Randomised multicentre clinical trial to evaluate voriconazole pre-emptive genotyping strategy in patients with risk of aspergillosis: vorigenipharm study protocol

• Published in: BMJ open Vol. 10; no. 10; p. e037443
• Main Authors: Monserrat Villatoro, Jaime, García García, Irene, Bueno, David, de la Cámara, Rafael, Estébanez, Miriam, López de la Guía, Ana, Abad-Santos, Francisco, Antón, Cristina, Mejía, Gina, Otero, María José, Ramírez García, Elena, Frías Iniesta, Jesús, Carcas, Antonio, Borobia, Alberto M
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.10.2020; BMJ Publishing Group
• Series: Protocol
• Subjects: Antifungal agents; Aspergillosis; Aspergillosis - drug therapy; Aspergillosis - genetics; Clinical medicine; Clinical practice guidelines; Clinical trials; Cost control; Disease prevention; Drug dosages; Efficiency; Fungal infections; Genetics and Genomics; Genotype; Guardians; Hematologic Diseases; Hematology; Hospitals; Humans; Informed consent; Leukemia; Metabolism; Morbidity; Mortality; Multicenter Studies as Topic; Patients; Pharmacogenetics; R&D; Research & development; Voriconazole - therapeutic use; clinical pharmacology; clinical trials; infectious diseases
• ISSN: 2044-6055; 2044-6055
• DOI: 10.1136/bmjopen-2020-037443

Invasive aspergillosis is the most important cause of morbidity and mortality in patients with haematological diseases. At present, voriconazole is the first-line treatment for invasive fungal disease. The pharmacokinetic interindividual variability of voriconazole depends on genetic factors. CYP450 is involved in 70%-75% of total metabolism of voriconazole, mainly CYP3A4 and CYP2C19, with the remaining 25%-30% of metabolism conducted by monooxygenase flavins. CYP2C19 single nucleotide polymorphisms could explain 50%-55% of variability in voriconazole metabolism. The main objective is to compare efficiency of pre-emptive voriconazole genotyping with routine practice. The primary outcome is serum voriconazole on the fifth day within the therapeutic range. The secondary outcome is the combined variables of therapeutic failure and adverse events within 90 days of first administration, associated with voriconazole. A total of 146 patients at risk of invasive aspergillosis who will potentially receive voriconazole will be recruited, and CYP2C19 will be genotyped. If the patient ultimately receives voriconazole, they will be randomised (1:1 experimental/control). In the experimental arm, patients will receive a dose according to a pharmacogenetic algorithm, including CYP2C19 genotype and clinical and demographic information. In the control arm, patients will receive a dose according to clinical practice guidelines. In addition, a Spanish National Healthcare System (NHS) point-of-view cost-effectiveness evaluation will be performed. Direct cost calculations for each arm will be performed. This trial will provide information about the viability and cost-effectiveness of the implementation of a pre-emptive voriconazole genotyping strategy in the Spanish NHS. A Spanish version of this protocol has been evaluated and approved by the La Paz University Hospital Ethics Committee and the Spanish Agency of Medicines and Medical Devices. Trial results will be submitted for publication in an open peer-reviewed medical speciality-specific publication. Eudra-CT: 2019-000376-41 and NCT04238884; Pre-results.