Stewart, StefanSeco-Meseguer, EnriqueDiago-Sempere, ElenaMarín-Candón, AliciaCarmona, MontserratEstébanez, MiriamLópez-Fernández, Luis AImaz-Iglesia, IñakiDel Mar García Saiz, MaríaLaserna-Mendieta, Emilio JPeiró, Ana MFarré, MagíRodriguez-Jimenez, ConsueloSaiz-Rodriguez, MiriamSanabria-Cabrera, JudithRosas-Alonso, RocíoAbad-Santos, FranciscoPedrosa-Pérez, LucíaCarcas, Antonio JGarcía García, IreneBorobia, Alberto MiPHARMGx study group2025-04-222025-04-222024-11-07Stewart S, Seco-Meseguer E, Diago-Sempere E, Marín-Candón A, Carmona M, Estébanez M, López-Fernández LA, Imaz-Iglesia I, Del Mar García Saiz M, Laserna-Mendieta EJ, Peiró AM, Farré M, Rodriguez-Jimenez C, Saiz-Rodriguez M, Sanabria-Cabrera J, Rosas-Alonso R, Abad-Santos F, Pedrosa L, Carcas AJ, García García I, Borobia AM; iPHARMGx study group. Phase IV adaptive randomised clinical trials evaluating efficacy and cost-efficacy of pre-emptive pharmacogenetic genotyping strategies in the Spanish National Health System: iPHARMGx Master Protocol and PREVESTATGx nested clinical trial. BMJ Open. 2024 Nov 7;14(11):e089823.https://hdl.handle.net/20.500.12105/26625Introduction: Genetic variations impact drug response, driving the need for personalised medicine through pre-emptive pharmacogenetic testing. However, the adoption of pre-emptive pharmacogenetic testing for commonly prescribed drugs, such as statins, outside of tertiary hospitals is limited due to a lack of pharmacoeconomic evidence to support widespread implementation by healthcare policy-makers. The Spanish Consortium for the Implementation of Pharmacogenetics (iPHARMGx Consortium) addresses this by developing a clinical trial master protocol that will govern multiple nested adaptive clinical trials that compare genotype-guided treatments to standard care in specific drug-gene-population triads, asses their cost-efficacy and identify novel biomarkers through advanced sequencing techniques. The first of these studies aims to assess whether a pre-emptive statin therapy genotyping scheme reduces the incidence of statin-associated muscle symptoms (SAMS) in a population at risk of cardiovascular disease susceptible of receiving high-intensity or moderate-intensity doses of statins: The PREVESTATGx trial. Methods and analysis: the PREVESTATGX trial is a multicentre, adaptive randomised controlled pragmatic phase IV clinical trial nested to the iPHARMGx master protocol with two parallel arms, aiming for superiority. Randomisation will be conducted on an individual basis with a centralised approach and stratification by centre. After inclusion in the trial and genotyping has been performed, subjects will be randomly allocated to experimental group (pharmacogenetic genotype-guided statin prescription) or standard-of-care statin prescription (as deemed by attending physician). The main objective is to assess the efficacy of a statin pre-emptive genotyping strategy in reducing the incidence of SAMS. A total of 225 subjects will be recruited among the 10 participating centres if no futility/efficacy boundary is reached in the prespecified interim analyses. Recruitment will be carried out during a 12-month period and subjects will be followed for a 9-month period. Ethics and dissemination: The PREVESTATGx trial received ethical approval on 24 April 2024. Results will be disseminated via publication in peer-reviewed journals as well as presentation at international conferences. Trial results will be submitted for publication in an open-access peer-reviewed medical speciality-specific publication. Trial registration number: EU CT number: 2023-509418-12-00/Clinical trial Identifier (ClinicalTrials.gov): NCT06262685. Protocol version 1.2 12 April 2024 (includes non-substantial modification number 14 June 2024). Trial registration of this study can be located at both the EU Clinical Trials Register available from https:// euclinicaltrials.eu/search-for-clinical-trials/?lang=en and https://clinicaltrials.gov. Registration on both websites was done before the enrolment of the first patient complying with European regulations. EU Clinical Trials Register is a primary registry according to the WHO.engVoRhttp://creativecommons.org/licenses/by-nc/4.0/Clinical-PharmacologyClinical TrialGeneticsLipid disordersPublic healthAdaptive Clinical Trials as TopicCardiovascular DiseasesClinical Trials, Phase IV as TopicCost-Benefit AnalysisGenotypeHumansHydroxymethylglutaryl-CoA Reductase InhibitorsPharmacogenomic TestingPrecision MedicineRandomized Controlled Trials as TopicSpainAttribution-NonCommercial 4.0 International395107691411e08982310.1136/bmjopen-2024-0898232044-6055BMJ openopen access