Immune Suppression Therapy for Acute Liver Failure

(TRIUMPH Trial)

Recruiting at 21 trial locations

Overseen By Katie Neighbors, MPH

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Must not be taking: Immunosuppressants, Chemotherapy

Disqualifiers: Hepatitis, HIV, Sepsis, Pregnancy, others

Prior Safety Data

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are currently on immunosuppressive agents, chemotherapy, biological therapies, or experimental drugs, you may need to stop, as these are part of the exclusion criteria.

What data supports the effectiveness of the drug Equine anti-thymocyte globulin (eATG) for treating acute liver failure?

Research shows that Equine anti-thymocyte globulin (eATG) has been used successfully in kidney transplant patients to prolong graft survival and reduce rejection episodes. This suggests it may help in managing immune responses in other transplant scenarios, like liver transplants. ^{1 2 3 4 5}

Is immune suppression therapy generally safe for humans?

Prednisolone, a common immune suppression drug, has been used in various liver conditions and is known to improve symptoms, but it can have serious side effects, especially at high doses. In children with autoimmune hepatitis, high doses of prednisone can lead to significant adverse effects, and alternative treatments like cyclosporine are sometimes used to avoid these issues. ^{6 7 8 9 10}

How does the drug Equine anti-thymocyte globulin and Prednisolone differ from other treatments for acute liver failure?

This drug combination is unique because it uses Equine anti-thymocyte globulin (eATG) to suppress the immune system, which is typically used in transplant patients to prevent rejection, and Prednisolone, a steroid that reduces inflammation and immune response. This approach is novel for acute liver failure, as there are no standard treatments specifically targeting immune suppression for this condition. ^{2 3 8 11 12}

Research Team

Estella Alonso, MD

Principal Investigator

Ann & Robert H Lurie Children's Hospital of Chicago

Valerie L Durkalski-Mauldin, PhD

Principal Investigator

Medical University of South Carolina

Ed Doo, MD

Principal Investigator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Averell Sherker, MD

Principal Investigator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Eligibility Criteria

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.

Inclusion Criteria

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

Females of reproductive potential should not plan on conceiving children during the study and must agree to use a medically accepted form of contraception

I am between 1 and 17 years old.

Exclusion Criteria

You have traveled to an area with a lot of cases of Hepatitis E in the last 3 months.

You have an active infection with certain viruses like Hepatitis or herpes.

You have tested positive for the virus that causes COVID-19.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either high-dose methylprednisolone or equine anti-thymocyte globulin or supportive care alone for 4 days, followed by a taper from days 5 to 42

6 weeks

Daily visits during initial 4 days, followed by regular visits during taper

Follow-up

Participants are monitored for safety and effectiveness after treatment with visits at 1 week, 2 weeks, 3 weeks, 6 weeks, 3 months, 6 months, and 12 months

12 months

7 visits (in-person or virtual) over 12 months

Treatment Details

Interventions

• Equine anti-thymocyte globulin (Immunosuppressant)
• Methylprednisolone (Corticosteroid)
• Prednisolone (Corticosteroid)

Trial Overview 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.

Participant Groups

Group I: High-dose methylprednisolone Experimental Treatment 2 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 globulin Experimental Treatment 4 Interventions

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

Group III: Supportive care Placebo Group 2 Interventions

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

Equine anti-thymocyte globulin is already approved in Canada for the following indications:

Approved in Canada as ATGAM for:

• Prevention and treatment of acute rejection in renal transplant patients
• Treatment of aplastic anemia

Who Is Running the Clinical Trial?

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Lead Sponsor

Trials

2,513

Recruited

4,366,000+

Ann & Robert H Lurie Children's Hospital of Chicago

Collaborator

Trials

275

Recruited

5,182,000+

Findings from Research

A four-and-a-half-year-old boy with progressive familial intrahepatic cholestasis underwent living-donor liver transplantation and initially received standard immunosuppressive therapy, but developed acute cellular rejection that did not respond to steroid treatments.

