TReatment for ImmUne Mediated PathopHysiology

Recruitment Status
RECRUITING
(See Contacts and Locations)Verified February 2026 by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Sponsor
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information Provided by (Responsible Party)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinicaltrials.gov Identifier
NCT04862221
Other Study ID Numbers:
PALF IRN/TRIUMPH
First Submitted
April 22, 2021
First Posted
April 26, 2021
Last Update Posted
March 9, 2026
Last Verified
February 2026

ClinicalTrials.gov processed this data on March 2026. Link to the current ClinicalTrials.gov record .

History of Changes

Study Details

Study Description

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 in an additional 20-30%. In the majority of cases, a specific cause of the liver injury is never determined. Recent research supports the theory that many of these patients have liver injury related to a hyperinflammatory immune response to everyday infections or environmental exposures. There is strong evidence to show that equine anti-thymocyte globulin and methylprednisolone slow the body's response to inflammation and improve the recovery of patients with other immune disorders and thus, may help patients with acute liver failure.

This is a phase 2b, double-blind, three arm, randomized, placebo controlled trial with restricted response adaptive randomization. The primary objective is to determine the efficacy and safety of high-dose methylprednisolone or equine anti-thymocyte globulin (eATG or ATGAM®) as compared to supportive care alone (placebo) for the treatment of acute liver failure in pediatric patients.

Approximately 160 patients who are equal to or greater than ≥ 1 and less than ≤ 18 years of age with pediatric acute liver failure (PALF) of undetermined etiology will be randomized to receive either high-dose methylprednisolone (Treatment 1) or eATG (ATGAM®) (Treatment 2) or supportive care alone (Treatment 3) on days 1 to 4 after study enrollment, followed by a gradual prednisolone taper (for the two active treatment arms 1 and 2) or a placebo taper (for treatment arm 3) on days 5 to 42.

The follow-up period includes visits at 1 week (Day 7), 2 weeks (Day 14), and 3 weeks (Day 21) after the day the participant started in the study. Early follow-up assessments will be performed either in the inpatient or ambulatory setting since some participants may be discharged before Day 7. In addition, families will be contacted by phone or email to schedule each follow-up at the study site for the 6 week, 3 month, 6 month and 12 month study visits.

This study includes a prospective observational cohort study of up to 50 patients with PALF who meet the randomized controlled trial (RCT) eligibility criteria and are willing to provide longitudinal observational data.

The findings of this trial have the potential to shift the treatment paradigm in PALF and advance the basic understanding of immune dysregulation disorders in childhood. The network includes 20 of the largest and most active pediatric liver centers in the US who have organized to support rigorous testing of the efficacy and safety of immunosuppressive therapy for these patients.

Recruitment into the randomized controlled trial stopped on February 17, 2026, but recruitment into the observational cohort will continue for about 6 months.

Condition or DiseaseIntervention/Treatment
Acute Liver FailureFulminant Hepatic FailureHepatic EncephalopathyAcute Liver InjuryImmune Dysregulation
Drug: High-dose methylprednisoloneDrug: Equine anti-thymocyte globulinDrug: Placebo for prednisolone

Study Design

Study TypeInterventional
Actual Enrollment163 participants
Design AllocationRandomized
Interventional ModelParallel Assignment
MaskingQuadruple
Primary PurposeTreatment
Official TitleA Phase 2b, Double-Blind, Three Arm, Randomized, Placebo Controlled Trial With Restricted Response Adaptive Randomization Testing the Efficacy and Safety of High Dose Methylprednisolone or Equine Anti-Thymocyte Globulin as Treatment for Acute Liver Failure in Pediatric Patients
Study Start DateFebruary 8, 2022
Actual Primary Completion Date2mos 3w from now
Actual Study Completion Date8mos 3w from now

