TReatment for ImmUne Mediated PathopHysiology

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Acute Liver Failure, Fulminant Hepatic Failure, Hepatic Encephalopathy, Acute Liver Injury, Immune Dysregulation

Intervention / Treatment
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* Drug: High-dose methylprednisolone
* Drug: Equine anti-thymocyte globulin
* Drug: Prednisolone
* Drug: Placebo for prednisolone
* Drug: Placebo for infusions
* Drug: Diphenhydramine
* Drug: Methylprednisolone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High-dose methylprednisolone<br>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<br>* 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.<br>* Other names: Solu-Medrol;Drug: Prednisolone<br>* 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<br>* Other names: 15 mg/mL oral solution National Drug Code: 50383-0042-24;|
| Experimental: Equine anti-thymocyte globulin<br>Intravenous equine anti-thymocyte globulin at a dose of 40 mg/kg/day for 4 days. | Drug: Equine anti-thymocyte globulin<br>* 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.<br>* Other names: ATGAM;Drug: Prednisolone<br>* 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<br>* Other names: 15 mg/mL oral solution National Drug Code: 50383-0042-24;Drug: Diphenhydramine<br>* Subjects in the eATG arm will receive pre-treatment medication diphenhydramine IV 1 mg/kg prior to start of eATG infusion.<br>* Other names: Benadryl;Drug: Methylprednisolone<br>* Subjects in the eATG arm will receive pre-treatment medication methylprednisolone IV 1 mg/kg prior to start of eATG infusion.<br>* Other names: Solu-Medrol;|
| Placebo Comparator: Supportive care<br>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<br>* 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<br>Drug: Placebo for infusions<br>* 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.<br>* Other names: 0.9% Sodium chloride;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hepatic insufficiency, liver diseases, liver failure, anti-thymocyte agents