36 Weeks Short-Term Optimization Treatment of Glucocorticosteroid in the Patients With Chronic Recurrent DILI

Sponsor

Beijing 302 Hospital (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03266146

Collaborator

(none)

Enrollment

Location

Arms

58.9

Anticipated Duration (Months)

1.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Drug-induced Liver Injury,Chronic	Drug: 36 Weeks Methylprednisolone Drug: 48 weeks Methylprednisolone	Phase 1/Phase 2

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 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.

Study Design

Study Type:

Interventional

Actual Enrollment :

90 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

The Efficacy and Safety of 36 Weeks Short-Term Optimization Treatment of Glucocorticosteroid in the Patients With Chronic Recurrent Drug-Induced Liver Injury

Actual Study Start Date :

Sep 2, 2017

Anticipated Primary Completion Date :

Jul 31, 2022

Anticipated Study Completion Date :

Jul 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 36 Weeks Methylprednisolone 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 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. Other Names: MEDROL,NDC0009-0056-02
Experimental: 48 Weeks Methylprednisolone 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 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. Other Names: MEDROL,NDC0009-0056-02

Arm

Intervention/Treatment

Experimental: 36 Weeks Methylprednisolone

Drug: 36 Weeks Methylprednisolone

Other Names:

MEDROL,NDC0009-0056-02

Experimental: 48 Weeks Methylprednisolone

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

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.

Other Names:

MEDROL,NDC0009-0056-02

Outcome Measures

Primary Outcome Measures

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. [From week 1 to week 60 or 72]
To analyze the clinical efficacy of glucocorticosteroid treatment

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.