36 Weeks Short-Term Optimization Treatment of Glucocorticosteroid 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 36 weeks short-term optimization treatment of glucocorticosteroid 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 1100 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. About 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. In our pre-clinical trials (NCT02651350), we found that the rate of recurrence of the glucocorticoid treatment group was significant lower (<10%) than the control group (about 50%) (P <0.001) and there was significant difference of liver histological change during baseline and treatment end between the glucocorticoid treatment group and the control group. Meanwhile, we did not find obvious glucocorticoid's side effect in the glucocorticoid treatment group. At the same time, we found that there was good effect in 36 weeks glucocorticoid treatment in several patients. Therefore, we shall design two groups on the basis of the ratio of 1:1, namely, 36 weeks of glucocorticoid treatment group and 48 weeks of glucocorticoid treatment group in order to evaluate the efficacy and safety of 36 weeks short-term optimization treatment of glucocorticosteroid in the patients with chronic recurrent DILI. Participants in 36 weeks of 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 20 weeks and reduction in doses of methylprednisolone by 4 mg per 4 weeks until drug withdrawal. Participants in 36 weeks of glucocorticoid treatment group also will receive standard treatment including reduced glutathione, glycyrrhizin, ademetionine, alprostadil, or ursodeoxycholic acid (UDCA).Participants will then be followed for 24 weeks. Participants in 48 weeks of 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 48 weeks of treatment group also will receive standard treatment including reduced glutathione, glycyrrhizin, ademetionine, alprostadil,or ursodeoxycholic acid (UDCA).Participants will then be followed for 24 weeks. The efficacy and safety of 36 weeks short-term optimization treatment of glucocorticosteroid in the patients with chronic recurrent DILI will be observed and compared with 48 weeks glucocorticosteroid treatment during the treatment and follow-up period.

Official Title
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The Efficacy and Safety of 36 Weeks Short-Term Optimization Treatment 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: 36 Weeks Methylprednisolone
* Drug: 48 weeks Methylprednisolone


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; The time of recurrence is 1 or more than 1; The definition of recurrence, meet any of the following conditions: the level of serum AST or ALT is elevated more than 5 fold ULN; the level of serum AST or ALT is two times higher than before; 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: 36 Weeks Methylprednisolone<br>Participants in 36 weeks of 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 20 weeks and reduction in doses of methylprednisolone by 4 mg per 4 weeks until drug withdrawal. Participants in 36 weeks of glucocorticoid treatment group also will receive standard treatment including reduced glutathione, glycyrrhizin, ademetionine, alprostadil, or ursodeoxycholic acid (UDCA). Participants will then be followed for 24 weeks. | Drug: 36 Weeks Methylprednisolone<br>* Participants in 36 weeks of 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 20 weeks and reduction in doses of methylprednisolone by 4 mg per 4 weeks until drug withdrawal. Participants in 36 weeks of glucocorticoid treatment group also will receive standard treatment including reduced glutathione, glycyrrhizin, ademetionine, alprostadil, or ursodeoxycholic acid (UDCA).The total treatment duration will be 36 weeks. Follow-up duration is 24 weeks.<br>* Other names: MEDROL,NDC0009-0056-02;|
| Experimental: 48 Weeks Methylprednisolone<br>Participants in 48 weeks of 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 48 weeks of treatment group also will receive standard treatment including reduced glutathione, glycyrrhizin, ademetionine, alprostadil, or ursodeoxycholic acid (UDCA). Participants will then be followed for 24 weeks. | Drug: 48 weeks Methylprednisolone<br>* Participants in 48 weeks of 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 36 weeks of glucocorticoid treatment group also will receive standard treatment including reduced glutathione, glycyrrhizin, ademetionine, alprostadil, or ursodeoxycholic acid (UDCA).The total treatment duration will be 48 weeks. Follow-up duration is 24 weeks.<br>* Other names: MEDROL,NDC0009-0056-02;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence rate of illness, namely, appearance of obviously abnormal liver function again during treatment and follow-up period. The definition of recurrence: The level of AST or ALT is elevated more than 5 fold ULN or is two times higher than before. | To analyze the clinical efficacy of glucocorticosteroid treatment | From week 1 to week 60 or 72 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The liver histological changes between two liver biopsies (baseline and treatment end) | To analyze the clinical efficacy of glucocorticosteroid treatment | At week 0 and at week 36 week or 48 week | 
| Days of normalization or falling by half compared to admission of liver functions including serum levels of ALT, AST, TBIL,GGT and ALP. | To analyze the clinical efficacy of glucocorticosteroid treatment | From week 1 to week 36 or 48 | 

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