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

Primary Purpose

Drug-induced Liver Injury,Chronic

Status
Completed
Phase
Phase 1
Locations
China
Study Type
Interventional
Intervention
Methylprednisolone
Standard Treatment
Sponsored by
Beijing 302 Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Drug-induced Liver Injury,Chronic focused on measuring Drug-induced Liver Injury, Recurrence, Methylprednisolone

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

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;

Sites / Locations

  • Beijing 302 hospital,China

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Methylprednisolone

Standard Treatment

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.
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.

Secondary Outcome Measures

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.
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.
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.

Full Information

First Posted
December 25, 2015
Last Updated
August 7, 2020
Sponsor
Beijing 302 Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT02651350
Brief Title
Efficacy and Safety of Glucocorticosteroid Treatment in the Patients With Chronic Recurrent DILI
Official Title
A Randomized Controlled Clinical Trial on the Efficacy and Safety of Glucocorticosteroid in the Patients With Chronic Recurrent Drug-induced Liver Injury
Study Type
Interventional

2. Study Status

Record Verification Date
July 2019
Overall Recruitment Status
Completed
Study Start Date
December 2015 (undefined)
Primary Completion Date
July 2019 (Actual)
Study Completion Date
July 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Beijing 302 Hospital

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Drug-induced Liver Injury,Chronic
Keywords
Drug-induced Liver Injury, Recurrence, Methylprednisolone

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
80 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Methylprednisolone
Arm Type
Experimental
Arm Description
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.
Arm Title
Standard Treatment
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Methylprednisolone
Other Intervention Name(s)
MEDROL,NDC0009-0056-02
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Standard Treatment
Other Intervention Name(s)
Routine liver protection drugs
Intervention Description
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.
Primary Outcome Measure Information:
Title
The relapse or recurrent rate of illness, namely, appearance of obviously abnormal liver function again during treatment and follow-up period
Description
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.
Time Frame
At week 24
Title
The relapse or recurrent rate of illness, namely, appearance of obviously abnormal liver function again during treatment and follow-up period
Description
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.
Time Frame
At week 72
Secondary Outcome Measure Information:
Title
Days of normalization of liver functions including serum levels of ALT, AST, TBIL,GGT and ALP.
Description
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.
Time Frame
From week 1 to week 12
Title
The liver histological changes between two liver biopsies
Description
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.
Time Frame
At week 0 and at week 48 week
Title
The number of participants with methylprednisolone treatment-related adverse events, such as severe osteopenia, uncontrolled hypertension
Description
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.
Time Frame
At week 24 and at week 72

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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;
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Zhengsheng Zou, Dr.
Organizational Affiliation
Beijing 302 Hospital,China.
Official's Role
Principal Investigator
Facility Information:
Facility Name
Beijing 302 hospital,China
City
Beijing
State/Province
Beijing
ZIP/Postal Code
100039
Country
China

