Pediatric Acute Liver Failure Immune Response Network (PALF IRN): Treatment for Immune Mediated Pathophysiology (TRIUMPH)

Project Summary
Pediatric Acute Liver Failure (PALF) is a rare, devastating condition that affects an estimated 250 children per
year in North America, causing death in approximately 15% and the need for liver transplantation (LT) in an
additional 20-30%. In the majority of cases, a specific cause of the liver injury is never determined. Recent
research conducted in these patients supports the theory that many of these patients have liver injury related to
a hyperinflammatory immune response to everyday infections or environmental exposures. Studies have
recently implicated T lymphocytes as the central drivers of the inflammatory process. Physicians caring for PALF
patients are searching for therapies that quiet this T cell response, dampen the inflammatory cascade and allow
the patient’s remaining liver cells to heal and regenerate. Clinical experience in children with abnormal
hyperinflammatory immune responses associated with other disease states such as Systemic Juvenile Idiopathic
Arthritis and Acquired Aplastic Anemia has demonstrated that both high dose corticosteroids and equine anti-
thymocyte globulin can suppress immune responses and reverse progressive tissue damage. The goal of the
Pediatric Acute Liver Failure Immune Response Network (PALF IRN) is to support a treatment trial of
immunosuppressive therapy using high dose corticosteroids or equine anti-thymocyte globulin to reverse harmful
inflammatory immune responses in children with PALF to prevent further disease progression and reduce
mortality and LT in this population. We propose the TReatment for ImmUne Mediated PathopHysiology
(TRIUMPH) trial, a double-blind, three arm, randomized, placebo controlled trial of high dose methylprednisolone
or equine anti-thymocyte globulin. We will test the hypothesis that survival with native liver at 21 days post
randomization will be significantly higher in patients receiving immunosuppressive therapy as compared to
patients that receive supportive care alone. We will also determine the safety of immunosuppressive therapy in
PALF patients and define the balance between risk of side-effects and treatment benefit. Our outcomes will
include not only clinical end-points such as patient survival, time to resolution of disease and adverse health
events, but also measures of patient reported outcomes during rehabilitation from the illness. Trial participants
will provide blood and liver samples that will be examined to better understand their immune responses,
especially that of T lymphocytes, in both the circulation and in the liver. Samples will be stored in a repository to
support future studies exploring new aspects of this rare disease.

Grant Number: 5U01DK127995-04
NIH Institute/Center: NIH
Principal Investigator: Estella Alonso