Severe Hepatitis Intervention With Emapalumab for Liver Disease (SHIELD)

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Hepatitis
• Intervention / Treatment: Drug: 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).

• Study Type: Interventional
• Enrollment (Estimated): 28
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Shanmuganathan Chandrakasan, MD; Phone Number: 404-727-8877; Email: Shanmuganathan.Chandrakasan@emory.edu
• Study Contact Backup: Name: Maria Frazer; Phone Number: 4047856162; Email: maria.frazer@choa.org

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Arthur M. Blank Children's Healthcare of Atlanta
      • Contact: Shanmuganathan Chandrakasan, MD; Phone Number: 404-727-8877; Email: Shanmuganathan.Chandrakasan@emory.edu
      • Contact: Kate Silvis; Email: Katherine.Silvis@choa.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Intervention Cohort; 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. Participants will be monitored closely for clinical improvement, laboratory normalization, and adverse events throughout the 56-day treatment period, with continued follow-up through Day 180 to assess long-term outcomes, including relapse, liver failure, survival, and safety.

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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Liver Failure	INR >2 on two consecutive occasions without hepatic encephalopathy (HE), or INR ≥1.5 with evidence of HE	30, 90, and 180 days after the start of emapalumab

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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	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	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.	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.	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.	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.	throughout study participation/ up to 180 days
Non-Response (NR)	Patients are considered non-responders if clinically relevant worsening with progression to liver failure.	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	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.	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.	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.	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.	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.	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.	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.	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.	After initial improvement during weaning or cessation of therapy, up to Day 180

Collaborators and Investigators

• Sponsor: Children's Healthcare of Atlanta
• Collaborators: Sobi, Inc.

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): September 1, 2031
• Study Completion (Estimated): September 1, 2032

Study Registration Dates

• First Submitted: May 29, 2026
• First Submitted That Met QC Criteria: July 31, 2026
• First Posted (Actual): August 4, 2026

Study Record Updates

• Last Update Posted (Actual): August 4, 2026
• Last Update Submitted That Met QC Criteria: July 31, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Hepatitis; Emapalumab; iSH-T; anti-IFN-gamma monoclonal antibody; Severe Hepatitis Associated with T-Cell Activation; Severe Hepatitis; Steroid-refractory hepatitis; steroid-dependent hepatitis; relapse hepatitis; Severe Hepatic Injury
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Hepatitis; Emapalumab
• Other Study ID Numbers: SHIELD (Jacobs Institute)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be stored. This will not include the participant's contact or identifying information. Rather, individual participants and their research data will be identified by a unique study identification number. The study data entry and study management systems used by clinical sites and research staff will be secured and password protected.

Neither data nor specimens will be shared across participating sites. Deidentified data that supports the findings of this study will be made available by the Principal Investigator, upon reasonable request.

At the end of the study, all records will continue to be kept in a secure location for as long a period as dictated by local IRB and Institutional regulations. All study databases will be de-identified and archived.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No