PMID- 34627141 OWN - NLM STAT- MEDLINE DCOM- 20211101 LR - 20230725 IS - 1471-2288 (Electronic) IS - 1471-2288 (Linking) VI - 21 IP - 1 DP - 2021 Oct 9 TI - Joint modelling of multivariate longitudinal clinical laboratory safety outcomes, concomitant medication and clinical adverse events: application to artemisinin-based treatment during pregnancy clinical trial. PG - 208 LID - 10.1186/s12874-021-01412-9 [doi] LID - 208 AB - 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. CI - (c) 2021. The Author(s). FAU - Patson, Noel AU - Patson N AD - School of Public Health, University of the Witwatersrand, Johannesburg, South Africa. noelpatson@gmail.com. AD - School of Public Health and Family Medicine, College of Medicine, University of Malawi, Blantyre, Malawi. noelpatson@gmail.com. FAU - Mukaka, Mavuto AU - Mukaka M AD - Mahidol Oxford Tropical Medicine Research Unit (MORU), Bangkok, Thailand. AD - Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, UK. FAU - D'Alessandro, Umberto AU - D'Alessandro U AD - Medical Research Council Unit, The Gambia at the London School of Hygiene and Tropical Medicine, Fajara, Gambia. FAU - Chapotera, Gertrude AU - Chapotera G AD - School of Public Health and Family Medicine, College of Medicine, University of Malawi, Blantyre, Malawi. FAU - Mwapasa, Victor AU - Mwapasa V AD - School of Public Health and Family Medicine, College of Medicine, University of Malawi, Blantyre, Malawi. FAU - Mathanga, Don AU - Mathanga D AD - School of Public Health and Family Medicine, College of Medicine, University of Malawi, Blantyre, Malawi. FAU - Kazembe, Lawrence AU - Kazembe L AD - Department of Biostatistics, University of Namibia, Windhoek, Namibia. FAU - Laufer, Miriam K AU - Laufer MK AD - Center for Vaccine Development and Global Health, University of Maryland, School of Medicine, Baltimore, MD, USA. FAU - Chirwa, Tobias AU - Chirwa T AD - School of Public Health, University of the Witwatersrand, Johannesburg, South Africa. LA - eng SI - ClinicalTrials.gov/NCT00852423 GR - D43 TW010075/TW/FIC NIH HHS/United States PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20211009 PL - England TA - BMC Med Res Methodol JT - BMC medical research methodology JID - 100968545 RN - 0 (Antimalarials) RN - 0 (Artemether, Lumefantrine Drug Combination) RN - 0 (Artemisinins) RN - C7D6T3H22J (Artemether) SB - IM MH - *Antimalarials/adverse effects MH - Artemether/therapeutic use MH - Artemether, Lumefantrine Drug Combination/therapeutic use MH - *Artemisinins/adverse effects MH - Female MH - Humans MH - Laboratories MH - *Malaria, Falciparum/drug therapy MH - Pregnancy PMC - PMC8501924 OTO - NOTNLM OT - Adverse events OT - Concomitant medication OT - Drug safety OT - Joint model OT - Randomised controlled trials COIS- The authors declare that they have no competing interests. EDAT- 2021/10/11 06:00 MHDA- 2021/11/03 06:00 PMCR- 2021/10/09 CRDT- 2021/10/10 20:24 PHST- 2021/03/22 00:00 [received] PHST- 2021/09/17 00:00 [accepted] PHST- 2021/10/10 20:24 [entrez] PHST- 2021/10/11 06:00 [pubmed] PHST- 2021/11/03 06:00 [medline] PHST- 2021/10/09 00:00 [pmc-release] AID - 10.1186/s12874-021-01412-9 [pii] AID - 1412 [pii] AID - 10.1186/s12874-021-01412-9 [doi] PST - epublish SO - BMC Med Res Methodol. 2021 Oct 9;21(1):208. doi: 10.1186/s12874-021-01412-9.