TReatment for ImmUne Mediated PathopHysiology

Hepatic Encephalopathy Clinical Trial

— TRIUMPH  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04862221
• Other study ID #: PALF IRN/TRIUMPH
• Secondary ID: U01DK062436
• Status: Recruiting
• Phase: Phase 2
• Start date: February 9, 2022
• Est. completion date: January 31, 2027

Study information

• Verified date: November 2023
• Source: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Contact: Katie Neighbors, MPH
• Phone: 312-227-4557
• Email: kneighbors[@]luriechildrens.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 163
• Est. completion date: January 31, 2027
• Est. primary completion date: January 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 18 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Liver Failure
• Acute Liver Injury
• Brain Diseases
• Fulminant Hepatic Failure
• Hepatic Encephalopathy
• Hepatic Insufficiency
• Liver Failure
• Liver Failure, Acute

Intervention

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.
• 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.
• 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
• 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
• 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.
• Diphenhydramine
Subjects in the eATG arm will receive pre-treatment medication diphenhydramine IV 1 mg/kg prior to start of eATG infusion.
• Methylprednisolone
Subjects in the eATG arm will receive pre-treatment medication methylprednisolone IV 1 mg/kg prior to start of eATG infusion.

Locations

Country	Name	City	State
United States	Emory Children's Healthcare of Atlanta	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Children's Hospital Boston	Boston	Massachusetts
United States	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	UT Southwestern Medical Center Children's Health	Dallas	Texas
United States	Duke University Medical Center - Duke Children's	Durham	North Carolina
United States	Texas Children's Hospital	Houston	Texas
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	The Children's Mercy Hospital	Kansas City	Missouri
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Yale New Haven Children's Hospital	New Haven	Connecticut
United States	NYP Morgan Stanley Children's Hospital	New York	New York
United States	The Mount Sinai Medical Center	New York	New York
United States	Lucile Packard Children's Hospital	Palo Alto	California
United States	The Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania
United States	St. Louis Children's Hospital	Saint Louis	Missouri
United States	Primary Children's Medical Center	Salt Lake City	Utah
United States	University of California San Francisco Benioff Children's Hospital	San Francisco	California
United States	Seattle Children's Hospital	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)	Ann & Robert H Lurie Children's Hospital of Chicago

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Survival with native liver (SNL)	Alive and without a liver transplant 21 days following randomization	21 days
Secondary	Survival with native liver (SNL)	Alive and without a liver transplant 6 months (180 days) following randomization	180 days