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Cholestatic Drug-induced Liver Injury (DILI)

Primary Purpose

Hepatitis, Toxic

Status
Unknown status
Phase
Phase 4
Locations
Taiwan
Study Type
Interventional
Intervention
Ursodeoxycholic Acid
Placebo
Sponsored by
Taipei Veterans General Hospital, Taiwan
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hepatitis, Toxic focused on measuring drug-induced liver injury, hepatitis, toxic, ursodeoxycholic acid

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Drug-induced liver injury, meet the DILIN criteria.

Exclusion Criteria:

  • Other systemic diseases may cause elevation of liver enzymes: viral hepatitis, alcoholic liver disease, autoimmune hepatitis, primary biliary cirrhosis, Wilson's disease, hemochromatosis, congestive heart failure, hypoxia, sepsis.

Sites / Locations

  • Taipei Veterans General HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

UDCA treatment

Placebo

Arm Description

Patients with drug-induced liver injury will be randomly allocated to UDCA treatment group: oral intake ursodeoxycholic acid (UDCA) 13-15 mg/kg BW/day into 3 divided doses after meal till the endpoint or the 8th week. UDCA is 100 mg per tab.

Patients with drug-induced liver injury will be randomly allocated to placebo group. The placebo is of the same color, size and shape as UDCA, and assumed 100 mg per tab. Patients in this group will orally intake 13-15 mg/Kg BW/day of placebo into 3 divided doses after meal as UDCA treatment group, till the endpoint or the 8th week.

Outcomes

Primary Outcome Measures

severe degree drug-induced liver injury, fatality or liver transplantation

Secondary Outcome Measures

Full Information

First Posted
January 12, 2010
Last Updated
June 8, 2010
Sponsor
Taipei Veterans General Hospital, Taiwan
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1. Study Identification

Unique Protocol Identification Number
NCT01141322
Brief Title
Cholestatic Drug-induced Liver Injury
Acronym
DILI
Official Title
Cholestatic Drug-induced Liver Injury: Correlation With Genotypes of UGT1A1 and 1A7, and Treatment Effect of Ursodeoxycholic Acid
Study Type
Interventional

2. Study Status

Record Verification Date
June 2010
Overall Recruitment Status
Unknown status
Study Start Date
August 2007 (undefined)
Primary Completion Date
April 2010 (Anticipated)
Study Completion Date
July 2010 (Anticipated)

3. Sponsor/Collaborators

Name of the Sponsor
Taipei Veterans General Hospital, Taiwan

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Cholestatic drug-induced liver injury (DILI) is the severe form of DILI with a grave outcome. Drug-metabolizing enzymes play an important role in the metabolism of drugs. The genetic polymorphism of drug-metabolizing enzymes may influence the activities and expression of these enzymes and thereby affect the susceptibility and severity of DILI. UDP-glucuronosyltransferase (UGT) is an important phase 2 detoxification enzyme, which is related to congenital hyperbilirubinemia. Recently, the genetic polymorphism of UGT1A1 was reported to be associated with jaundice induced by some drugs, and UGT1A7 was shown to be related to the susceptibility of hepatocellular carcinoma and other cancers. Ursodeoxycholic acid (UDCA ) is a hydrophilic bile acid that is increasingly used for the treatment of various cholestatic disorders. The aims of this study are (1) to assess the association of the genetic polymorphism of UGT1A1 and 1A7, and the susceptibility and severity of drug-induced liver injury (DILI), with emphasis on the cholestatic DILI; (2) to evaluate the treatment effect of UDCA in the DILI, with special reference to the cholestatic hepatotoxicity.
Detailed Description
Cholestatic drug-induced liver injury (DILI) is the severe form of DILI with a grave outcome. Drug-metabolizing enzymes play an important role in the metabolism of drugs. The genetic polymorphism of drug-metabolizing enzymes may influence the activities and expression of these enzymes and thereby affect the susceptibility and severity of DILI. UDP-glucuronosyltransferase (UGT) is an important phase 2 detoxification enzyme, which is related to congenital hyperbilirubinemia. Recently, the genetic polymorphism of UGT1A1 was reported to be associated with jaundice induced by some drugs, and UGT1A7 was shown to be related to the susceptibility of hepatocellular carcinoma and other cancers. Ursodeoxycholic acid (UDCA ) is a hydrophilic bile acid that is increasingly used for the treatment of various cholestatic disorders. The aims of this study are (1) to assess the association of the genetic polymorphism of UGT1A1 and 1A7, and the susceptibility and severity of drug-induced liver injury (DILI), with emphasis on the cholestatic DILI; (2) to evaluate the treatment effect of UDCA in the DILI, with special reference to the cholestatic hepatotoxicity. Owing to the limited number of DILI patients, 3 years are needed in this study. Each year, a total of 60 patients with DILI and 60 age- and sex-matched controls will be enrolled in this study. Their genetic polymorphisms of UGT1A1 and UGT1A7 will be assessed using the real time PCR, or PCR with RFLP. The DILI patients will be randomized to UDCA Treatment group and Control group. UDCA 13-15 mg/kg/day with 3 divided doses will be administered to the patients with Treatment group. The frequencies of genotypes of UGT1A1 and 1A7 will be compared between DILI cases and controls, survival cases and non-survival cases, and cholestatic and non-cholestatic cases. Chi-square test, with or without Yates' correction, will be used to compare the categorical parameters. A paired t test will be performed to compare the continuous parameters. Odds ratios (OR) and confidence intervals (CI) will be calculated using a logistic regression analysis. The multivariate logistic regression analysis will be applied to check on the OR, adjusted with other possible risk factors. Survival rates will be estimated from survival curves based on the Kaplan-Meier method and compared with the log-rank test between the UDCA Treatment group and Control group. We believe that this pharmacogenetic study may help us realize the pathogenesis of cholestatic DILI, and the clinical trial can elucidate the therapeutic value of UDCA in the DILI, especially in the cholestatic hepatotoxicity.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatitis, Toxic
Keywords
drug-induced liver injury, hepatitis, toxic, ursodeoxycholic acid

