ABSTRACT
AIMS: Source data verification (SDV) has been reported to account for up to 25% of the budget in clinical trials (CT) and cost-benefit of SDV has been questioned. Guidelines for risk-based monitoring (RBM) were published in 2013 by agencies and in 2016, ICH-GCP-E6-(R2) added a requirement for risk-based approaches. This report will perform a comparison of the impact of RBM vs classic monitoring (CM) on data quality (defined as accuracy of data reporting from source data to final trial data) and expected impact on costs of CTs. METHODS: Data on residual errors from four, large comparable randomised CTs were examined by post-trial SDV. Observed discrepancies were analysed in the categories of "overall" data, "major efficacy" and "major safety". In each category, the residual error rate was calculated as the number of discrepancies divided by the number of data-fields verified. RESULTS: A total of 1 716 087 data points were verified using CM and 323 174 using RBM. The overall error rate was 0.40% for RBM and 0.37% for CM (P < 0.01). For major efficacy, defined by risk assessment, the error rate was 0.15% and 0.28% (P < 0.0001); in major safety, defined by risk assessment, the error rate was 0.49% and 0.67% (P = 0.15), both in favour of the RBM approach. CONCLUSION: These empirical data, directly comparing RBM with CM, suggest that RBM improves data quality regarding data-points of major importance to trial outcomes, efficacy and major safety. Overall, the RBM approach showed a correlation to reduced amount of data collection errors with major relevance for interpretation of study results and subject safety as well as reducing on-site monitoring and data cleaning resources.
Subject(s)
Data Accuracy , Research Design , Humans , Data Collection , Risk Assessment , Cost-Benefit AnalysisABSTRACT
AIMS: In vitro studies have demonstrated that formation of reactive oxygen species (ROS) contributes to the effect of bactericidal antibiotics. The formation of ROS is not restricted to bacteria, but also occurs in mammalian cells. Oxidative stress is linked to several diseases. This study investigates whether antibiotic drugs induce oxidative stress in healthy humans as a possible mechanism for adverse reactions to the antibiotic drugs. METHODS: This study contains information from two randomised, controlled trials. Participants underwent 1 week treatment with clarithromycin, trimethoprim, phenoxymethylpenicillin (penicillin V), or placebo. Oxidative modifications were measured as 24-h urinary excretion of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo), and plasma levels of malondialdehyde before and after treatment as a measurement of DNA oxidation, RNA oxidation, and lipid peroxidation, respectively. RESULTS: Clarithromycin significantly increased urinary excretion of 8-oxodG by 22.0% (95% confidence interval (CI): 3.6-40.4%) and 8-oxoGuo by 14.9% (95% CI: 3.7-26.1%). Further, we demonstrated that trimethoprim significantly lowered urinary excretion of 8-oxodG by 21.7% (95% CI: 5.8-37.6%), but did not influence urinary excretion of 8-oxoGuo. Penicillin V did not influence urinary excretion of 8-oxodG or 8-oxoGuo. None of the antibiotic drugs influenced plasma levels of malondialdehyde. CONCLUSION: Clarithromycin significantly increases oxidative nucleic acid modifications. Increased oxidative modifications might explain some of clarithromycin's known adverse reactions. Trimethoprim significantly lowers DNA oxidation but not RNA oxidation. Penicillin V had no effect on oxidative nucleic acid modifications.
Subject(s)
Anti-Bacterial Agents/pharmacology , DNA/chemistry , Oxidative Stress/drug effects , RNA/chemistry , Reactive Oxygen Species/metabolism , 8-Hydroxy-2'-Deoxyguanosine , Adult , Biomarkers/urine , Clarithromycin/pharmacology , Deoxyguanosine/analogs & derivatives , Deoxyguanosine/urine , Guanosine/analogs & derivatives , Guanosine/urine , Healthy Volunteers , Humans , Lipid Peroxidation/drug effects , Male , Malondialdehyde/blood , Oxidation-Reduction , Penicillin V/pharmacology , Placebos , Trimethoprim/pharmacology , Young AdultABSTRACT
Trimethoprim antagonize the actions of folate by inhibition of dihydrofolate reductase. This could diminish serum folate levels in humans and causes folate deficiency in some patients. We conducted a randomized, double-blind, placebo-controlled trial, to investigate the effect of trimethoprim on serum folate levels in healthy participants after a 7-day trial period. Thirty young, healthy males were randomly allocated to receive trimethoprim, 200 mg twice daily, and 30 were randomly allocated to placebo. Before trial initiation, participant numbers were given randomly generated treatment allocations within sealed opaque envelopes. Participants and all staff were kept blinded to treatment allocations during the trial. Serum folate was measured at baseline and at end of trial. In the 58 participants analyzed (30 in the trimethoprim group and 28 in the placebo group), 8 had folate deficiency at baseline. Within the trimethoprim group, serum folate was significantly decreased (P = 0.018) after the trial. We found a mean decrease in serum folate among trimethoprim exposed of 1.95 nmol/L, compared with a 0.21 nmol/L mean increase in the placebo group (P = 0.040). The proportion of folate-deficient participants increased significantly within the trimethoprim group (P = 0.034). No serious adverse events were observed. In conclusion, we found that a daily dose of 400 mg trimethoprim for 7 days significantly lowered serum folate levels in healthy study participants.
