalumab

Secondary Outcomes

Complete Response (CR)

A complete response (CR) is defined by normalization or near-normalization of liver injury markers and hepatic function. Patients achieving CR will demonstrate an ALT \< 2.5X ULN together with an INR ≤ 1.2.

Time frame: throughout study participation/ up to 180 days

Cytokine and Chemokine Profiling

The cytokine milieu including interferon-γ, interferon-stimulated gene products, TNF-α, IL-6, IL-18, CXCL9, and others will be quantified to define the inflammatory environment at baseline and during treatment.

Time frame: through study participation/ up to 180 days

Emapalumab Immunologic Effects

Change in circulating activated CD8+ T cells from the initiation of emapalumab to Days 7, 14, 30, 60, 90, and 180 of study

Time frame: through study completion/ up to 180 days

Incidence and Severity of Adverse Events

Incidence of all adverse events of all grades as defined by CTCAE version 5.0

Time frame: from first emapalumab dose through study completion, up to 180 days

Population Summary Measure

The population summary measure will be the Complete Response rate, which will be estimated as the number of participants with Complete Response divided by the total number of participants in the efficacy sample population.

Time frame: throughout study participation/ up to 180 days

Time to First Complete Response

Time to first CR will be estimated using time-to-event methods. Death or liver transplant before CR will be treated as competing risks, and cumulative incidence functions will be used to estimate probabilities.

Time frame: throughout study participation/ up to 180 days

Partial Response (PR)

This is defined as an ALT decrease 50% from initiation of emapalumab, but ALT \>2.5X ULN with INR\< 1.2.

Time frame: throughout study participation/ up to 180 days

Sustained Response Off Therapy (SR)

ALT levels remaining \< 2.5X ULN for at least two consecutive months after completion of emapalumab.

Time frame: throughout study participation/ up to 180 days

Non-Response (NR)

Patients are considered non-responders if clinically relevant worsening with progression to liver failure.

Time frame: After 4 doses of emapalumab/ about 2 weeks after start of therapy

Proportion of Patients with Overall Response (CR or PR)

The proportion of patients achieving overall response (OR, defined as CR or PR) will be reported at Week 8 with exact confidence intervals. Missing values will be treated as non-response

Time frame: from first dose of emapalumab to week 8 of therapy

Time to First Overall Response (OR)

Time to first OR will be analyzed using cumulative incidence methods, with death or liver transplant treated as competing risks.

Time frame: throughout study participation/ up to 180 days

Sustained CR Off Therapy at Day 180

The proportion of patients achieving a sustained CR off therapy (SROT) at Day 180 will be summarized with exact confidence intervals. Patients without Day 180 data or therapy information will be considered non-SROT.

Time frame: 180 days on study therapy

Overall Survival with Native Liver

Survival with native liver will be estimated using Kaplan-Meier methods. Survival probabilities and 95% confidence intervals will be presented at each landmark time point.

Time frame: days 30, 60, 90, and 180

Proportion of Patients Receiving Liver Transplantation:

Cumulative incidence of transplant will be calculated at Days 30, 90, and 180, with death as a competing risk.

Time frame: days 30, 90, and 180

Change in Systemic Inflammatory Markers

Longitudinal changes in sIL2R, and CXCL9 will be evaluated using mixed-effects models for repeated measures.

Time frame: throughout study participation/ up to 180 days

Change in Circulating Activated CD8+ T Cells

Changes in activated CD8+ T cells over time will be analyzed similarly with mixed-effects models, supplemented by graphical summaries.

Time frame: throughout study participation/ up to 180 days

Corticosteroid Exposure and Time to Discontinuation

Cumulative corticosteroid exposure (prednisone equivalents) will be summarized descriptively. Time to discontinuation will be estimated using Kaplan-Meier methods, with competing-risk analyses considering death or transplant.

Time frame: throughout study participation/ up to 180 days

Incidence of Hepatitis Relapses

Defined as ALT re-elevation with concurrent sIL2R and CXCL9 rise. Time-to-relapse will be summarized with cumulative incidence functions.

Time frame: After initial improvement during weaning or cessation of therapy, up to Day 180

Severe Hepatitis Intervention With Emapalumab for Liver Disease

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts