An international study to investigate and optimise the safety of discontinuing valproate in young men and women with epilepsy: Protocol.

Valproate is the most effective treatment for idiopathic generalised epilepsy. Currently, its use is restricted in women of childbearing potential owing to high teratogenicity. Recent evidence extended this risk to men's offspring, prompting recommendations to restrict use in everybody aged <55 years. This study will evaluate mortality and morbidity risks associated with valproate withdrawal by emulating a hypothetical randomised-controlled trial (called a "target trial") using retrospective observational data. The data will be drawn from ~250m mainly US patients in the TriNetX repository and ~60m UK patients in Clinical Practice Research Datalink (CPRD). These will be scanned for individuals aged 16-54 years with epilepsy and on valproate who either continued, switched to lamotrigine or levetiracetam, or discontinued valproate between 2014-2024, creating four groups. Randomisation to these groups will be emulated by baseline confounder adjustment using g-methods. Mortality and morbidity outcomes will be assessed and compared between groups over 1-10 years, employing time-to-first-event and recurrent events analyses. A causal prediction model will be developed from these data to aid in predicting the safest alternative antiseizure medications. Together, these findings will optimise informed decision-making about valproate withdrawal and alternative treatment selection, providing immediate and vital information for patients, clinicians and regulators.

Informations de copyright

Copyright: © 2024 Mbizvo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Déclaration de conflit d'intérêts

A.G.M. declares i) a UCB Pharma grant paid to University of Liverpool for the National Audit of Seizure Management in Hospitals (NASH) study, which is unrelated to the submitted work; ii) an Angelini grant to be paid to University of Liverpool as co-applicant for A multi-method PRoject to maximise efficient and equitable pathways tO suPport from a rEgional epiLepsy centre (PROPEL), which is unrelated to the submitted work; iii) Honoraria paid to University of Liverpool for lectures unrelated to the submitted work given at educational events sponsored by Sanofi, Eiasi, and GSK; iii) Support from Angelini for attendance unrelated to the submitted work at the 2024 International League Against Epilepsy (ILAE) congress. G.K.M declares an Angelini grant to be paid to University of Liverpool as co-applicant on the PROPEL study, which is unrelated to the submitted work; ii) Honoraria to be paid to University of Liverpool for delivering a lecture at an educational event sponsored by Angelini which was unrelated to the submitted work. The remaining authors declare no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All authors confirm there are no patents, products in development or marketed products associated with this research to declare.