TReatment for ImmUne Mediated PathopHysiology (TRIUMPH)

A 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

TReatment for ImmUne Mediated PathopHysiology (TRIUMPH) is a multi-center, three arm, randomized, controlled trial of immunosuppressive therapy for children with acute liver failure. The study will determine if suppressing inflammatory responses with either corticosteroids or equine anti-thymocyte globulin therapy improves survival for children with this rare, life-threatening condition.

Study Overview

• Status: Active, not recruiting
• Conditions: Hepatic Encephalopathy; Acute Liver Failure; Fulminant Hepatic Failure; Acute Liver Injury; Immune Dysregulation
• Intervention / Treatment: Drug: High-dose methylprednisolone; Drug: Prednisolone; Drug: Equine anti-thymocyte globulin; Drug: Diphenhydramine; Drug: Methylprednisolone; Drug: Placebo for prednisolone; Drug: Placebo for infusions

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Palo Alto, California, United States, 94304
      • Lucile Packard Children's Hospital
    • San Diego, California, United States, 92123
      • Rady Children's Hospital
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert H. Lurie Children's Hospital of Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital Boston
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • The Children's Mercy Hospital
    • St Louis, Missouri, United States, 63110
      • St. Louis Children's Hospital
  • New York
    • New York, New York, United States, 10032
      • NYP Morgan Stanley Children's Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Children's Hospital Vanderbilt
  • Texas
    • Dallas, Texas, United States, 75235
      • UT Southwestern Medical Center Children's Health
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.; Other Names: Solu-Medrol; Drug: Prednisolone; Subjects will receive prednisolone 1 mg/kg on Days 5-13 followed by a gradual taper with discontinuation at 42 Days as indicated below. Days 5 - 13 Prednisolone PO 1 mg/kg/day (max 50 mg/day) Days 14- 20 Prednisolone PO 0.5 mg/kg/day (max 25 mg/day) Days 21 - 27 Prednisolone PO 0.3 mg/kg/day (max 15 mg/day) Days 28 - 34 Prednisolone PO 0.1 mg/kg/day (max 5 mg/day) Days 35 - 41 Prednisolone PO 0.1 mg/kg every OTHER day (max 5 mg every other day) Day 42 Discontinue; Other Names: 15 mg/mL oral solution National Drug Code: 0121-0885-08
Experimental: Equine anti-thymocyte globulin; Intravenous equine anti-thymocyte globulin at a dose of 40 mg/kg/day for 4 days.	Drug: Prednisolone; Subjects will receive prednisolone 1 mg/kg on Days 5-13 followed by a gradual taper with discontinuation at 42 Days as indicated below. Days 5 - 13 Prednisolone PO 1 mg/kg/day (max 50 mg/day) Days 14- 20 Prednisolone PO 0.5 mg/kg/day (max 25 mg/day) Days 21 - 27 Prednisolone PO 0.3 mg/kg/day (max 15 mg/day) Days 28 - 34 Prednisolone PO 0.1 mg/kg/day (max 5 mg/day) Days 35 - 41 Prednisolone PO 0.1 mg/kg every OTHER day (max 5 mg every other day) Day 42 Discontinue; Other Names: 15 mg/mL oral solution National Drug Code: 0121-0885-08; 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.; Other Names: ATGAM; Drug: Diphenhydramine; Subjects in the eATG arm will receive pre-treatment medication diphenhydramine IV 1 mg/kg prior to start of eATG infusion.; Other Names: Benadryl; Drug: Methylprednisolone; Subjects in the eATG arm will receive pre-treatment medication methylprednisolone IV 1 mg/kg prior to start of eATG infusion.; Other Names: Solu-Medrol
Placebo Comparator: 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; Drug: Placebo for infusions; Subjects randomized to the supportive care alone arm will receive normal saline in place of all study treatments (skin test, premedication and IV infusions) on Days 1-4 given at the same volume and duration as the eATG infusions.; Other Names: 0.9% Sodium chloride
No Intervention: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival with native liver (SNL)	Alive and without a liver transplant 21 days following randomization	21 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival with native liver (SNL)	Alive and without a liver transplant 6 months (180 days) following randomization	180 days

Collaborators and Investigators

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Collaborators: Ann & Robert H Lurie Children's Hospital of Chicago
• Investigators: Principal Investigator: Estella M Alonso, MD, Ann & Robert H Lurie Children's Hospital of Chicago; Principal Investigator: Valerie L Durkalski-Mauldin, PhD, Medical University of South Carolina; Study 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)

Publications and helpful links

General Publications

• Chapin CA, Squires JE, Horslen SP, Alonso EM. Equipoise in pediatric acute liver failure. J Pediatr Gastroenterol Nutr. 2024 May;78(5):1001-1004. doi: 10.1002/jpn3.12166. Epub 2024 Feb 26. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): February 9, 2022
• Primary Completion (Actual): August 3, 2026
• Study Completion (Estimated): February 1, 2027

Study Registration Dates

• First Submitted: April 23, 2021
• First Submitted That Met QC Criteria: April 23, 2021
• First Posted (Actual): April 27, 2021

Study Record Updates

• Last Update Posted (Actual): August 12, 2026
• Last Update Submitted That Met QC Criteria: August 10, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: liver failure; hepatic insufficiency; liver diseases; anti-thymocyte agents
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolic Diseases; Digestive System Diseases; Brain Diseases, Metabolic; Nutritional and Metabolic Diseases; Liver Diseases; Liver Failure; Hepatic Insufficiency; Liver Failure, Acute; Hepatic Encephalopathy; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Hydrocarbons, Aromatic; Polycyclic Compounds; Amines; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Inorganic Chemicals; Chlorine Compounds; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Benzene Derivatives; Pregnadienetriols; Ethylamines; Biological Products; Complex Mixtures; Sodium Compounds; Immune Sera; Benzhydryl Compounds; Chlorides; Hydrochloric Acid; Prednisolone; Methylprednisolone; Methylprednisolone Hemisuccinate; Antilymphocyte Serum; Diphenhydramine; Sodium Chloride
• Other Study ID Numbers: PALF IRN/TRIUMPH; U01DK062436 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be available at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Central Repository. The public use dataset, along with the study protocol, the data dictionary, annotated case report forms and a brief set of instructions ("Readme" file) will be provided.
• IPD Sharing Time Frame: Release of the public use dataset will follow the NIDDK guidelines that study data analyzed for publications must be shared with the broader scientific community at the time of publication. Also, the study data analyzed for publications will be submitted to the NIDDK-CR when the manuscript is accepted for publication or at the time of publication.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No