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
24935270
Citation
Chalasani NP, Hayashi PH, Bonkovsky HL, Navarro VJ, Lee WM, Fontana RJ; Practice Parameters Committee of the American College of Gastroenterology. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2014 Jul;109(7):950-66; quiz 967. doi: 10.1038/ajg.2014.131. Epub 2014 Jun 17.
Results Reference
background
PubMed Identifier
26671593
Citation
Moreno L, Sanchez-Delgado J, Vergara M, Casas M, Miquel M, Dalmau B. Recurrent drug-induced liver injury (DILI) with ciprofloxacin and amoxicillin/clavulanic. Rev Esp Enferm Dig. 2015 Dec;107(12):767-8. doi: 10.17235/reed.2015.3810/2015.
Results Reference
background
PubMed Identifier
24507072
Citation
Tencate V, Komorowski R, Cronin D, Hong J, Gawrieh S. A case study: refractory recurrent autoimmune hepatitis following liver transplantation in two male patients. Transplant Proc. 2014 Jan-Feb;46(1):298-300. doi: 10.1016/j.transproceed.2013.09.028.
Results Reference
background
PubMed Identifier
21338638
Citation
Lucena MI, Kaplowitz N, Hallal H, Castiella A, Garcia-Bengoechea M, Otazua P, Berenguer M, Fernandez MC, Planas R, Andrade RJ. Recurrent drug-induced liver injury (DILI) with different drugs in the Spanish Registry: the dilemma of the relationship to autoimmune hepatitis. J Hepatol. 2011 Oct;55(4):820-7. doi: 10.1016/j.jhep.2010.12.041. Epub 2011 Feb 19.
Results Reference
background
PubMed Identifier
21674554
Citation
Suzuki A, Brunt EM, Kleiner DE, Miquel R, Smyrk TC, Andrade RJ, Lucena MI, Castiella A, Lindor K, Bjornsson E. The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug-induced liver injury. Hepatology. 2011 Sep 2;54(3):931-9. doi: 10.1002/hep.24481. Epub 2011 Aug 8.
Results Reference
background
PubMed Identifier
21396413
Citation
Weiler-Normann C, Schramm C. Drug induced liver injury and its relationship to autoimmune hepatitis. J Hepatol. 2011 Oct;55(4):747-9. doi: 10.1016/j.jhep.2011.02.024. Epub 2011 Mar 9. No abstract available.
Results Reference
background
PubMed Identifier
26104271
Citation
Bessone F, Lucena MI, Roma MG, Stephens C, Medina-Caliz I, Frider B, Tsariktsian G, Hernandez N, Bruguera M, Gualano G, Fassio E, Montero J, Reggiardo MV, Ferretti S, Colombato L, Tanno F, Ferrer J, Zeno L, Tanno H, Andrade RJ. Cyproterone acetate induces a wide spectrum of acute liver damage including corticosteroid-responsive hepatitis: report of 22 cases. Liver Int. 2016 Feb;36(2):302-10. doi: 10.1111/liv.12899. Epub 2015 Jul 16.
Results Reference
background
PubMed Identifier
21725992
Citation
Sugimoto K, Ito T, Yamamoto N, Shiraki K. Seven cases of autoimmune hepatitis that developed after drug-induced liver injury. Hepatology. 2011 Nov;54(5):1892-3. doi: 10.1002/hep.24513. Epub 2011 Aug 9. No abstract available.
Results Reference
background
PubMed Identifier
22038865
Citation
Fujiwara K, Yokosuka O. Histological discrimination between autoimmune hepatitis and drug-induced liver injury. Hepatology. 2012 Feb;55(2):657. doi: 10.1002/hep.24768. No abstract available.
Results Reference
background
PubMed Identifier
20513004
Citation
Manns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli-Vergani G, Vergani D, Vierling JM; American Association for the Study of Liver Diseases. Diagnosis and management of autoimmune hepatitis. Hepatology. 2010 Jun;51(6):2193-213. doi: 10.1002/hep.23584. No abstract available.
Results Reference
background
PubMed Identifier
24681128
Citation
Fontana RJ, Hayashi PH, Gu J, Reddy KR, Barnhart H, Watkins PB, Serrano J, Lee WM, Chalasani N, Stolz A, Davern T, Talwakar JA; DILIN Network. Idiosyncratic drug-induced liver injury is associated with substantial morbidity and mortality within 6 months from onset. Gastroenterology. 2014 Jul;147(1):96-108.e4. doi: 10.1053/j.gastro.2014.03.045. Epub 2014 Mar 27.
Results Reference
background
PubMed Identifier
35362188
Citation
Wang JB, Huang A, Wang Y, Ji D, Liang QS, Zhao J, Zhou G, Liu S, Niu M, Sun Y, Tian H, Teng GJ, Chang BX, Bi JF, Peng XX, Xin S, Xie H, Ma X, Mao YM, Liangpunsakul S, Saxena R, Aithal GP, Xiao XH, Zhao J, Zou Z. Corticosteroid plus glycyrrhizin therapy for chronic drug- or herb-induced liver injury achieves biochemical and histological improvements: a randomised open-label trial. Aliment Pharmacol Ther. 2022 May;55(10):1297-1310. doi: 10.1111/apt.16902. Epub 2022 Mar 31.
Results Reference
derived

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

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