What is the mechanism of action of this treatment?

Corticosteroids and equine anti-thymocyte globulin (ATG) are common treatments for liver injury due to their immunosuppressive properties. Corticosteroids provide broad immunosuppression and anti-inflammatory effects, which help reduce overall immune-mediated damage to liver cells, crucial for preventing further liver injury and promoting healing. Equine ATG specifically targets T-cells, reducing their activity and proliferation. This targeted approach is important because T-cells are key players in the immune response that can exacerbate liver injury. By diminishing T-cell activity, ATG helps decrease the immune-mediated attack on the liver, potentially improving patient outcomes.

What side effects are associated with this type of intervention?

Corticosteroids, used for their broad immunosuppressive and anti-inflammatory effects, can cause side effects such as hyperglycemia, increased susceptibility to infections, bone loss, fractures, and neuropsychiatric issues. Equine anti-thymocyte globulin (ATG), which provides T-cell specific immunosuppression, can lead to side effects including serum sickness, anaphylaxis, fever, chills, leukopenia, and increased risk of infections. Both treatments aim to modulate the immune response but come with significant potential adverse effects that need to be managed carefully.

What prior FDA approvals exist?

Corticosteroids like prednisone have been approved for their broad immunosuppressive and anti-inflammatory effects in treating liver conditions such as autoimmune hepatitis. Equine anti-thymocyte globulin, which provides T-cell specific immunosuppression, is used in severe cases like acute liver failure and organ transplant rejection. These treatments help manage inflammation and immune-mediated liver damage.

What other types of research exist?

Promising novel alternatives to corticosteroids and equine anti-thymocyte globulin for liver injury patients in 2024 may include IL-1 receptor antagonists like anakinra and monoclonal antibodies targeting specific immune pathways, such as TNF inhibitors or IL-6 inhibitors. These therapies provide targeted immunosuppression and anti-inflammatory effects.

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Immunosuppressant

Immune Suppression Therapy for Acute Liver Failure (TRIUMPH Trial)

Phase 2

Recruiting

Led By Valerie L Durkalski-Mauldin, PhD

Research Sponsored by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

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

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

Must not have

Therapy with an immunosuppressive agent, including chemotherapy, biological therapies or an experimental drug or device within the past 6 weeks

Diagnosis of acute drug or toxin-induced liver injury

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 180 days

Summary

This trial tests two treatments that reduce immune activity in children with severe, unexplained liver failure. The treatments work by calming the immune system to prevent it from harming the liver.

Who is the study for?

The TRIUMPH study is for children aged 1-17 with acute liver failure, who agree to use contraception if applicable. They must consent to participate and have a specific level of liver injury. Excluded are those with psychiatric disorders, imminent death risk, recent drug use or immunosuppressive therapy, organ transplants, COVID-19 infection, certain infections or vaccinations, allergies to horse dander, pregnancy/breastfeeding women, HIV/AIDS patients, travelers to Hepatitis E regions recently.

What is being tested?

TRIUMPH evaluates the effectiveness of immunosuppressants (high-dose methylprednisolone or equine anti-thymocyte globulin) versus placebo in improving survival rates among children with life-threatening acute liver failure. This randomized trial will compare three groups: one receiving corticosteroids; another getting equine anti-thymocyte globulin; and a third given placebos.

What are the potential side effects?

Possible side effects include immune system suppression leading to increased infection risk; allergic reactions especially related to horse-derived products; hormonal imbalances due to steroids like weight gain and mood changes; high blood sugar levels; increased appetite; trouble sleeping.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am between 1 and 17 years old.

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I have liver injury with specific blood clotting test results and may or may not have brain function changes due to liver failure.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I haven't taken any immunosuppressive drugs, including chemotherapy, in the last 6 weeks.

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I have liver damage caused by a drug or toxin.

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I have been diagnosed with acute Wilson disease.

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I have received a solid organ or stem cell transplant.

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I have been diagnosed with aplastic anemia before joining this study.

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I have liver damage caused by reduced blood flow.

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I am HIV positive or have been diagnosed with AIDS.

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I currently have sepsis.

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I have been diagnosed with autoimmune hepatitis.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 180 days

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~180 days

This trial's timeline: 3 weeks for screening, Varies for treatment, and 180 days for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Secondary study objectives

Survival with native liver (SNL)