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
Participant
Allocation
Randomized
Enrollment
180 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
UDCA treatment
Arm Type
Experimental
Arm Description
Patients with drug-induced liver injury will be randomly allocated to UDCA treatment group: oral intake ursodeoxycholic acid (UDCA) 13-15 mg/kg BW/day into 3 divided doses after meal till the endpoint or the 8th week. UDCA is 100 mg per tab.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Patients with drug-induced liver injury will be randomly allocated to placebo group. The placebo is of the same color, size and shape as UDCA, and assumed 100 mg per tab. Patients in this group will orally intake 13-15 mg/Kg BW/day of placebo into 3 divided doses after meal as UDCA treatment group, till the endpoint or the 8th week.
Intervention Type
Drug
Intervention Name(s)
Ursodeoxycholic Acid
Other Intervention Name(s)
ursodil, UDCA, urso
Intervention Description
ursodeoxycholic acid 13-15 mg/kg BW/day into 3 divided doses after meal till endpoint or the 8th week.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
The placebo is of the same color, size and shape as UDCA, and assumed 100 mg per tab. Patients in this group will orally intake 13-15 mg/Kg BW/day of placebo into 3 divided doses after meal as UDCA treatment group, till the endpoint or the 8th week.
Primary Outcome Measure Information:
Title
severe degree drug-induced liver injury, fatality or liver transplantation
Time Frame
8 weeks

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Drug-induced liver injury, meet the DILIN criteria. Exclusion Criteria: Other systemic diseases may cause elevation of liver enzymes: viral hepatitis, alcoholic liver disease, autoimmune hepatitis, primary biliary cirrhosis, Wilson's disease, hemochromatosis, congestive heart failure, hypoxia, sepsis.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Yi-Shin Huang, M.D.
Phone
+886-2-2871-2121
Ext
2015
Email
yshuang@vghtpe.gov.tw
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Yi-Shin Huang, M.D.
Organizational Affiliation
Taipei Veterans General Hospital, Taipei, Taiwan
Official's Role
Principal Investigator
Facility Information:
Facility Name
Taipei Veterans General Hospital
City
Taipei
ZIP/Postal Code
11217
Country
Taiwan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Yi-Shin Huang, M.D.
Phone
+886-2-2871-2121
Ext
2015
Email
yshuang@vghtpe.gov.tw
First Name & Middle Initial & Last Name & Degree
Yi-Shin Huang, M.D.

12. IPD Sharing Statement

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Cholestatic Drug-induced Liver Injury

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