TRIUMPH: TReatment for ImmUne Mediated PathopHysiology

Sponsor
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
Overall Status
Recruiting
CT.gov ID
NCT04862221
Collaborator
Ann & Robert H Lurie Children's Hospital of Chicago (Other)
160
20
3
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Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
Phase 2

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 Design

Study Type:
Interventional
Anticipated Enrollment :
160 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
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
Actual Study Start Date :
Feb 9, 2022
Anticipated Primary Completion Date :
Apr 1, 2025
Anticipated Study Completion Date :
Jan 1, 2026

Arms and Interventions

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: 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: 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: 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
  • Outcome Measures

    Primary Outcome Measures

    1. Survival with native liver (SNL) [21 days]

      Alive and without a liver transplant 21 days following randomization

    Secondary Outcome Measures

    1. Survival with native liver (SNL) [180 days]

      Alive and without a liver transplant 6 months (180 days) following randomization

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    1 Year to 18 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Children's Hospital Los Angeles Los Angeles California United States 90027
    2 Lucile Packard Children's Hospital Palo Alto California United States 94304
    3 University of California San Francisco Benioff Children's Hospital San Francisco California United States 94158
    4 Children's Hospital Colorado Aurora Colorado United States 80045
    5 Yale New Haven Children's Hospital New Haven Connecticut United States 06510
    6 Emory Children's Healthcare of Atlanta Atlanta Georgia United States 30322
    7 Ann & Robert H. Lurie Children's Hospital of Chicago Chicago Illinois United States 60611
    8 Riley Hospital for Children Indianapolis Indiana United States 46202
    9 Children's Hospital Boston Boston Massachusetts United States 02115
    10 The Children's Mercy Hospital Kansas City Missouri United States 64108
    11 St. Louis Children's Hospital Saint Louis Missouri United States 63110
    12 The Mount Sinai Medical Center New York New York United States 10029
    13 Duke University Medical Center - Duke Children's Durham North Carolina United States 27710
    14 Cincinnati Children's Hospital Medical Center Cincinnati Ohio United States 45229
    15 The Children's Hospital of Philadelphia Philadelphia Pennsylvania United States 19104
    16 Children's Hospital of Pittsburgh Pittsburgh Pennsylvania United States 15224
    17 UT Southwestern Medical Center Children's Health Dallas Texas United States 75235
    18 Texas Children's Hospital Houston Texas United States 77030
    19 Primary Children's Medical Center Salt Lake City Utah United States 84112
    20 Seattle Children's Hospital Seattle Washington United States 98105

    Sponsors and Collaborators

    • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
    • 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 Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
    ClinicalTrials.gov Identifier:
    NCT04862221
    Other Study ID Numbers:
    • PALF IRN/TRIUMPH
    • U01DK062436
    First Posted:
    Apr 27, 2021
    Last Update Posted:
    Aug 8, 2022
    Last Verified:
    Aug 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Aug 8, 2022