Pharmacogenomics for Better Treatment of Fungal Infections in Cancer
- Conditions
- Haematological MalignancyBlood CancerInfectious DiseaseFungal Infection
- Interventions
- Other: genotype-directed dosing with dosing software based on therapeutic drug monitoring
- Registration Number
- NCT06510699
- Lead Sponsor
- The University of Queensland
- Brief Summary
This project aims to address invasive fungal infections in patients with blood cancer, 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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 104
- Age ≥ 2 years.
- Written informed consent obtained.
- Decision to prescribe voriconazole.
- Diagnosed with haematological malignancy or disorder.
- Admitted to a trial site, or sufficient outpatient follow-up appointments are feasible
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Precision Care genotype-directed dosing with dosing software based on therapeutic drug monitoring Voriconazole dosing will be initiated using current standard care dosing. Samples for TDM and genotype testing will be collected. Based on the results of these tests on Day 5, 8, 14, and up to day 30 ( ± 1 day) patients will be evaluated for dose adjustment using dosing software that includes patient data including TDM and genotype data.
- Primary Outcome Measures
Name Time Method Therapeutic trough voriconazole concentration at Day 8 Day 8 Proportion of patients with measured therapeutic trough voriconazole concentration at Day 9 (+/- 1 day)
- Secondary Outcome Measures
Name Time Method Number of days of antifungal therapy Assessed over 30 days Number of days of antifungal therapy
Simulated therapeutic trough voriconazole exposure at Day 14 Day 14 Proportion of patients with simulated therapeutic trough voriconazole exposure at Day 14
Measured therapeutic trough voriconazole exposure at both Days 8 and 14 Days 8 and 14 Proportion of patients with measured therapeutic trough voriconazole exposure at both Days 8 and 14
Days to achieve first measured therapeutic trough voriconazole exposure Assessed over 30 days Number of days to achieve first measured therapeutic trough voriconazole exposure
Measured therapeutic trough voriconazole exposure at Day 14. Day 14 Proportion of patients with measured therapeutic trough voriconazole exposure at Day 14.
Simulated therapeutic trough voriconazole exposure at both Days 8 and 14 Days 8 and 14 Proportion of patients with simulated therapeutic trough voriconazole exposure at both Days 8 and 14
Simulated therapeutic trough voriconazole exposure from Day 8 to Day 30 Day 8 to Day 30 Proportion of patients with simulated therapeutic trough voriconazole exposure from Day 8 to Day 30
Simulated therapeutic trough voriconazole exposure at Day 8 Day 8 Proportion of patients with simulated therapeutic trough voriconazole exposure at Day 8
Doses to achieve first measured therapeutic trough voriconazole exposure. Assessed over 30 days Number of doses to achieve first measured therapeutic trough voriconazole exposure.
Number of doses of antifungal therapy Assessed over 30 days Number of doses of antifungal therapy
Percent difference in dose when dose adjustment is performed Assessed over 30 days Percent difference in dose when dose adjustment is performed (i) on the first occasion and (ii) on subsequent occasions (set to 0 if no adjustment).
Length of hospital stay post-randomisation Assessed over 30 days Length of hospital stay post-randomisation
Number of patients experiencing at least one adverse event Assessed over 30 days Number of patients experiencing at least one adverse event
Number and type of adverse events Assessed over 30 days Number and type of adverse events
Clinical cure or stable disease Assessed over 30 days Proportion of patients achieving invasive fungal disease (IFD) clinical cure or stable disease; defined by treating team, if indication is IFD treatment
Patients with no reported fungal infection during course Assessed over 30 days Proportion of patients with no reported fungal infection during course, if indication is IFD prophylaxis.
All-cause mortality at 30 days Assessed over 30 days All-cause mortality at 30 days
Clinical success Assessed over 30 days Proportion of patients achieving clinical success, defined as an absence of a clinical deterioration or event that requires a change of therapy
Hospital free days Day 30 Number of hospital free days at day 30
Trial Locations
- Locations (7)
Royal Brisbane & Women's Hospital
🇦🇺Brisbane, Queensland, Australia
Peter MacCallum Cancer Centre
🇦🇺Melbourne, Victoria, Australia
Sydney Children's Hospital Network
🇦🇺Sydney, New South Wales, Australia
Westmead Hospital
🇦🇺Sydney, New South Wales, Australia
Royal Adelaide Hospital
🇦🇺Adelaide, South Australia, Australia
Fred Hutchinson Cancer Centre
🇺🇸Seattle, Washington, United States
Children's Hospital Queensland
🇦🇺South Brisbane, Queensland, Australia