Rechallenge, Potential Drug Induced Liver Injury (Kaiser)

Completed

• Conditions: Drug-induced Liver Injury
• Interventions: Drug: Prescription drugs with known hepatotoxicity

• Registration Number: NCT01584765
• Lead Sponsor: GlaxoSmithKline

Brief Summary

Drug re-administration or rechallenge should be avoided after drug-induced liver injury (DILI) to avoid recurrent and fatal injury. Rechallenge outcomes vary considerably by drug and patient subjects. In order to better predict these outcomes, the objective of this analysis is to assess clinical outcomes of positive drug rechallenge following possible drug-induced liver injury. Electronic medical records from Kaiser Permanente California (KPSC), a managed care organization, will be utilized to identify patients who experience possible drug-induced liver injury following exposure to medications associated with hepatotoxicity, and who are then rechallenged with the medication.

Detailed Description

Not available

Study Timeline

• Study Start: 2012-02
• Study First Submitted: 2012-04-12
• Study First Submitted QC: 2012-04-23
• Study First Posted: 2012-04-25
• Primary Completion: 2013-04
• Study Completion: 2013-04
• Status Verified: 2014-07
• Last Update Submitted: 2014-07-03
• Last Update Posted: 2014-07-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 1

Inclusion Criteria

• Patients who received at least one prescription for a suspect drug between Jan 1, 2003 and June 30, 2009 (drug initiation period)

• Patients who experienced incident DILI event (identified by ALT ≥3xULN or AP ≥2xULN within 6 months of suspect drug administration) during the first exposure period that:

  1. Resolved to within normal limits of ALT (for hepatocellular & mixed) or AP (for cholestatic) within 180 days or
  2. Resolved to ALT < 3xULN (for hepatocellular & mixed) within 90 days or AP<2xULN (for cholestatic) within 180 days or
  3. Dropped by ≥50% of (Peak ALT - ULN) for hepatocellular or of (Peak AP - ULN) for cholestatic or mixed within 180 days

• Patients who were rechallenged with the same suspect drug; rechallenge will include first rechallenge event for the analysis.

• Patients who had at least of 12 months of continuous membership and drug benefit prior to and on the dispensing index date (inclusive). There is no minimum restriction of continuous membership plus drug benefit after the start date.

• Patients who were 18 years of age or older at the time of the first drug dispensing (index date) during the drug initiation period Jan 1, 2003 and June 30, 2009. Each patient's first prescription for the study drugs during the drug initiation period will be identified as index prescription.

• Patients who had health insurance coverage with full medical, pharmacy and lab benefits at the index date.

Exclusion Criteria

• Patients meeting the definition of chronic liver injury and exhibiting persistent ALT≥3xULN or AP or bilirubin ≥2xULN within 90 days after initial injury
• Patients with chronic liver injury diagnostic codes or included in KPSC disease registries preceding the initial or rechallenge liver injury

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Rechallenge	Prescription drugs with known hepatotoxicity	positive, negative, indeterminate and intermediate rechallenge subtypes
Severe positive rechallenge	Prescription drugs with known hepatotoxicity	Subtype of positive rechallenge is defined as: ALT≥5 xULN or AP ≥2 xULN and bilirubin ≥2 xULN with one of the following: INR ≥1.5, Ascites, or Encephalopathy where time from liver chemistry elevation to INR≥1.5,ascites, or encephalopathy is less than 26 weeks in the absence of underlying cirrhosis; other organ failure considered due to DILI; liver-related hospitalization

Primary Outcome Measures

Name	Time	Method
Liver injury rechallenge	Up to seven and a half years	Liver injury in relation to rechallenge types (positive, negative, indeterminate and intermediate) for hepatocellular, cholestatic and mixed DILI, respectively, defined according to Danan \& Benichou, 1993, J Clin Epidemiol, 46(11): p. 1323-30.

Secondary Outcome Measures

Name	Time	Method
Severe positive rechallenge	Up to seven and a half years	Severe positive rechallenge, defined as: ALT≥5 xULN or AP≥2 xULN and bilirubin≥2 xULN with one of the following: INR≥1.5, Ascites, or Encephalopathy where time from liver chemistry elevation to INR≥1.5,ascites, or encephalopathy\<26 weeks in the absence of underlying cirrhosis; other organ failure considered due to DILI; or liver-related hospitalization. In subjects not meeting the definition of chronic liver injury and exhibiting persistent ALT≥3xULN or AP or bilirubin ≥2xULN after initial injury, positive drug rechallenge is defined as a doubling of ALT, alkaline phosphatase or bilirubin.