Hepatitis
Conditions
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
Brief summary
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
DRUGEmapalumab
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.
Sponsors
Children's Healthcare of Atlanta
Sobi, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 30 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Liver Failure | 30, 90, and 180 days after the start of emapalumab | INR \>2 on two consecutive occasions without hepatic encephalopathy (HE), or INR ≥1.5 with evidence of HE |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response (CR) | throughout study participation/ up to 180 days | 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. |
| Cytokine and Chemokine Profiling | through study participation/ up to 180 days | 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. |
| Emapalumab Immunologic Effects | through study completion/ up to 180 days | Change in circulating activated CD8+ T cells from the initiation of emapalumab to Days 7, 14, 30, 60, 90, and 180 of study |
| Incidence and Severity of Adverse Events | from first emapalumab dose through study completion, up to 180 days | Incidence of all adverse events of all grades as defined by CTCAE version 5.0 |
| Population Summary Measure | throughout study participation/ up to 180 days | 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 to First Complete Response | throughout study participation/ up to 180 days | 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. |
| Partial Response (PR) | throughout study participation/ up to 180 days | This is defined as an ALT decrease 50% from initiation of emapalumab, but ALT \>2.5X ULN with INR\< 1.2. |
| Sustained Response Off Therapy (SR) | throughout study participation/ up to 180 days | ALT levels remaining \< 2.5X ULN for at least two consecutive months after completion of emapalumab. |
| Non-Response (NR) | After 4 doses of emapalumab/ about 2 weeks after start of therapy | Patients are considered non-responders if clinically relevant worsening with progression to liver failure. |
| Proportion of Patients with Overall Response (CR or PR) | from first dose of emapalumab to week 8 of therapy | 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 to First Overall Response (OR) | throughout study participation/ up to 180 days | Time to first OR will be analyzed using cumulative incidence methods, with death or liver transplant treated as competing risks. |
| Sustained CR Off Therapy at Day 180 | 180 days on study therapy | 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. |
| Overall Survival with Native Liver | days 30, 60, 90, and 180 | 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. |
| Proportion of Patients Receiving Liver Transplantation: | days 30, 90, and 180 | Cumulative incidence of transplant will be calculated at Days 30, 90, and 180, with death as a competing risk. |
| Change in Systemic Inflammatory Markers | throughout study participation/ up to 180 days | Longitudinal changes in sIL2R, and CXCL9 will be evaluated using mixed-effects models for repeated measures. |
| Change in Circulating Activated CD8+ T Cells | throughout study participation/ up to 180 days | Changes in activated CD8+ T cells over time will be analyzed similarly with mixed-effects models, supplemented by graphical summaries. |
| Corticosteroid Exposure and Time to Discontinuation | throughout study participation/ up to 180 days | 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. |
| Incidence of Hepatitis Relapses | After initial improvement during weaning or cessation of therapy, up to Day 180 | Defined as ALT re-elevation with concurrent sIL2R and CXCL9 rise. Time-to-relapse will be summarized with cumulative incidence functions. |
Countries
United States
Contacts
CONTACTShanmuganathan Chandrakasan, MD
CONTACTMaria Frazer
Outcome results
None listed