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
,
Xandra García-González,
Alberto M Borobia,
Antonio J Carcas,
Miriam Estébanez,
Montserrat Carmona,
Irene García García,
Francisco Abad-Santos,
Luis A López-Fernández,
Esther Cubo,
Iñaki Imaz-Iglesia,
Alicia Marín-Candón,
Miriam Saiz-Rodríguez,
Irene Taladriz-Sender,
Pedro Arias,
Rocío Rosas-Alonso,
Enrique Seco-Meseguer,
Stefan Stewart,
Elena Diago-Sempere,
María del Mar García Saiz,
Emilio J Laserna-Mendieta,
Ana M Peiró,
Magí Farré,
Consuelo Rodriguez-Jimenez,
Judith Sanabria-Cabrera,
Lucia Pedrosa,
Ignacio Bernardino,
Javier Guiijarro-Eguinoa,
Arturo Gómez López De Las Huertas,
Susana Martín-López,
Olga Hladun Alvaro,
Vicente Arrate,
Ana Fries,
Daniel Rodriguez Díaz,
Fernando Marqués García,
Núria Alonso Pedrol,
Modesto M Maestre Muñiz,
Leticia Rodríguez Alcolado,
Carlos Ortiz-Bautista,
Angela Remesal-Doblado,
María Isabel Lucena,
Zaida Salmón González,
Inmaculada Coca-Prieto
Affiliations
Cancer Care Research and Engagement, UK
Xandra García-González
Alberto M Borobia
Pharmacology Department. School of Medicine, Autonomous University of Madrid, Madrid, Spain
Antonio J Carcas
Clinical Pharmacology Department, Hospital Universitario La Paz, Madrid, Spain
Miriam Estébanez
Internal Medicine Department, Hospital Central de la Defensa Gomez Ulla, Madrid, Spain
Montserrat Carmona
Health Technology Assessment Agency, Instituto de Salud Carlos III, Madrid, Spain
Irene García García
Clinical Pharmacology Department, Hospital Universitario La Paz, Madrid, Spain
Francisco Abad-Santos
UICEC Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria La Princesa (IP), Hospital Universitario de la Princesa, Madrid, Spain
Luis A López-Fernández
Pharmacy Department, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Maranon, Madrid, Spain
Esther Cubo
Iñaki Imaz-Iglesia
Health Technology Assessment Agency (AETS), Instituto de Salud Carlos III, Madrid, Spain
Alicia Marín-Candón
Clinical Pharmacology Department, Hospital Universitario La Paz, Madrid, Spain
Miriam Saiz-Rodríguez
Research Unit, Fundación Burgos por la Investigación de la Salud, Hospital Universitario de Burgos, Burgos, Spain
Irene Taladriz-Sender
Pedro Arias
Rocío Rosas-Alonso
Pharmacogenetics Laboratory, Genetics Department, Hospital Universitario La Paz, Madrid, Spain
Enrique Seco-Meseguer
Clinical Pharmacology Department, Hospital Universitario La Paz, Madrid, Spain
Stefan Stewart
Clinical Pharmacology Department, Hospital Universitario La Paz, Madrid, Spain
Elena Diago-Sempere
Clinical Pharmacology Department, Hospital Universitario La Paz, Madrid, Spain
Department of Gastroenterology, Research Unit, Hospital General de Tomelloso, Tomelloso, Castilla-La Mancha, Spain
Ana M Peiró
Unidad de Farmacología Clínica, Unidad del Dolor, Alicante Department of Health-General Hospital, Alicante, Comunidad Valenciana, Spain
Magí Farré
Department of Clinical Pharmacology, Pharmacogenomics Unit, Hospital Germans Trias i Pujol, Badalona, Catalunya, Spain
Consuelo Rodriguez-Jimenez
Clinical Trials Unit, Pharmacology Department, Hospital Universitario de Canarias, La Laguna, Canarias, Spain
Judith Sanabria-Cabrera
Servicio de Farmacología Clínica, IBIMA Plataforma BIONAND, Universidad de Málaga, Málaga, Spain, Platform for Clinical Research and Clinical Trials IBIMA, Hospital Universitario Virgen de la Victoria, Malaga, Andalucía, Spain
Lucia Pedrosa
Health Technology Assessment Agency (AETS), Instituto de Salud Carlos III, Madrid, Spain
Introduction 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.