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

Enrollment

Locations

Arms

46.7

Anticipated Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

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
Acute Liver Failure Fulminant Hepatic Failure Hepatic Encephalopathy Acute Liver Injury Immune Dysregulation	Drug: High-dose methylprednisolone Drug: Equine anti-thymocyte globulin Drug: Prednisolone Drug: Placebo for prednisolone Drug: Placebo for infusions Drug: Diphenhydramine Drug: Methylprednisolone	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

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

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

Survival with native liver (SNL) [21 days]
Alive and without a liver transplant 21 days following randomization

Secondary Outcome Measures

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:

Inclusion Criteria:

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.
Age is greater than or equal to 1 year and less than 18 years of age.
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.
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:

Evidence of active infection with Hepatitis A, B, C, E or evidence of acute herpes simplex virus (HSV) or adenovirus infection
Travel within the past 3 months to an area highly endemic for Hepatitis E
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.
Aplastic anemia as defined by standardized criteria [1] diagnosed prior to enrollment
Diagnosis of autoimmune Hepatitis (AIH)
Diagnosis of acute Wilson disease
Diagnosis of inborn error of metabolism Note: Suspicion of metabolic disease is not an exclusion for entry into the Trial.
Diagnosis of acute drug or toxin-induced liver injury
History of recreational drug use within the past 4 weeks
Therapy with an immunosuppressive agent, including chemotherapy, biological therapies or an experimental drug or device within the past 6 weeks
Liver injury due to ischemia
Liver dysfunction diagnosed more than 6 weeks prior to screening
History of allergy to horse dander
Sepsis
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
Solid organ or stem cell transplant recipient
Pregnant or breast-feeding at the time of proposed study entry
Clinical AIDS or HIV positive
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
Received a live-virus vaccine within 4 weeks of study entry
Positive test result for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection
Psychiatric or addictive disorders that would preclude obtaining informed consent/assent
Patient is unwilling or unable to adhere with study requirements and procedures
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)