Rechallenge, Potential Drug Induced Liver Injury (Kaiser)
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Rechallenge positive, negative, indeterminate and intermediate rechallenge subtypes |
Drug: Prescription drugs with known hepatotoxicity
14 prescription drugs with known hepatotoxicity : Amoxicillin/clavulanate, nitrofurantoin, isoniazid, trimethoprim-sulfamethoxazole, duloxetine, valproate, interferon-beta, ciprofloxacin, lamotrigine, phenytoin, diclofenac, terbinafine, levofloxacin, aripiprazole
|
| Severe positive rechallenge 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 |
Drug: Prescription drugs with known hepatotoxicity
14 prescription drugs with known hepatotoxicity : Amoxicillin/clavulanate, nitrofurantoin, isoniazid, trimethoprim-sulfamethoxazole, duloxetine, valproate, interferon-beta, ciprofloxacin, lamotrigine, phenytoin, diclofenac, terbinafine, levofloxacin, aripiprazole
|
Outcome Measures
Primary Outcome Measures
- 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
- 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.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Patients who received at least one prescription for a suspect drug between Jan 1, 2003 and June 30, 2009 (drug initiation period)
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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:
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Resolved to within normal limits of ALT (for hepatocellular & mixed) or AP (for cholestatic) within 180 days or
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Resolved to ALT < 3xULN (for hepatocellular & mixed) within 90 days or AP<2xULN (for cholestatic) within 180 days or
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Dropped by ≥50% of (Peak ALT - ULN) for hepatocellular or of (Peak AP - ULN) for cholestatic or mixed within 180 days
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Patients who were rechallenged with the same suspect drug; rechallenge will include first rechallenge event for the analysis.
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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.
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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.
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Patients who had health insurance coverage with full medical, pharmacy and lab benefits at the index date.
Exclusion Criteria:
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Patients meeting the definition of chronic liver injury and exhibiting persistent ALT≥3xULN or AP or bilirubin ≥2xULN within 90 days after initial injury
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Patients with chronic liver injury diagnostic codes or included in KPSC disease registries preceding the initial or rechallenge liver injury
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- GlaxoSmithKline
Investigators
- Study Director: GSK Clinical Trials, GlaxoSmithKline
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 115983
- WEUKBRE5538