Efficacy and Safety of Glucocorticosteroid Treatment in the Patients With Chronic Recurrent DILI

Phase 1

Completed

• Conditions: Drug-induced Liver Injury,Chronic
• Interventions: Drug: Standard Treatment; Drug: Methylprednisolone

• Registration Number: NCT02651350
• Lead Sponsor: Beijing 302 Hospital

Brief Summary

This study is to observe the efficacy and safety of glucocorticosteroid treatment in the patients with chronic recurrent drug-induced liver injury (DILI).

Detailed Description

Drug-induced liver injury (DILI) refers to liver diseases caused by drugs and toxic substances. DILI is a clinical event that can be associated with severe outcomes such as acute liver failure. Up to now, approximately 1000 drugs, herbal products, vitamins and illicit compounds are associated with liver injury. Recently, the incidence of DILI is rising. In our hospital, hospitalized patients with DILI was increased from 1.39% in 2002 to 2.31% in 2006, and further up to 3.17% in 2011, which indicated 2.3-folds increase over last ten years.15% to 20% patients with acute DILI are prone to chronic liver disease. For patients with chronic recurrent DILI, routine liver protective treatment was difficult to rescue abnormal liver functions. Moreover, increasing health care costs seriously affect the patient's quality of life. Glucocorticosteroids can inhibit the non-specific inflammation and permeability of the capillary bile duct, limit the activation of T lymphocytes, and selectively inhibit B lymphocytes to produce antibodies, thus preventing or delaying the immune-induced liver injury. Glucocorticoid treatment of severe DILI has accepted some recognition, but the effect of repeated episodes of chronic DILI, due to a lack of randomized controlled studies, is still unclear. Therefore, we shall design two groups on the basis of the ratio of 1:1, namely, glucocorticoid treatment group and standard treatment alone group. Participants in glucocorticoid treatment group will receive methylprednisolone,48mg/d for the 1st week, 32mg/d for the 2nd week, 24mg/d for the next two weeks, followed by 16mg/d for 32 weeks and reduction in doses of methylprednisolone by 4 mg per 4 weeks until drug withdrawal. Participants in glucocorticoid treatment group also receive standard treatment including reduced glutathione, glycyrrhizin, ademetionine, alprostadil,or ursodeoxycholic acid (UDCA) in the first 12 weeks. Participants in standard treatment group will only receive treatment by routine liver protection drugs including reduced glutathione, glycyrrhizin, ademetionine, alprostadil, or ursodeoxycholic acid (UDCA) in the first 12 weeks.The efficacy and safety of glucocorticoid treatment in the patients with chronic recurrent DILI will be observed during the treatment and follow-up period.

Study Timeline

• Study Start: 2015-12
• Study First Submitted: 2015-12-25
• Study First Submitted QC: 2016-01-07
• Study First Posted: 2016-01-11
• Status Verified: 2019-07
• Primary Completion: 2019-07
• Study Completion: 2019-07
• Last Update Submitted: 2020-08-07
• Last Update Posted: 2020-08-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 80

Inclusion Criteria

1. Meet with ACG clinic guidelines for diagnostic criteria of chronic DILI;

2. Meet any of the following conditions:

   • serum AST or ALT ≥ 10 fold ULN;
   • serum AST or ALT ≥ 5 fold ULN and TBIL ≥ 2 fold ULN;
   • liver histology indicates bridging necrosis or multiacinar necrosis or moderate or more inflammation or inflammation G3 or more;

3. Women of childbearing age had a negative urine pregnancy test, and the subjects are willing to have no family planning during the study and to take effective measures;

4. Voluntary participation, understanding and signing of informed consent, comply with the requirements of the research;

Exclusion Criteria

1. Patients with serious pre-existent comorbid conditions (vertebral compression fractures,psychosis,active peptic ulcer, brittle diabetes,uncontrolled hypertension;
2. Patients with intolerances to prednisone;
3. Patients with severe infection receiving antibiotics, anti-fungal,anti-viral therapy;
4. Viral hepatitis,alcoholic or non-alcoholic liver disease,Wilson's disease or other inherited metabolic liver diseases.
5. Pregnancy or desire of pregnancy;
6. Breast-feeding;
7. Liver cancer or other malignant tumor;

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Standard Treatment	Standard Treatment	Participants will only receive standard treatment (namely,routine liver protection drugs) including reduced glutathione, glycyrrhizin, ademetionine, alprostadil,or ursodeoxycholic acid (UDCA) from week 0 through week 12 study visit. Participants will then be followed until week 72 study visit.
Methylprednisolone	Standard Treatment	Participants will receive methylprednisolone from week 0 through week 48 study visit in combination with standard treatment including reduced glutathione, glycyrrhizin, ademetionine, alprostadil,or ursodeoxycholic acid (UDCA) in the first 12 weeks. Participants will then be followed until week 72 study visit.
Methylprednisolone	Methylprednisolone	Participants will receive methylprednisolone from week 0 through week 48 study visit in combination with standard treatment including reduced glutathione, glycyrrhizin, ademetionine, alprostadil,or ursodeoxycholic acid (UDCA) in the first 12 weeks. Participants will then be followed until week 72 study visit.

Primary Outcome Measures

Name	Time	Method
The relapse or recurrent rate of illness, namely, appearance of obviously abnormal liver function again during treatment and follow-up period	At week 72	The biochemical relapse rate was analyzed by either intention to treat (ITT) or per protocol set (PPS). Biochemical relapse was characterized either by the serum alanine transaminase (ALT) or aspartate aminotransferase (AST) ≥ 3 × upper limits of normal (ULN) or alkaline phosphatase (ALP) ≥ 2 × ULN, or by at least 2 folds increase in serum ALT or AST or ALP from the abnormal index lately.

Secondary Outcome Measures

Name	Time	Method
The number of participants with methylprednisolone treatment-related adverse events, such as severe osteopenia, uncontrolled hypertension	At week 24 and at week 72	The adverse effects in each group were evaluated according to the Common Terminology Criteria for Adverse Events (version 5.0). The types of steroid-related adverse effects referred to the EASL/AASLD autoimmune hepatitis Guidelines. Adverse effects occurred in both the treatment period and the follow-up period were combined to evaluate.
Days of normalization of liver functions including serum levels of ALT, AST, TBIL,GGT and ALP.	From week 1 to week 12	The normalization time(days) of biochemistry was defined as the days of normalization of each biochemical parameter (ALT, AST, TBil, ALP and gamma-glutamyl transpeptidase), respectively.
The liver histological changes between two liver biopsies	At week 0 and at week 48 week	Histological improvement was defined as at least two points reduce in the activity score, or at least one point decrease in the fibrosis score in accordance to Ishak scoring system.

Trial Locations

Locations (1)

Beijing 302 hospital,China; 🇨🇳 Beijing, Beijing, China