Clinical Trials Logo

Clinical Trial 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. To describe characteristics, clinical features, and risk factors for acute liver injury in patients exposed and unexposed to antibiotics.

2. To estimate the overall risk of acute liver injury associated with antibiotics exposure (users and non-users) in each database

3. To estimate the risk of acute liver injury associated with various antibiotics classes

4. To estimate the risk of acute liver injury associated with specific individual antibiotics

5. To assess the effect of dose and duration of use for specific individual antibiotics.

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

The proposed studies will be collected in populations from the following databases: The General Practice Research Database [GPRD] (UK), Health Improvement Network [THIN] (UK), BIFAP [Base de datos Informatizada para estudios Farmacoepidemiologicos en Atencion Primaria] (Spain)- the Bavarian Claims Database (Germany), Mondriaan (Netherlands), and the National Databases of Denmark.


Clinical Trial Description

Acute liver injury is one of the most important safety concerns, being the leading cause for drug withdrawal from the market on safety grounds. For most suspected hepatotoxic drugs the only existing information comes from spontaneous reports, lacking appropriate risk quantification through formal epidemiological studies. A few population-based studies examining the risk of acute and clinically relevant liver injury among users of various drugs have been published, reporting an elevated risk of liver injury in users of antibiotics. As acute liver injury is often idiosyncratic and because its diagnostic criteria used in epidemiological studies have been variable, the reported range of incidences of acute liver injury caused by antibiotics is broad. In the United Kingdom (UK), case-control studies investigating the effect of antibiotics on acute liver injury have generated odds ratios ranging from 94.8 for the combination of amoxicillin/clavulanic acid to 6.2 for tetracyclines. Age, sex, alcohol intake, concomitant medication and comorbidities have been proposed as risk factors for antibiotic induced liver injury and may have influenced the quantification of risk estimates. In the present protocol, we propose to further quantify the risk of acute liver injury associated with antibiotics in the general population using different study designs and in different primary care databases, and to compare the results to evaluate the impact of design and population differences on the outcome of the study association.

Acute liver injury or hepatotoxicity in this study implies chemical, drug driven liver damage which can be classified based on clinical presentation and laboratory features ranging from asymptomatic mild biochemical abnormalities to acute liver failure. The most common classification used for drug induced liver injury (DILI) is according to laboratory abnormalities (hepatocellular, cholestatic or mixed) and according to mechanism of toxicity (direct, immune-mediated, idiosyncratic, or mitochondrial toxicity). Being idiosyncratic in most cases, reactions often cannot be reproduced experimentally in laboratory animals. The relationship between the dose and the occurrence or severity of the reaction is not constant, and the latent period between drug exposure and sensitivity reaction is rather variable. The infrequency of DILI, though with significant impact, and complicated case ascertainment in pharmacoepidemiological studies has led to wide ranges of reported incidence rates. A recent study, using data from the GPRD database, reported crude incidence rates of liver injury caused by any type of drug ranging from 1 to 18 per 100,000 prescriptions. The Drug-Induced Liver Injury Network (DILIN), a US based collaboration between academic and health institutions to study the aetiology and prevention of DILI, found antibiotics to be the largest class of agents to cause drug-induced liver injury. UK based estimates of incidence rates of antibiotic induced liver injury range from 2.5 to 8.6 per 100,000 users.

Antibiotics are a type of antimicrobial used to treat infections and are amongst the twenty most prescribed drugs in England, with approximately 38.7 million prescriptions dispensed in 2009. The most frequently prescribed type of antibiotics is penicillins, a group of bactericidal antibiotics that interfere with bacterial cell wall synthesis. Other bactericidal antibiotics include cephalosporins and aminoglycosides. Antibiotics with bacteriostatic mechanisms of action, inhibiting the growth or proliferation of bacterial cells, include tetracyclines, macrolides, sulphonamides and quinolones. Most types of antibiotics have been associated with drug-induced liver injury.

Liver injury accounts for 10% of all adverse reactions to drugs and is the most frequent reason for withdrawal of medications from the market. This study would provide a valuable contribution to our current knowledge as drug induced liver injury is the most common cause of acute liver failure and antibiotics are the largest drug class of agents, with the highest exposure prevalence, to cause acute liver injury. ;


Study Design

Time Perspective: Retrospective


Related Conditions & MeSH terms


NCT number NCT01587768
Study type Observational
Source GlaxoSmithKline
Contact
Status Completed
Phase N/A
Start date November 2011
Completion date July 2014

See also
  Status Clinical Trial Phase
Completed NCT04079790 - Pharmacokinetics of Gepotidacin Tablets in Adults and Adolescents Subjects Phase 1
Completed NCT01934205 - To Evaluate Plasma and Pulmonary Pharmacokinetics of GSK2140944 Phase 1
Not yet recruiting NCT02177721 - Clinical Benefit, Safety and PK of Raxibacumab in Subjects Exposed to Bacillus Anthracis Phase 4
Suspended NCT01132417 - In Vitro Activity of Tigecycline Among Key Bacterial Pathogens Exhibiting Multidrug Resistance N/A
Completed NCT00539994 - Retapamulin Ointment in Healthy Adults Nasally Colonized With Staphylococcus Aureus Phase 2
Completed NCT01610388 - A Study to Investigate the Safety, Tolerability and Pharmacokinetics of Oral and Intravenous GSK1322322 in Healthy Subjects Phase 1
Completed NCT01262885 - A Randomized, Single Blind, Placebo Controlled Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Single Oral Doses and Repeat Escalating Oral Doses of GSK2251052 in Healthy Adult Subjects Phase 1
Completed NCT00427141 - A Three-Part Study Of GSK580416 In Healthy Subjects Phase 1
Completed NCT04620486 - Effect of BPA on Anchor Antibiotic Continuity in the ED: Randomized Controlled Trial N/A
Recruiting NCT06451172 - Novel Antisense Oligonucleotide Eye Drops for Treating Antibiotic-Resistant Bacterial Keratitis Early Phase 1
Not yet recruiting NCT06440304 - Therapeutic Options for CRAB Phase 4
Completed NCT02292498 - Thermal Imaging to Diagnose and Monitor Suspected Bacterial Infections N/A
Withdrawn NCT01039610 - A Single Center Four Part Study in Healthy Adult Subjects to Evaluate: the Safety, Tolerability and Pharmacokinetics of a Single Oral Dose and Repeat Escalating Oral Doses of GSK945237; the Effect of Linezolid on Hematology Safety Parameters; and the Effects of GSK945237 and Moxifloxacin on QTc. Phase 1
Completed NCT00259909 - Observational Study Of An Electronic Questionnaire In Patients With Chronic Obstructive Pulmonary Disease (COPD) N/A
Completed NCT00828867 - Single Dose Escalation First Time in Human PK Study Phase 1
Completed NCT01431989 - Amoxicillin Bioequivalence Study Brazil - Fast Phase 1
Completed NCT02778672 - Thermal Imaging of the Lung on a Smartphone to Differentiate Bacterial From Non Bacterial Causes of Pneumonia N/A
Completed NCT00896558 - A Repeat Dose Escalation Study to Investigate the Safety, Tolerability and Pharmacokinetics of GSK1322322 in Healthy Subjects Phase 1
Completed NCT02045797 - Dose-Ranging Study of GSK2140944 in the Treatment of Subjects With Suspected or Confirmed Gram-Positive Acute Bacterial Skin and Skin Structure Infections Phase 2
Active, not recruiting NCT05752019 - TAAI Erasmus Research Initiative to Fight CF: Monitoring Inflammation in CF Lung Disease Into a New Era