Pharmacogenomics for Better Treatment of Fungal Infections Clinical Trial

This project aims to address invasive fungal infections in patients, by precision dosing of voriconazole based on CYP2C19 genotype testing with Bayesian dose-forecasting dosing software to develop patient-centric and maximally effective dosing regimens. This study investigates if voriconazole increases the proportion of patients achieving therapeutic exposure at day 8 of dosing compared with standard care; and will assess factors that influence the implementation of genotype testing and dosing software in the healthcare system, including fidelity, feasibility, acceptability and cost-effectiveness. It will recruit at least 104 kids and adults in a parallel-group randomised clinical trial. A hybrid feasibility sub-study will assess the scalability of genotype-directed dosing to ensure sustainable integration of the interventions into the clinical workflow. A health economic sub-study will evaluate the costs, health outcomes and cost-effectiveness of genotype-directed testing compared to standard care.

Participants will be randomly assigned to standard care or precision care. Current standard of care at trial-site institutions uses weight-based (mg/kg) initial dosing of voriconazole, with dose adjustment based on standard therapeutic drug monitoring (TDM) results of measured voriconazole concentrations based on clinical judgement. In precision care, voriconazole dosing will be initiated using current standard dosing. Samples for the TDM and genotype testing will be collected. Based on results of these tests on Day 5 (+/- 1 day) patients will be evaluated for dose adjustment using dosing software that includes patient data, TDM and genotype data. Trial procedures: following baseline data collection and randomisation genotype testing will be performed on Day 1. The precision care group have dose adjustment performed on Days 5, 9, 15, and 22 using genotype and/or TDM results in dosing software. The standard care group will have TDM performed, and dose adjustments in accordance with usual clinical practice. Blood sampling for TDM will be performed 24-hours prior to dose adjustment, with additional blood samples collected on Days 1 and 2 in both standard care and precision care groups. All blood sampling, genotype testing and dose adjustments will be performed +/- day to support feasibility. The primary objective is to compare the proportion of patients achieving therapeutic voriconazole exposure at Day 8 when using precision care compared to standard care. Secondary objectives are: 1. Clinical: comparison of clinical success of voriconazole treatment between precision care and standard care groups, where clinical success is defined as an absence of clinical deterioration or event that requires a change of therapy. 2. Antifungal exposure: to compare antifungal exposure over the first 28 days of therapy between precision care and standard care groups. 3. Comparative precision care methodologies: compare if there is a difference in daily dose recommendations between using a genotype nomogram, dosing software with TDM, or a combination of dose adjustment in precision care. 4. Feasibility of precision care interventions: to determine if it is feasible to perform the measurement of voriconazole concentrations and genotype testing for use in dosing software in time to intervene prior to Day 5 and/or Day 9 dose adjustment. 5. Genotype: describe clinical success of voriconazole between genotypes. The implementation feasibility sub-study will assess the scalability of precision care to support optimal voriconazole dosing by tailoring the intervention to each trial setting and measuring outcomes with the involvement of key stakeholders (end-users, health administrators, consumers, community members). Data will be collected to ascertain Fidelity including: 1) assess barriers and enablers; 2) identify prioritise the factors influencing delivery and tailor these to fit local settings; 3) assess intended fidelity to the precision care intervention. Data wi Покажи пълното описание...

Inclusion Criteria: * Age ≥ 2 years. * Written informed consent obtained. * Decision to prescribe voriconazole. * Admitted to a trial site, or sufficient outpatient follow-up appointments are feasible Exclusion Criteria: * Post-allogeneic haematopoietic stem cell transplant (HCT) patient, without access to pre HCT DNA * Death is likely imminent within 7 days. * Previously randomised to this trial