Study details:

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 will be collected to ascertain Feasibility or the extent to which precision care can be successfully used in each study setting via completion of the feasibility implementation measure (FIM) at baselines and quarterly thereafter, including qualitative interviews at the end of the study. Data will be collected to ascertain Acceptability or whether end-users perceive precision care as agreeable or satisfactory by survey and qualitative interviews with pharmacists, physicians and health administrators. Data will be collected to undertake an economic evaluation to determine the cost-effectiveness of precision versus standard care, exploring individual level data, incremental cost effectiveness ratios (ICERs) at day 14 and 30; and cost-utility analysis to demonstrate if precision care offers value for money at Day 30 in the Australian setting.

The health economic evaluation will include use of surveys to capture: 1) healthcare usage of trial participants; 2) implementation feasibility measures; and 3) implementation costs. Data will be collected to ascertain scalability or the ability to expand the efficacy of precision care on a small scale in controlled conditions to real world conditions to a greater proportion of the population. Therapeutic trough voriconazole exposures (concentrations) In this trial, serum concentrations \> 1 mg/L (minimum effective concentration) and \< 5 mg/L (maximum safe concentration) are defined as the therapeutic range.

Treating clinicians may nominate an individualised patient target within this range prior to randomisation and that range will be applied during the trial. Where dosing software is being applied, the software will be programmed to target 2. 5 mg/L.

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