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Background  In drug trials, clinical adverse events (AEs), concomitant medication and laboratory safety outcomes are repeatedly collected to support drug safety evidence. Despite the potential correlation of these outcomes, they are typically analysed separately, potentially leading to misinformation and inefficient estimates due to partial assessment of safety data. Using joint modelling, we investigated whether clinical AEs vary by treatment and how laboratory outcomes (alanine amino-transferase, total bilirubin) and concomitant medication are associated with clinical AEs over time following artemisinin-based antimalarial therapy.    Methods  We used data from a trial of artemisinin-based treatments for malaria during pregnancy that randomized 870 women to receive artemether–lumefantrine (AL), amodiaquine–artesunate (ASAQ) and dihydroartemisinin–piperaquine (DHAPQ). We fitted a joint model containing four sub-models from four outcomes: longitudinal sub-model for alanine aminotransferase, longitudinal sub-model for total bilirubin, Poisson sub-model for concomitant medication and Poisson sub-model for clinical AEs. Since the clinical AEs was our primary outcome, the longitudinal sub-models and concomitant medication sub-model were linked to the clinical AEs sub-model via current value and random effects association structures respectively. We fitted a conventional Poisson model for clinical AEs to assess if the effect of treatment on clinical AEs (i.e. incidence rate ratio (IRR)) estimates differed between the conventional Poisson and the joint models, where AL was reference treatment.    Results  Out of the 870 women, 564 (65%) experienced at least one AE. Using joint model, AEs were associated with the concomitant medication (log IRR 1.7487; 95% CI: 1.5471, 1.9503;  p  < 0.001) but not the total bilirubin (log IRR: -0.0288; 95% CI: − 0.5045, 0.4469;  p  = 0.906) and alanine aminotransferase (log IRR: 0.1153; 95% CI: − 0.0889, 0.3194;  p  = 0.269). The Poisson model underestimated the effects of treatment on AE incidence such that log IRR for ASAQ was 0.2118 (95% CI: 0.0082, 0.4154;  p  = 0.041) for joint model compared to 0.1838 (95% CI: 0.0574, 0.3102;  p  = 0.004) for Poisson model.    Conclusion  We demonstrated that although the AEs did not vary across the treatments, the joint model yielded efficient AE incidence estimates compared to the Poisson model. The joint model showed a positive relationship between the AEs and concomitant medication but not with laboratory outcomes.    Trial registration  ClinicalTrials.gov:  NCT00852423

bmc medical research methodology

Joint modelling of multivariate longitudinal clinical laboratory safety outcomes, concomitant medication and clinical adverse events: application to artemisinin-based treatment during pregnancy clinical trial