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.
