WEUKBRE5555: IMI PROTECT(Work Package 2): Liver Injury & Antibiotics

NCT01587768 | Completed

• 2 other identifiers: 115738WEUKBRE5559
• Study Type: observational
• Target: 1
• Locations: 0 countries
• Sites: N/A

Brief Summary

The studies described in this protocol are all performed within the framework of PROTECT (Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium) Workpackage 2 (WP2) and Workgroup 1. The primary aim of these studies is to develop, test and disseminate methodological standards for the design, conduct and analysis of Pharmacoepidemiological (PE) studies applicable to different safety issues and using different data sources. To achieve this, results from PE studies on 5 key adverse events (AEs) performed in different databases will be evaluated. Therefore, emphasis will be on the methodological aspects of the studies in this protocol and not on the clinical consequences of the association under investigation. The standards to develop will contribute to decreasing the discrepancies in results from different studies in the future and increase the usefulness and reliability of these studies for benefit-risk assessment in the EU. We propose to assess the association between antibiotics use and idiopathic acute liver injury with different study designs (descriptive, cohort, nested case-control and case crossover) across different primary care databases and to compare the results between databases, across designs to evaluate the impact of design/database/population differences on the outcome of the studied association. Specific aims (in each database):

1. 1.To describe characteristics, clinical features, and risk factors for acute liver injury in patients exposed and unexposed to antibiotics.
2. 2.To estimate the overall risk of acute liver injury associated with antibiotics exposure (users and non-users) in each database
3. 3.To estimate the risk of acute liver injury associated with various antibiotics classes
4. 4.To estimate the risk of acute liver injury associated with specific individual antibiotics
5. 5.To assess the effect of dose and duration of use for specific individual antibiotics.
6. 6.To compare the results of a case-control study with the results of a retrospective cohort study and self-controlled case series study in the different databases

Conditions

Infections, Bacterial

Keywords

Acute liver injury; antibiotics

Outcome Measures

Primary Outcomes (1)

• Idiopathic acute liver injury

  Idiopathic acute liver injury, defined at least with one of the following conditions (A+B or A+C): A - A diagnosis of liver injury (codes listed in tables 1a, 1b, 1c) with a referral to a specialist or hospital. Together with B - An increase of more than two times the upper limit of the normal range in alanine aminotransferase (ALT) or C - A combined increase in aspartate aminotransferase (AST), alkaline phosphatase (AP) and total bilirubin provided one of them is twice the upper limit of the respective normal range.

  Up to six years following drug exposure

Study Arms (3)

Patients with a definite case of acute liver injury

The information recorded in the patients' medical record met all the criteria to be classified as idiopathic acute liver injury and the patient presents with at least with one of the following conditions (A+B or A+C): A - A diagnosis of liver injury (codes listed in tables 1a, 1b, 1c) with a referral to a specialist or hospital. Together with B - An increase of more than two times the upper limit of the normal range in alanine aminotransferase (ALT) or C - A combined increase in aspartate aminotransferase (AST), alkaline phosphatase (AP) and total bilirubin provided one of them is twice the upper limit of the respective normal range.

Drug: Antibiotic prescription during the study period between January 1, 2004 and December 31, 2009

Patients with a probable case of acute liver injury

The information recorded in the patients' medical file was compatible with idiopathic acute liver injury, but not fulfilling all conditions and criteria to be defined as definite case. For example, patients identified with a READ or ICPC code for acute liver injury with a hospitalization or visit to a specialist but without complete laboratory criteria or patients identified with a READ or ICPC code for acute liver injury without a referral to a hospital/specialist, and with or without complete laboratory data.

Drug: Antibiotic prescription during the study period between January 1, 2004 and December 31, 2009

Non-cases

Any potential or probable case that was excluded in one of the previous steps and those with insufficient data to determine their case status. Patients presenting normal liver function tests (LFTs), alcohol related problems, gallbladder disease, pancreatic disease, or other liver diseases with clear aetiology such as viral, alcoholic or autoimmune, or presence of other well defined pathology known to cause acute liver injury will be considered non-cases.

Drug: Antibiotic prescription during the study period between January 1, 2004 and December 31, 2009

Interventions

Antibiotic prescription during the study period between January 1, 2004 and December 31, 2009 DRUG

Antibiotics will be analysed overall, by class (tetracyclines, penicillins and betalactamics, cephalosporins, macrolides, aminoglycosides, quinolones and other antibiotics (sulphonamides \& others combinations)) and individually. The antibiotics administered to patients include: cefuroxime axetil, cefuroxime sodium, ceftazidime sodium, amoxicillin, amoxicillin/ clavulanate, ampicillin, ampicillin/cloxacillin, flucloxacillin, ticarcillin, and ticarcillin/ clavulanate.

Non-cases; Patients with a definite case of acute liver injury; Patients with a probable case of acute liver injury

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

The primary source population will be comprised of patients of all ages with an active or died registration status during the study period of January 1, 2004 to December 31, 2009. Patients must have attained one year of enrolment with the general practioner (GP) and one year of computerized prescription history. From the aforementioned source population, two study cohorts will be selected. The first cohort will include all patients who received at least one antibiotic prescription during the study period. For this cohort, the date of first prescription of an antibiotic after meeting the eligibility criteria (entry date) defines the start of follow-up (start date), for the exposed cohort. The second cohort will be selected from the same source population among patients who have not received an antibiotic prescription during the study period and in the year before the entry date (date when the patient meet the eligibility criteria and enter in the study).

You may qualify if:

• Individuals with an active or died registration status d during the study period of January 1, 2004 to December 31, 2009
• Individuals enrolled at least one year with the with the GP and having one year of computerized prescription history

You may not qualify if:

• Individuals with Read codes for idiopathic acute liver injury/disease, ICD-10 codes for Acute Liver injury, or CIAP codes for Idiopathic Acute Liver injury prior to start date
• Individuals with one of the following diagnoses prior to the start date: cancer, alcoholism, alcohol related problems, gallbladder disease, pancreatic disease, and other chronic liver diseases.

Sponsors & Collaborators

• GlaxoSmithKline: lead

MeSH Terms

Conditions

Bacterial Infections

Condition Hierarchy (Ancestors)

Bacterial Infections and Mycoses; Infections

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: observational
• Time Perspective: RETROSPECTIVE
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 23, 2012
• First Posted: April 30, 2012
• Study Start: November 1, 2011
• Primary Completion: July 1, 2014
• Study Completion: July 1, 2014
• Last Updated: December 10, 2014

Record last verified: 2014-12