The introduction of muromonab-CD3 therapy after repeated steroid failure led to a significant recovery in liver function tests and overall health, indicating its potential effectiveness in treating severe graft rejection in pediatric liver transplant patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Muromonab-CD3 for the successful treatment of early chronic rejection after pediatric liver transplantation: report of a case. Hori, T., Nguyen, JH., Uemoto, S.[2021]

In a study involving 50 transplant recipients, the combination of equine antithymocyte globulin (ATG) with azathioprine and prednisone significantly prolonged allograft survival and reduced the severity of rejection episodes, with only three kidneys lost to rejection.

The treatment with ATG did not lead to serious hematologic or systemic side effects, and the rate of infections was comparable to other transplant studies, suggesting it is a safe option for immunosuppression in transplant patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical evaluation of equine antithymocyte globulin in recipients of renal allografts: Analysis of survival, renal function, rejection, histocompatibility, and complications. Diethelm, AG., Aldrete, JS., Shaw, JF., et al.[2019]

In a study of 49 patients who underwent their first liver transplantation for hepatitis C, those who received anti-thymocyte globulin (ATG) during the induction phase had a significantly lower rate of HCV recurrence (26.9% vs 73.9%) compared to those receiving standard therapy.

Despite the reduced HCV recurrence, the use of ATG did not impact overall patient survival rates at 1 and 2 years, nor did it significantly affect the rates of acute cellular rejection, infections, or neoplasms, although there was a higher incidence of fungal infections in the ATG group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of anti-thymocyte globulin during immunosuppression induction in patients with hepatitis C after liver transplantation. Garcia-Saenz-de-Sicilia, M., Olivera-Martinez, MA., Grant, WJ., et al.[2021]

Prednisone, especially in combination with azathioprine, is effective in treating autoimmune hepatitis by improving symptoms and prolonging survival, with the combination preferred due to fewer side effects from corticosteroids.

Treatment should be personalized based on disease severity, with histologic examination recommended before withdrawing medication to confirm remission, and alternative therapies available for patients who do not respond to standard treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment strategies in autoimmune hepatitis. Czaja, AJ.[2019]

In a study of 22 hepatitis C virus (HCV)+ liver transplant patients using Thymoglobulin induction and tacrolimus monotherapy, the approach allowed for lower dosages of tacrolimus and a successful weaning process without major rejection complications.

While the recurrence rate of hepatitis C was similar between the Thymoglobulin group and a conventional treatment group, the Thymoglobulin-treated patients had significantly lower HCV RNA loads, suggesting a potential benefit that warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preliminary results of a "prope" tolerogenic regimen with thymoglobulin pretreatment and hepatitis C virus recurrence in liver transplantation. De Ruvo, N., Cucchetti, A., Lauro, A., et al.[2019]

In a pilot study involving 32 children with autoimmune hepatitis, treatment with oral cyclosporine for 6 months led to biochemical remission in 25 out of 30 patients, with all patients normalizing their liver enzyme levels by 1 year.

Cyclosporine was well-tolerated, with only mild adverse effects that resolved after discontinuation, suggesting it may be a safer alternative to high-dose prednisone in managing autoimmune hepatitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short-term cyclosporine induces a remission of autoimmune hepatitis in children. Alvarez, F., Ciocca, M., Cañero-Velasco, C., et al.[2019]

In a study of 50 children with autoimmune hepatitis, both prednisone plus azathioprine (PRED-AZA) and cyclosporine (CsA) were found to be equally effective, but PRED-AZA led to faster remission (8.6 weeks) compared to CsA (13.6 weeks).

While both treatments had similar safety profiles, PRED-AZA was associated with a higher incidence of Cushingoid syndrome, while CsA led to more cases of gingival hypertrophy, indicating that treatment choice may depend on individual patient characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Autoimmune Hepatitis in Children: Prednisone Plus Azathioprine Versus Cyclosporine: A Randomized Trial. Cuarterolo, ML., Ciocca, M., López, S., et al.[2021]

Prednisone and its active form, prednisolone, are key treatments for autoimmune hepatitis, working by suppressing immune responses and reducing inflammation in the liver.

