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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomized Controlled Clinical Trial on the Efficacy and Safety of Glucocorticosteroid in the Patients With Chronic Recurrent Drug-induced Liver Injury

Conditions
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Drug-induced Liver Injury,Chronic

Intervention / Treatment
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* Drug: Methylprednisolone
* Drug: Standard Treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Meet with ACG clinic guidelines for diagnostic criteria of chronic DILI; 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; 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; Voluntary participation, understanding and signing of informed consent, comply with the requirements of the research; Exclusion Criteria: Patients with serious pre-existent comorbid conditions (vertebral compression fractures,psychosis,active peptic ulcer, brittle diabetes,uncontrolled hypertension; Patients with intolerances to prednisone; Patients with severe infection receiving antibiotics, anti-fungal,anti-viral therapy; Viral hepatitis,alcoholic or non-alcoholic liver disease,Wilson's disease or other inherited metabolic liver diseases. Pregnancy or desire of pregnancy; Breast-feeding; Liver cancer or other malignant tumor;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Methylprednisolone<br>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. | Drug: Methylprednisolone<br>* Participants 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 will also receive standard treatment including reduced glutathione, glycyrrhizin, ademetionine, alprostadil, or ursodeoxycholic acid (UDCA) in the first 12 weeks.The total treatment duration will be 48 weeks. Follow-up duration is 24 weeks.<br>* Other names: MEDROL,NDC0009-0056-02;Drug: Standard Treatment<br>* 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.<br>* Other names: Routine liver protection drugs;|
| Active Comparator: Standard Treatment<br>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. | Drug: Standard Treatment<br>* 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.<br>* Other names: Routine liver protection drugs;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The relapse or recurrent rate of illness, namely, appearance of obviously abnormal liver function again during treatment and follow-up period | 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. | At week 24 | 
| The relapse or recurrent rate of illness, namely, appearance of obviously abnormal liver function again during treatment and follow-up period | 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. | At week 72 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Days of normalization of liver functions including serum levels of ALT, AST, TBIL,GGT and ALP. | 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. | From week 1 to week 12 | 
| The liver histological changes between two liver biopsies | 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. | At week 0 and at week 48 week | 
| The number of participants with methylprednisolone treatment-related adverse events, such as severe osteopenia, uncontrolled hypertension | 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. | At week 24 and at week 72 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug-induced Liver Injury, Recurrence, Methylprednisolone