TReatment for ImmUne Mediated PathopHysiology (TRIUMPH)

April 1, 2024 updated by: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

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

Recruiting

Conditions

Intervention / Treatment

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.

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.

Study Type

Interventional

Enrollment (Estimated)

163

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • California
      • Los Angeles, California, United States, 90027
        • Recruiting
        • Children's Hospital Los Angeles
        • Contact:
        • Principal Investigator:
          • Beth Carter, MD
      • Palo Alto, California, United States, 94304
        • Recruiting
        • Lucile Packard Children's Hospital
        • Contact:
        • Principal Investigator:
          • Amrita Narang, MD
      • San Francisco, California, United States, 94158
        • Recruiting
        • University of California San Francisco Benioff Children's Hospital
        • Contact:
        • Principal Investigator:
          • Philip Rosenthal, MD
    • Colorado
      • Aurora, Colorado, United States, 80045
        • Recruiting
        • Children's Hospital Colorado
        • Contact:
        • Principal Investigator:
          • Shikha Sundaram, MD
    • Connecticut
      • New Haven, Connecticut, United States, 06510
        • Recruiting
        • Yale New Haven Children's Hospital
        • Contact:
        • Principal Investigator:
          • Rima Fawaz, MD
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Recruiting
        • Emory Children's Healthcare of Atlanta
        • Contact:
        • Principal Investigator:
          • Rene Romero, MD
    • Illinois
      • Chicago, Illinois, United States, 60611
        • Recruiting
        • Ann & Robert H. Lurie Children's Hospital of Chicago
        • Contact:
        • Principal Investigator:
          • Catherine Chapin, MD
    • Indiana
      • Indianapolis, Indiana, United States, 46202
        • Recruiting
        • Riley Hospital for Children
        • Contact:
        • Principal Investigator:
          • Kyla Tolliver, MD
    • Massachusetts
      • Boston, Massachusetts, United States, 02115
    • Missouri
      • Kansas City, Missouri, United States, 64108
        • Recruiting
        • The Children's Mercy Hospital
        • Contact:
        • Principal Investigator:
          • Ryan Fischer, MD
      • Saint Louis, Missouri, United States, 63110
        • Recruiting
        • St. Louis Children's Hospital
        • Contact:
        • Principal Investigator:
          • David Rudnick, MD PhD
    • New York
      • New York, New York, United States, 10029
        • Recruiting
        • The Mount Sinai Medical Center
        • Contact:
        • Principal Investigator:
          • Jaime Chu, MD
      • New York, New York, United States, 10032
        • Recruiting
        • NYP Morgan Stanley Children's Hospital
        • Contact:
    • North Carolina
      • Durham, North Carolina, United States, 27710
        • Withdrawn
        • Duke University Medical Center - Duke Children's
    • Ohio
      • Cincinnati, Ohio, United States, 45229
        • Recruiting
        • Cincinnati Children's Hospital Medical Center
        • Contact:
        • Principal Investigator:
          • Anna Peters, MD PhD
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • Recruiting
        • The Children's Hospital of Philadelphia
        • Contact:
        • Principal Investigator:
          • Kathleen Loomes, MD
      • Pittsburgh, Pennsylvania, United States, 15224
        • Recruiting
        • Children's Hospital of Pittsburgh
        • Contact:
        • Principal Investigator:
          • James Squires, MD
    • Texas
      • Dallas, Texas, United States, 75235
        • Recruiting
        • UT Southwestern Medical Center Children's Health
        • Contact:
        • Principal Investigator:
          • Norberto Rodriguez-Baez, MD
      • Houston, Texas, United States, 77030
        • Recruiting
        • Texas Children's Hospital
        • Contact:
        • Principal Investigator:
          • Anna Banc-Husu, MD MSCI
    • Utah
      • Salt Lake City, Utah, United States, 84112
        • Recruiting
        • Primary Children's Medical Center
        • Contact:
        • Principal Investigator:
          • Kyle Jensen, MD
    • Washington
      • Seattle, Washington, United States, 98105
        • Recruiting
        • Seattle Children's Hospital
        • Contact:
        • Principal Investigator:
          • Pamela Valentino, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

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 normalized ratio (INR) of ≥ 1.5 and < 2.0 (not corrected by vitamin K) with evidence of hepatic encephalopathy (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. Positive test result for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection
  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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

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: 50383-0042-24
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: 50383-0042-24
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Survival with native liver (SNL)
Time Frame: 21 days
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)
Time Frame: 180 days
Alive and without a liver transplant 6 months (180 days) following randomization
180 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

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)

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 9, 2022

Primary Completion (Estimated)

January 31, 2026

Study Completion (Estimated)

January 31, 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)

April 2, 2024

Last Update Submitted That Met QC Criteria

April 1, 2024

Last Verified

November 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

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 of within six months of the publication date for the primary outcome publication or within two years of the date that the database is locked for analysis, whichever occurs first.

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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