Groups and Cohorts

Group/CohortIntervention/Treatment
High-dose methylprednisolone
Intravenous methylprednisolone at an initial dose of 10 mg/kg/day for 3 days, 5 mg/kg/day on day 4.
Drug: High-dose methylprednisolone
Subjects in the high-dose methylprednisolone arm will receive an initial dose of methylprednisolone IV 10 mg/kg/day for 3 days and 5 mg/kg/day on Day 4. Normal saline will be used as placebo pre-medications and infusions given at the same volume and duration as the eATG infusions.
Equine anti-thymocyte globulin
Intravenous equine anti-thymocyte globulin at a dose of 40 mg/kg/day for 4 days.
Drug: Equine anti-thymocyte globulin
Subjects will receive eATG IV 40 mg/kg/day on Days 1- 4. Day 1 eATG infusion is run over 8 hours and Day 2-4 infusions are run over 4 hours.
Supportive care
Supportive care will be administered as determined by the clinical team at participating clinical sites in accordance with their local practices and standards.
Drug: Placebo for prednisolone
Subjects will receive 1 mg/kg/day of oral placebo for prednisolone on days 5-13 followed by a gradual taper to discontinuation at 42 days as indicated below. Subjects receiving oral placebo will be given a solution that closely resembles the treatment drug. Days 5 - 13 Placebo for Prednisolone PO 1 mg/kg/day (max 50 mg/day) Days 14- 20 Placebo for Prednisolone PO 0.5 mg/kg/day (max 25 mg/day) Days 21 - 27 Placebo for Prednisolone PO 0.3 mg/kg/day (max 15 mg/day) Days 28 - 34 Placebo for Prednisolone PO 0.1 mg/kg/day (max 5 mg/day) Days 35 - 41 Placebo for Prednisolone PO 0.1 mg/kg every OTHER day (max 5 mg every other day) Day 42 Discontinue
Observational Cohort
This study includes a prospective observational cohort study of patients with Pediatric Acute Liver Failure who meet the randomized controlled trial eligibility criteria and are willing to provide longitudinal observational data. Patients who provide consent will receive the enrolling institution's standard of care and will be followed for up to 90-days for clinical (observational) assessments and biospecimen collection for the biorepository.

Outcome Measures

Primary Outcome Measures
  1. Survival with native liver (SNL)
    Alive and without a liver transplant 21 days following randomization
Secondary Outcome Measures
  1. Survival with native liver (SNL)
    Alive and without a liver transplant 6 months (180 days) following randomization

