Glucocorticoids for Acute Drug Induced Liver Injury With Hyperbilirubinemia

Official title

Efficacy and Safety of Glucocorticoids for Acute Drug Induced Liver Injury With Hyperbilirubinemia: A Multicenter Randomized Controlled Trial

Overview

Drug-induced liver injury (DILI) can lead to potentially fatal complications, such as acute liver failure and even death. In clinical practice, glucocorticoids have been considered in some cases of DILI, especially patients with hyperbilirubinemia. However, the available evidence remains controversial and its quality is also very limited. Herein, a multicenter randomized controlled trial (RCT) has been designed to explore the efficacy and safety of glucocorticoids in patients with acute DILI and hyperbilirubinemia.

Detailed description

Overall, 232 patients with acute DILI with hyperbilirubinemia will be enrolled. They will be randomly assigned at a ratio of 1:1 to the conventional treatment alone or combined with glucocorticoids groups. The primary endpoint is the improvement of DILI after treatment on second week. Secondary endpoints include the improvement of DILI on fourth week, rates of progressive liver injury, liver failure, liver transplantation, survival, and adverse events. Exploratory endpoints will assess the beneficial population and changes of inflammatory factors following glucocorticoid treatment.

Interventions

• Drug Methylprednisolone
  Initially, an intravenous dose of 1 mg/kg/day of methylprednisolone will be administered for one week, with the possibility of extending treatment to two weeks if necessary. Following this, participants will receive oral methylprednisolone tablets, starting at a dose of 40 mg/day. The oral dosage will be gradually tapered based on the participants' condition over a period of 1 to 3 months.
• Drug Magnesium isoglycyrrhizinate
  It is suitable for patients with hepatocellular or mixed DILI. A daily dose of 0.15g to 0.2g
• Drug Glutathione
  It is suitable for patients with hepatocellular or mixed DILI. A daily dose of 1.2g to 1.8g
• Drug Silymarin
  It is suitable for patients with hepatocellular or mixed DILI. The dosage is 140 mg, taken 2 to 3 times per day.
• Drug Polyene Phosphatidylcholine
  It is suitable for patients with hepatocellular or mixed DILI. The dosage is 228mg-456mg, taken 3 times per day.
• Drug Ursodeoxycholic acid capsules
  It is suitable for patients with cholestatic or mixed DILI. A daily dose of 10mg-15mg/kg/day.
• Drug Ademetionine 1,4-Butanedisulfonate
  It is suitable for patients with cholestatic or mixed DILI. A daily dose of 0.5g to 1g.
• Procedure Plaslna exchange
  It is suitable for patients whose condition continues to worsen or even develop to liver failure.
• Procedure Liver transplantation
  It is suitable for patients whose condition continues to worsen or even develop to liver failure.

Primary outcome measures

• Improvement of DILI on the second week [Time frame: 2 weeks]

Secondary outcome measures (9)

• Improvement of DILI on the fourth week [Time frame: 4 weeks]
• Progressive liver injury on the second week [Time frame: 2 weeks]
• Progressive liver injury on the fourth week [Time frame: 4 weeks]
• Improvement of liver enzymes on the second week [Time frame: 2 weeks]
• Improvement of liver enzymes on the fourth week [Time frame: 4 weeks]
• Liver failure [Time frame: 3 months]
• Liver transplantation [Time frame: 3 months]
• Survival [Time frame: 3 months]
• Adverse events [Time frame: 3 months]

Eligibility criteria

Inclusion criteria

• A definite diagnosis of acute DILI;
• 5×ULN ≤ TBIL level at baseline ≤ 20×ULN;
• Age 18-80 years old;
• Sign the informed consent form.

Exclusion criteria

• Other causes of liver injury, including viral hepatitis, cytomegalovirus infection, Epstein-Barr virus infection, Herpes virus infection, autoimmune liver disease, alcoholic liver disease, hypoxic/ischemic liver disease, Budd-Chiari syndrome, biliary tract disease, Wilson's disease, hemochromatosis, and α1-antitrypsin deficiency;
• Immune checkpoint inhibitors or gynura segetum induced DILI;
• Absolute contraindications to glucocorticoids, such as systemic mold infections or allergies;
• A history of glucocorticoid therapy within 3 months before enrollment;
• A history of diseases requiring glucocorticoid maintenance therapy, such as rheumatoid arthritis, systemic lupus erythematosus, systemic dermatomyositis, etc;
• A history of liver transplantation;
• Received artificial liver therapy before enrollment;
• Malignant tumor of the liver, bile duct, pancreas or liver metastasis
• Acute liver failure;
• Renal dysfunction, creatinine Cr≥133μmol/L;
• Neutrophil count <1,000,000,000/L;
• Active tuberculosis;
• Severe cardiopulmonary diseases;
• Recent surgery or trauma;
• Mental illness;
• Pregnancy or lactation;
• Participated in other clinical studies within 3 months before enrollment;
• Other conditions judged by the clinician to be inappropriate for study participation.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Department of Gastroenterology, General Hospital of Northern Theater Command (formerly cal — Shenyang

Publications

• Hou FQ, Zeng Z, Wang GQ. Hospital admissions for drug-induced liver injury: clinical features, therapy, and outcomes. Cell Biochem Biophys. 2012 Nov;64(2):77-83. doi: 10.1007/s12013-012-9373-y. PMID 22806342
• Hu PF, Wang PQ, Chen H, Hu XF, Xie QP, Shi J, Lin L, Xie WF. Beneficial effect of corticosteroids for patients with severe drug-induced liver injury. J Dig Dis. 2016 Sep;17(9):618-627. doi: 10.1111/1751-2980.12383. PMID 27426618
• Chai L, Wang R, Teschke R, Jin S, Deng J, Qi X. Successful corticosteroid therapy for severe liver injury secondary to herbal traditional Chinese medicine, Mega Defends X, assessed for causality by the updated RUCAM: A case report. Medicine (Baltimore). 2024 Aug 23;103(34):e39439. doi: 10.1097/MD.0000000000039439. PMID 39183394
• Mao Y, Ma S, Liu C, Liu X, Su M, Li D, Li Y, Chen G, Chen J, Chen J, Zhao J, Guo X, Tang J, Zhuge Y, Xie Q, Xie W, Lai R, Cai D, Cai Q, Zhi Y, Li X; Technology Committee on DILI Prevention, Management, Chinese Medical Biotechnology Association; Study Group on Drug-Induced Liver Disease, Chinese Society of Hepatology, Chinese Medical Association. Chinese guideline for the diagnosis and treatment of PMID 38402364
• Li Q, Lin Y, Zeng X, Zhou L, Wang F, Ye Q, Gao Y, Guo L, Zhu J, Li J, Li Y, Shao L, Hu Y, Xiao J, Jia A, Wang D, Chang L, Wang J, Zhang J, Wang R, Gao F, Wu Q, Hu P, Zhu C, Cai L, Ran Y, Li Y, Zhang J, Ran Y, Wang C, Wang N, Zhang J, Zhang X, Li J, Sun J, Chu Y, Ma Y, Wang T, Zheng Z, Shen Y, Qi X, Xie W. Efficacy and safety of glucocorticoids for acute drug-induced liver injury with hyperbilirubi PMID 42080196

Identifiers

NCT: NCT06922669 · XHNKKY-ASDILI-RCT

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