WP6 Replication Study: The risk of acute liver injury associated with the use of antibiotics: Population based case control study

Study type

• Study type:
  Non-interventional study
• Scope of the study:
  Assessment of risk minimisation measure implementation or effectiveness

  Other
• If ‘other’, further details on the scope of the study:
  Replication of previous anlysis in the same database, followed by sensitivity analyses

Non-interventional study

• Non-interventional study design:
  Case-control

Study drug and medical condition

• Anatomical Therapeutic Chemical (ATC) code:
  (J01) ANTIBACTERIALS FOR SYSTEMIC USE

  ANTIBACTERIALS FOR SYSTEMIC USE
• Medical condition to be studied:
  Liver injury

Population studied

• Age groups:
  Children (2 to < 12 years)

  Adolescents (12 to < 18 years)

  Adults (18 to < 46 years)

  Adults (46 to < 65 years)

  Adults (65 to < 75 years)

  Adults (75 to < 85 years)

  Adults (85 years and over)
• Estimated number of subjects:
  12000

Study design details

• Main study objective:
  The main objective is to replicate a previous analysis of data in the same database, blinded to the results, under the same work programme (http://www.imi-protect.eu/) . This will be followed by an examination of the robustness of the strength of the association, altering a variety of parameters. Validation of Acute Liver Injury may be sought through a GP questionnaire.
• Outcomes:
  To estimate the relative risk of acute liver injury associated with antibiotics exposure (users vs. non-users).To estimate the relative risk of acute liver injury comparing various antibiotics classes.To estimate the relative risk of acute liver injury comparing specific individual antibiotics. A questionnaire to GP may seek validation of the computerised diagnosis. To assess the effect of dose and duration of use for specific individual antibiotics.Various definitions of exposure time, recovery time, and criteria for inclusion of confounders/ effect modifiers will be will be altered to examine the robustness of the association.
• Data analysis plan:
  The population based case control study will be analysed by conditional logistic regression. Matching will be on age at birth, gender and Practice. Odds ratios and 95% confidence intervals will be computed to examine the association between first occurrence of idiopathic acute liver injury and exposure to antibiotics (as a group, in different classes (tetracycline, penicillins & betalactamic, cephalosporin, macrolides, aminoglycosides, quinolones and other antibiotics and combinations), and individual drugs where possible).A series of bivariate models will be examined to evaluate the contribution of confounder / effect modification variables. Stepwise inclusion methods will be used to improve model fit evaluated by the Likelihood Ratio test. A full model with all such variables will be constructed.These procedures will be repeated in sensitivity analyses, changing exposure window length, definitions for case inclusion, and extending the length of liver injury recovery time.