Eligibility Criteria

Ages Eligible for Study(Child, Adult)
Sexes Eligible for StudyAll
Accepts Healthy VolunteersNo
Inclusion Criteria
1. Patient with liver injury of ≤ 6 weeks duration resulting in an international normalization ratio (INR) of ≥ 1.5 or \< 2.0 (not corrected by vitamin K) with evidence of hepatic encephalopathy (HE), INR of ≥ 1.5 or \< 2.0 for at least 7 days duration without evidence of HE or INR ≥ 2.0 without evidence of HE. 2. Age is greater than or equal to 1 year and less than 18 years of age. 3. Patient or their legally authorized representative(s) (LAR) must consent (and assent, if applicable) to be in the study and must have signed and dated an approved informed consent form which conforms to federal and institutional guidelines. 4. Females of reproductive potential should not plan on conceiving children during the study and must agree to use a medically accepted form of contraception.
Exclusion Criteria
1. Evidence of active infection with Hepatitis A, B, C, E or evidence of acute herpes simplex virus (HSV) or adenovirus infection 2. Travel within the past 3 months to an area highly endemic for Hepatitis E 3. Diagnosis of hemophagocytic lymphohistiocytosis (HLH) Note: Patients with a history of consanguinity and/or central nervous system (CNS) dysfunction that is exaggerated compared to the degree of liver dysfunction (as judged by the site investigator) will not be enrolled until results of rapid genetic testing are available. Turn-around time for genetic testing results is estimated to be 72-96 hours. 4. Aplastic anemia as defined by standardized criteria \[1\] diagnosed prior to enrollment 5. Diagnosis of autoimmune Hepatitis (AIH) 6. Diagnosis of acute Wilson disease 7. Diagnosis of inborn error of metabolism Note: Suspicion of metabolic disease is not an exclusion for entry into the Trial. 8. Diagnosis of acute drug or toxin-induced liver injury 9. History of recreational drug use within the past 4 weeks 10. Therapy with an immunosuppressive agent, including chemotherapy, biological therapies or an experimental drug or device within the past 6 weeks 11. Liver injury due to ischemia 12. Liver dysfunction diagnosed more than 6 weeks prior to screening 13. History of allergy to horse dander 14. Sepsis 15. Imminent risk of death as judged by the clinical site investigator, including but not limited to; signs of cerebral herniation at the time of enrollment and presence of intractable arterial hypotension 16. Solid organ or stem cell transplant recipient 17. Pregnant or breast-feeding at the time of proposed study entry 18. Clinical AIDS or HIV positive 19. History of any form of malignant neoplasm and/or tumors treated within five years prior to study entry (other than non-melanoma skin cancer or in situ cervical cancer) or where there is current evidence of recurrent or metastatic disease 20. Received a live-virus vaccine within 4 weeks of study entry 21. Patients with positive respiratory secretion testing for respiratory viral infection including SARS-CoV-2, influenza and respiratory syncytial virus only if they also have declining respiratory function 22. Psychiatric or addictive disorders that would preclude obtaining informed consent/assent 23. Patient is unwilling or unable to adhere with study requirements and procedures 24. Currently receiving other experimental therapies

Contacts and Locations

Sponsors and CollaboratorsNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Locations
Children's Hospital Los Angeles | Los Angeles California, United States, 90027Lucile Packard Children's Hospital | Palo Alto California, United States, 94304Rady Children's Hospital | San Diego California, United States, 92123University of California San Francisco Benioff Children's Hospital | San Francisco California, United States, 94158Children's Hospital Colorado | Aurora Colorado, United States, 80045Yale New Haven Children's Hospital | New Haven Connecticut, United States, 06510Children's Healthcare of Atlanta - Arthur M. Blank Hospital | Atlanta Georgia, United States, 30322Ann & Robert H. Lurie Children's Hospital of Chicago | Chicago Illinois, United States, 60611Riley Hospital for Children | Indianapolis Indiana, United States, 46202Children's Hospital Boston | Boston Massachusetts, United States, 02115The Children's Mercy Hospital | Kansas City Missouri, United States, 64108St. Louis Children's Hospital | St Louis Missouri, United States, 63110The Mount Sinai Medical Center | New York New York, United States, 10029NYP Morgan Stanley Children's Hospital | New York New York, United States, 10032Duke University Medical Center - Duke Children's | Durham North Carolina, United States, 27710Cincinnati Children's Hospital Medical Center | Cincinnati Ohio, United States, 45229Cleveland Clinic Children's | Cleveland Ohio, United States, 44195The Children's Hospital of Philadelphia | Philadelphia Pennsylvania, United States, 19104Children's Hospital of Pittsburgh | Pittsburgh Pennsylvania, United States, 15224Children's Hospital Vanderbilt | Nashville Tennessee, United States, 37232UT Southwestern Medical Center Children's Health | Dallas Texas, United States, 75235Texas Children's Hospital | Houston Texas, United States, 77030Primary Children's Medical Center | Salt Lake City Utah, United States, 84112Seattle Children's Hospital | Seattle Washington, United States, 98105
Investigators
Principal Investigator: Estella M Alonso, MD, Ann & Robert H Lurie Children's Hospital of ChicagoPrincipal Investigator: Valerie L Durkalski-Mauldin, PhD, Medical University of South CarolinaStudy Director: Ed Doo, MD, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)Study Director: Averell Sherker, MD, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study Documents (Full Text)
Documents provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): Informed Consent Form  August 2, 2021