Risk of Acute Liver Injury in Users of Antimicrobials

Completed

• Conditions: Drug-Induced Liver Injury
• Interventions: Drug: Moxifloxacin (Avelox, BAY12-8039); Drug: Amoxicillin, Amoxicillin plus clavulanic acid, Cefuroxime, Clarithromycin, Doxycycline, Levofloxacin, Telithromycin

• Registration Number: NCT01434173
• Lead Sponsor: Bayer

Brief Summary

Moxifloxacin is a broad-spectrum antibacterial agent used to treat common community-acquired respiratory tract infections, complicated intra-abdominal infections, and pelvic inflammatory disease. In the clinical development program, moxifloxacin was associated with some hepatic adverse drug reactions. To evaluate further the hepatic safety profile of moxifloxacin, a retrospective cohort study with nested case-control analysis will be conducted to assess the rate of noninfectious acute liver injury among new users of moxifloxacin and of other antimicrobials prescribed for similar indications, including amoxicillin, amoxicillin plus clavulanic acid, cefuroxime, clarithromycin, doxycycline, levofloxacin, and telithromycin.

The study will be implemented in the population included in the HealthCore Integrated Research Database (HIRD). Eligible patients are adults aged 18 years and older with continuous enrollment in the HIRD for at least 6 months before their first claim for a prescription for a study antimicrobial. Follow-up will start at the date of the first prescription until the date of the earliest of the following events: noninfectious acute liver injury, occurrence of an exclusion criterion, end of study period, disenrollment from database, or death. Patients with chronic alcoholism or cirrhosis, infectious hepatitis, HIV/AIDS, or pregnant women will not be included.

Detailed Description

Study design is called 'Cohort study with nested case-control analysis"

Study Timeline

• Study Start: 2001-07
• Primary Completion: 2009-03
• Study Completion: 2009-03
• Study First Submitted: 2011-07-08
• Study First Submitted QC: 2011-09-13
• Study First Posted: 2011-09-14
• Status Verified: 2014-07
• Last Update Submitted: 2014-07-07
• Last Update Posted: 2014-07-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 1299056

Inclusion Criteria

• All persons meeting the following criteria during the study period (July 1, 2001, through March 31, 2009) are eligible for study inclusion:
• First insurance claim for a dispensing of one of the study antimicrobials during the study period ("new users")
• Aged 18 years old or older
• Continuous enrollment in the study database for at least 6 months prior to start of follow-up (which is the date of the first claim for any of the study antimicrobials)
• Patient data defined as acceptable for research purposes according to the quality criteria of the HIRD

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Exclusion Criteria

• Pregnant women
• Patients with chronic alcoholism or cirrhosis
• Patients with history of acute and/or chronic infectious hepatitis or HIV/AIDS

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Group 1	Moxifloxacin (Avelox, BAY12-8039)	-
Group 2	Amoxicillin, Amoxicillin plus clavulanic acid, Cefuroxime, Clarithromycin, Doxycycline, Levofloxacin, Telithromycin	-

Primary Outcome Measures

Name	Time	Method
Incidence ratio of noninfectious acute liver injury fulfilling the International Consensus Meeting criteria for drug-induced liver disorders in the study population during periods of treatment with each of the study antimicrobials and nonuse	From the first day of full exposure of a study antimicrobial (day after the date of dispensing) to the end of follow-up (up to 8 years)
Incidence rate ratio of noninfectious acute liver injury fulfilling the International Consensus Meeting criteria for drug-induced liver disorders during treatment with each of the study antimicrobials compared to that during of nonuse	From the first day of full exposure of a study antimicrobial (day after the date of dispensing) to the end of follow-up (up to 8 years)

Secondary Outcome Measures

Name	Time	Method
Incidence rate and incidence rate ratio of noninfectious severe hepatocellular injury as defined by the Hy's Law criteria modified by the FDA Working Group (FDA Working group, 2000; Temple, 2006; Navarro and Senior, 2006)	From the first day of full exposure of a study antimicrobial (day after the date of dispensing) to the end of follow-up (up to 8 years)
Incidence rate and incidence rate ratio of noninfectious acute liver failure, defined as acute liver injury with evidence of coagulation abnormality and any degree of mental alteration (encephalopathy) (Polson and Lee, 2005)	From the first day of full exposure of a study antimicrobial (day after the date of dispensing) to the end of follow-up (up to 8 years)
Cumulative incidence of noninfections acute liver injury, noninfectious severe hepatocellular injury, and noninfectious acute liver failure at weekly intervals after the start of first episode of treatment with each of the study antimicrobials	From the first day of full exposure of a study antimicrobial (day after the date of dispensing) to the end of follow-up (up to 8 years)