Side effects data

From 2023 Phase 1 & 2 trial • 307 Patients • NCT02348216

83%

Pyrexia

53%

Hypotension

50%

Neutropenia

45%

Fatigue

38%

Constipation

35%

Neutrophil count decreased

35%

Nausea

33%

Anaemia

33%

Headache

30%

Confusional state

28%

Diarrhoea

28%

Hypokalaemia

28%

Hypophosphataemia

25%

Thrombocytopenia

25%

White blood cell count decreased

23%

Arthralgia

23%

Tremor

20%

Chills

20%

Vomiting

20%

Hypogammaglobulinaemia

20%

Dyspnoea

20%

Decreased appetite

18%

Leukopenia

18%

Lymphocyte count decreased

18%

Hypoxia

15%

Platelet count decreased

15%

Insomnia

15%

Cough

15%

Tachycardia

15%

Muscular weakness

15%

Dizziness

15%

Hyponatraemia

13%

Sinus tachycardia

13%

Asthenia

13%

Abdominal pain

13%

Somnolence

10%

Covid-19

10%

Hyperglycaemia

10%

Hypomagnesaemia

10%

Aphasia

10%

Anxiety

10%

Pollakiuria

10%

Hypertension

10%

Lymphopenia

10%

Nasal congestion

Pneumonia

Seizure

Dry mouth

Oedema peripheral

Upper respiratory tract infection

Urinary tract infection

Fall

Encephalopathy

Agitation

Depression

Urinary incontinence

Urinary retention

Hiccups

Erythema

Deep vein thrombosis

Pain in extremity

Malaise

Febrile neutropenia

B-cell lymphoma

Mental status changes

Vision blurred

Odynophagia

Rectal haemorrhage

Peripheral swelling

Head injury

Weight decreased

Dehydration

Hypoalbuminaemia

Back pain

Neck pain

Squamous cell carcinoma

Apraxia

Dementia

Dysarthria

Paraesthesia

Dry skin

Pruritus

Embolism

Oral candidiasis

Vitreous floaters

Anal incontinence

Influenza like illness

Respiratory syncytial virus infection

Bone pain

Oropharyngeal pain

Pancytopenia

Hypocalcaemia

Alopecia

Rhinitis

Dyspraxia

Leukoencephalopathy

Ascites

Wound

Non-cardiac chest pain

Rash maculo-papular

Staphylococcal infection

Pneumocystis jirovecii pneumonia

Sepsis

Urosepsis

Covid-19 pneumonia

Escherichia sepsis

Human herpesvirus 6 encephalitis

Amyotrophy

Lung neoplasm malignant

Cognitive disorder

Seizure like phenomena

Syncope

Chronic obstructive pulmonary disease

Respiratory failure

Toxic skin eruption

Atrial fibrillation

Bradycardia

Sinus bradycardia

Abdominal pain upper

Dyspepsia

Dysphagia

Stomatitis

Toothache

Gait disturbance

Oedema

Pain

Conjunctivitis

Skin abrasion

Alanine aminotransferase increased

Blood bilirubin increased

Blood fibrinogen decreased

Serum ferritin increased

Hyperkalaemia

Hypernatraemia

Myalgia

Disturbance in attention

Dysgraphia

Memory impairment

Post herpetic neuralgia

Delirium

Hallucination

Restlessness

Acute kidney injury

Haematuria

Pulmonary oedema

Hyperhidrosis

Night sweats

Rash

Hip fracture

Gastrooesophageal reflux disease

Tongue ulceration

Toxic encephalopathy

Herpes zoster

Blood creatinine increased

C-reactive protein increased

Dysuria

Muscle spasms

100%

80%

60%

40%

20%

Study treatment Arm

Phase 2 (Safety Management Study): Cohort 6

Phase 2 (Safety Management Study): Cohort 4

Phase 2 (Pivotal Study): Cohort 2

Phase 2 (Safety Management Study): Cohort 3

Phase 2 (Safety Management Study): Cohort 5

Retreatment Axicabtagene Ciloleucel: Phase 1

Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 6

Phase 2 (Pivotal Study): Cohort 1

Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 2

Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 1

Phase 1 Study: Axicabtagene Ciloleucel and Conditioning Chemotherapy

Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 4

Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 5

Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 3

Trial Design

3Treatment groups

Experimental Treatment

Placebo Group

Group I: High-dose methylprednisoloneExperimental Treatment2 Interventions

Intravenous methylprednisolone at an initial dose of 10 mg/kg/day for 3 days, 5 mg/kg/day on day 4.

Group II: Equine anti-thymocyte globulinExperimental Treatment4 Interventions

Intravenous equine anti-thymocyte globulin at a dose of 40 mg/kg/day for 4 days.

Group III: Supportive carePlacebo Group2 Interventions

Supportive care will be administered as determined by the clinical team at participating clinical sites in accordance with their local practices and standards.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

High-dose methylprednisolone

2015

Completed Phase 2

~310

Prednisolone

2005

Completed Phase 4

~3570

Methylprednisolone

2015

Completed Phase 4

~2280

Diphenhydramine

2002

Completed Phase 4

~1170

0 / 11Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Corticosteroids and equine anti-thymocyte globulin (ATG) are common treatments for liver injury due to their immunosuppressive properties. Corticosteroids provide broad immunosuppression and anti-inflammatory effects, which help reduce overall immune-mediated damage to liver cells, crucial for preventing further liver injury and promoting healing. Equine ATG specifically targets T-cells, reducing their activity and proliferation. This targeted approach is important because T-cells are key players in the immune response that can exacerbate liver injury. By diminishing T-cell activity, ATG helps decrease the immune-mediated attack on the liver, potentially improving patient outcomes.

Chemical induction of hepatic apoptosis in rodents.Thymoquinone, an Active Constituent of Black Seed Attenuates CCl4 Induced Liver Injury in Mice via Modulation of Antioxidant Enzymes, PTEN, P53 and VEGF Protein.Herbal Compound "Jiedu Huayu" Reduces Liver Injury in Rats via Regulation of IL-2, TLR4, and PCNA Expression Levels.