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.

Immunosuppressant

Immune Suppression Therapy for Acute Liver Failure (TRIUMPH Trial)

Cleveland, OH

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 21 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.

See full description

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.Check my eligibility

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.See study design

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.

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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.

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Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 21 days

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~21 days

This trial's timeline: 3 weeks for screening, Varies for treatment, and 21 days for reporting.

Treatment Details

Study Objectives

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

Primary study objectives

Survival with native liver (SNL)

Side effects data

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

86%

Pyrexia

61%

Anaemia

57%

Hypotension

44%

Fatigue

44%

Headache

42%

Chills

40%

Decreased appetite

38%

Tachycardia

38%

Diarrhoea

35%

Neutrophil count decreased

34%

Neutropenia

32%

Platelet count decreased

31%

Thrombocytopenia

31%

Hypoxia

30%

White blood cell count decreased

30%

Hypocalcaemia

30%

Hypokalaemia

30%

Tremor

29%

Nausea

29%

Hypoalbuminaemia

27%

Febrile neutropenia

26%

Hyponatraemia

26%

Encephalopathy

25%

Sinus tachycardia

25%

Hypophosphataemia

25%

Confusional state

23%

Cough

22%

Vomiting

19%

Constipation

17%

Leukopenia

17%

Alanine aminotransferase increased

17%

Back pain

17%

Aphasia

16%

Oedema peripheral

16%

Lymphocyte count decreased

16%

Hyperglycaemia

16%

Arthralgia

16%

Dizziness

14%

Aspartate aminotransferase increased

14%

Weight decreased

14%

Muscular weakness

14%

Dyspnoea

13%

Hypogammaglobulinaemia

13%

Myalgia

13%

Somnolence

12%

Anxiety

12%

Pleural effusion

12%

Hypertension

10%

Abdominal pain

Pneumonia

Dry mouth

Pain in extremity

Insomnia

Urinary incontinence

Hyperkalaemia

Memory impairment

Acute kidney injury

Pruritus

Lymphopenia

Pain

Atrial fibrillation

Clostridium difficile infection

Abdominal distension

Asthenia

Non-cardiac chest pain

Upper respiratory tract infection

Fall

Dehydration

Hypomagnesaemia

Dysgeusia

Agitation

Pulmonary oedema

Sinus bradycardia

Malaise

Lung infection

Atrial flutter

Rash maculo-papular

B-cell lymphoma

Dysphagia

Blood creatinine increased

Weight increased

Malnutrition

Hallucination

Mental status changes

Haematuria

Urinary retention

Nasal congestion

Oropharyngeal pain

Upper-airway cough syndrome

Wheezing

Speech disorder

Urinary tract infection

Ejection fraction decreased

Ventricular arrhythmia

Ventricular tachycardia

Flatulence

Herpes zoster

Sinusitis

Blood alkaline phosphatase increased

Blood bilirubin increased

Metabolic acidosis

Neck pain

Dysarthria

Seizure

Hiccups

Vision blurred

Dyspepsia

Bone pain

Ascites

Fluid overload

Cardiac arrest

Escherichia bacteraemia

Peripheral swelling

Squamous cell carcinoma

Clostridium difficile colitis

Abdominal pain upper

Gastrooesophageal reflux disease

Gait disturbance

Rhinitis

Flank pain

Muscle spasms

Restlessness

Dysuria

Pollakiuria

Atelectasis

Tachypnoea

Alopecia

Dry skin

Rash

Capillary leak syndrome

Deep vein thrombosis

Vitreous floaters

Histiocytosis haematophagic

Supraventricular tachycardia

Tumour pain

Local swelling

Excoriation

Blood lactate dehydrogenase increased

Electrocardiogram QT prolonged

Influenza

Pancytopenia

Acute left ventricular failure

Haemophagocytic lymphohistiocytosis

Bacteraemia

Cytomegalovirus enteritis

Klebsiella infection

Oral herpes

Pneumonia staphylococcal

Troponin T increased

Lactic acidosis

Basal cell carcinoma

Carcinoma in situ

Myelodysplastic syndrome

Depressed level of consciousness

Swelling

Lethargy

Leukoencephalopathy

Presyncope

Delirium

Acute respiratory failure

Aspiration

Reexpansion pulmonary oedema

Candida infection

Shock

Bradycardia

Ear pain

Anal incontinence

Rectal haemorrhage

Stomatitis

Oedema

Oral candidiasis

Infusion related reaction

Procedural pain

Skin abrasion

Blood immunoglobulin G decreased

Oxygen saturation decreased

Serum ferritin increased

Hypermagnesaemia

Groin pain

Disturbance in attention

Paraesthesia

Post herpetic neuralgia

Bradyphrenia

Depression

Disorientation

Urinary tract obstruction

Scrotal oedema

Rhinorrhoea

Erythema

Bone marrow failure

Head discomfort

100%

80%

60%

40%

20%

Study treatment Arm

Phase 2 (Pivotal Study): Cohort 1

Phase 2 (Pivotal Study): Cohort 2

Phase 2 (Safety Management Study): Cohort 3

Phase 2 (Safety Management Study): Cohort 4

Phase 2 (Safety Management Study): Cohort 5

Phase 2 (Safety Management Study): Cohort 6

Retreatment Axicabtagene Ciloleucel: Phase 1

Retreatment Axicabtagene Ciloleucel: Phase 2 Cohort 6

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

~3530

Methylprednisolone

2021

Completed Phase 4

~2360

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.