Budesonide combined with azathioprine has shown to be more effective and safer than traditional prednisone-based treatments in treatment-naive patients, making it a promising frontline option for noncirrhotic patients with uncomplicated autoimmune hepatitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug choices in autoimmune hepatitis: part A--Steroids. Czaja, AJ.[2013]

In a rat model of toxic hepatitis, hepatoprotectors containing phospholipids (eplir and essentiale) combined with prednisolone reduced the immunosuppressive effects of the glucocorticoid, as indicated by less thymus atrophy.

The combination treatment led to an increase in blood lymphocytes, splenic blasts, and enhanced functional activity of immune cells, suggesting a potential strategy to mitigate the side effects of glucocorticoids in liver toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Hepatoprotectors containing phospholipids decrease the immunosuppressive effect of prednisolone in rats with experimental toxic hepatitis]. Vengerovskiĭ, AI., Ogorodova, LM., Perevozchikova, TV.[2016]

In chronic active hepatitis, treatment with prednisolone (with or without azathioprine) has been shown to improve clinical and liver histological outcomes, while azathioprine alone does not provide any benefit over placebo.

In primary biliary cirrhosis, corticosteroids like prednisolone are not recommended due to the risk of bone thinning, and azathioprine offers only marginal benefits, highlighting the need for careful patient selection in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunosuppressive therapy in chronic liver disease. Sherlock, S.[2013]

In a study of 20 liver transplant recipients treated with anti-thymocyte globulin (ATG) for steroid-resistant rejection, all patients showed significant improvement in liver function, with median AST levels dropping from 172 to 34 U/l and total bilirubin from 9.1 to 1.3 mg/dl, indicating ATG's efficacy in reversing severe rejection.

Despite the successful reversal of rejection, complications such as recurrent hepatitis C virus (HCV) and various infections were notable, highlighting the need for ongoing monitoring and management of these risks post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-thymocyte globulin for the treatment of acute cellular rejection following liver transplantation. Schmitt, TM., Phillips, M., Sawyer, RG., et al.[2022]

In a study of 16,898 adult liver transplant patients, the combination of anti-thymocyte globulin (ATG) and steroids showed significantly worse graft survival for patients with hepatitis C compared to daclizumab and steroids, indicating that ATG may not be the best choice for these patients.

Daclizumab induction provided satisfactory outcomes for liver transplantation across all liver diseases, including hepatitis C, suggesting it is a more effective option for long-term graft survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcome of induction immunosuppression for liver transplantation comparing anti-thymocyte globulin, daclizumab, and corticosteroid. Uemura, T., Schaefer, E., Hollenbeak, CS., et al.[2021]

References

1. Japan pubmed.ncbi.nlm.nih.gov

Muromonab-CD3 for the successful treatment of early chronic rejection after pediatric liver transplantation: report of a case. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Clinical evaluation of equine antithymocyte globulin in recipients of renal allografts: Analysis of survival, renal function, rejection, histocompatibility, and complications. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Impact of anti-thymocyte globulin during immunosuppression induction in patients with hepatitis C after liver transplantation. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Treatment strategies in autoimmune hepatitis. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Preliminary results of a "prope" tolerogenic regimen with thymoglobulin pretreatment and hepatitis C virus recurrence in liver transplantation. [2019]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Short-term cyclosporine induces a remission of autoimmune hepatitis in children. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Autoimmune Hepatitis in Children: Prednisone Plus Azathioprine Versus Cyclosporine: A Randomized Trial. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Drug choices in autoimmune hepatitis: part A--Steroids. [2013]

9. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Hepatoprotectors containing phospholipids decrease the immunosuppressive effect of prednisolone in rats with experimental toxic hepatitis]. [2016]

10. Italy pubmed.ncbi.nlm.nih.gov

Immunosuppressive therapy in chronic liver disease. [2013]

11. United States pubmed.ncbi.nlm.nih.gov

Anti-thymocyte globulin for the treatment of acute cellular rejection following liver transplantation. [2022]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Outcome of induction immunosuppression for liver transplantation comparing anti-thymocyte globulin, daclizumab, and corticosteroid. [2021]