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

95%

Pyrexia

61%

Diarrhoea

59%

Hypotension

46%

Anaemia

46%

Fatigue

39%

Neutropenia

39%

Headache

32%

Neutrophil count decreased

29%

Nausea

27%

Chills

27%

Cough

24%

Platelet count decreased

17%

Leukopenia

17%

Thrombocytopenia

17%

Dizziness

17%

Tachycardia

15%

Vomiting

15%

Hypogammaglobulinaemia

15%

Pneumonia

15%

White blood cell count decreased

15%

Hypokalaemia

15%

Hypophosphataemia

15%

Hypoxia

15%

Constipation

12%

Alanine aminotransferase increased

12%

Back pain

12%

Encephalopathy

12%

Tremor

12%

C-reactive protein increased

12%

Somnolence

10%

Aspartate aminotransferase increased

10%

Lymphocyte count decreased

10%

Arthralgia

10%

Aphasia

10%

Confusional state

10%

Pancytopenia

10%

Herpes zoster

10%

Weight increased

10%

Pain in extremity

B-cell lymphoma

Dysphagia

Chest pain

Puncture site pain

Nasopharyngitis

Upper respiratory tract infection

Gamma-glutamyltransferase increased

Immunoglobulins decreased

Serum ferritin increased

Dyspnoea

Febrile neutropenia

Lymphopenia

Blood creatinine increased

Decreased appetite

Lung infection

Oedema peripheral

Immune effector cell-associated neurotoxicity syndrome

Respiratory failure

Sinus tachycardia

Dry mouth

Dyspepsia

Asthenia

Oral candidiasis

Sinusitis

Hypoalbuminaemia

Hypomagnesaemia

Hyponatraemia

Myalgia

Neck pain

Dysarthria

Paraesthesia

Hallucination

Insomnia

Acute kidney injury

Pollakiuria

Pleural effusion

Hyperhidrosis

Hypertension

Abdominal pain

Anal incontinence

Lymphadenopathy

Influenza like illness

Dry skin

Malaise

Atelectasis

Haemoptysis

Photophobia

Blood lactate dehydrogenase increased

Meningitis

Myelitis

Bone marrow failure

Pneumocystis jirovecii pneumonia

Sepsis

Pancreatitis

Adenovirus infection

Bacteraemia

Bronchitis

Cytomegalovirus colitis

Encephalitis

Radius fracture

Musculoskeletal pain

Acute myeloid leukaemia

Prostate cancer

Disturbance in attention

Dysgraphia

Quadriplegia

Depression

Anuria

Cystitis haemorrhagic

Haematuria

Pneumonitis

Atrial fibrillation

Tinnitus

Abdominal pain upper

Stomatitis

Toothache

Peripheral swelling

Clostridium difficile infection

Conjunctivitis

Respiratory syncytial virus infection

Urinary tract infection

Blood alkaline phosphatase increased

Hyperglycaemia

Bone pain

Muscle spasms

Muscular weakness

Cancer pain

Myelodysplastic syndrome

Memory impairment

Agitation

Disorientation

Dysuria

Urinary incontinence

Urinary retention

Nasal congestion

Rhinorrhoea

Alopecia

Erythema

Pruritus

Capillary leak syndrome

Dehydration

Cardiac arrest

Atypical pneumonia

Car t-cell-related encephalopathy syndrome

Renal failure

Vision blurred

Ascites

Oedema

Oropharyngeal pain

Rash

Respiratory tract infection

Sinus bradycardia

Hypocalcaemia

100%

80%

60%

40%

20%

Study treatment Arm

Phase 2 (Safety Management Study): Cohort 4

Phase 2 (Safety Management Study): Cohort 6

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

~1210

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.