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Trial record 1 of 11 for:    treatment for immune mediated pathophysiology
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TReatment for ImmUne Mediated PathopHysiology (TRIUMPH)

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ClinicalTrials.gov Identifier: NCT04862221
Recruitment Status : Recruiting
First Posted : April 27, 2021
Last Update Posted : October 31, 2022
Sponsor:
Collaborator:
Ann & Robert H Lurie Children's Hospital of Chicago
Information provided by (Responsible Party):
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

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.

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Study Type : Interventional  (Clinical Trial)
Estimated 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 : February 9, 2022
Estimated Primary Completion Date : April 2025
Estimated Study Completion Date : January 2026


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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 0.9% Sodium chloride




Primary Outcome Measures :
  1. Survival with native liver (SNL) [ Time Frame: 21 days ]
    Alive and without a liver transplant 21 days following randomization


Secondary Outcome Measures :
  1. Survival with native liver (SNL) [ Time Frame: 180 days ]
    Alive and without a liver transplant 6 months (180 days) following randomization



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   1 Year to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04862221


Contacts
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Contact: Katie Neighbors, MPH 312-227-4557 kneighbors@luriechildrens.org
Contact: Monica Martino 843-876-2616 martmoni@musc.edu

Locations
Show Show 20 study locations
Sponsors and Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Ann & Robert H Lurie Children's Hospital of Chicago
Investigators
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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)
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Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier: NCT04862221    
Other Study ID Numbers: PALF IRN/TRIUMPH
U01DK062436 ( U.S. NIH Grant/Contract )
First Posted: April 27, 2021    Key Record Dates
Last Update Posted: October 31, 2022
Last Verified: October 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
Supporting Materials: Study Protocol
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.
URL: https://repository.niddk.nih.gov/home/

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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):
hepatic insufficiency
liver diseases
liver failure
anti-thymocyte agents
Additional relevant MeSH terms:
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Liver Failure
Hepatic Insufficiency
Hepatic Encephalopathy
Liver Failure, Acute
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Liver Diseases
Digestive System Diseases
Brain Diseases, Metabolic
Metabolic Diseases
Diphenhydramine
Promethazine
Methylprednisolone
Methylprednisolone Acetate
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone acetate
Prednisolone hemisuccinate
Prednisolone phosphate
Antilymphocyte Serum
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists