Clinical trial NCT06510699: Pharmacogenomics for Better Treatment of Fungal Infections in Cancer
Official title: Randomized Clinical Trial to Evaluate the Use of Genotype-based Dosing of Voriconazole in Patients With Haematological Malignancy
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Fungal Infection
Haematological Malignancy
Blood Cancer
Infectious Disease
Keywords: infection
cancer
pharmacogenomic
genotype-based dosing
CYP2C19
Lead sponsor: The University of Queensland
Sponsor class: OTHER
Collaborators: name: Metro North Hospital and Health Service
name: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
name: University of Sydney
name: Western Sydney Local Health District
name: Sydney Children's Hospitals Network
name: Peter MacCallum Cancer Centre, Australia
name: University of Melbourne
name: Queensland Children's Hospital
name: Royal Adelaide Hospital
name: Pathology Queensland
name: Royal Brisbane and Women's Hospital
First posted: 2024-07-19
Enrollment: 104
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: PRAGMATIC is a parallel-group randomised (1:1) clinical trial aiming to recruit at least 104 patients. A hybrid feasibility sub-study will assess the scalability of genotype directed dosing to ensure a 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.
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

* 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

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

Primary outcomes:
measure: Therapeutic trough voriconazole concentration at Day 8
timeFrame: Day 8
Secondary outcomes:
measure: Simulated therapeutic trough voriconazole exposure at Day 8
timeFrame: Day 8
measure: Measured therapeutic trough voriconazole exposure at Day 14.
timeFrame: Day 14
measure: Simulated therapeutic trough voriconazole exposure at Day 14
timeFrame: Day 14
measure: Measured therapeutic trough voriconazole exposure at both Days 8 and 14
timeFrame: Days 8 and 14
measure: Simulated therapeutic trough voriconazole exposure at both Days 8 and 14
timeFrame: Days 8 and 14
measure: Simulated therapeutic trough voriconazole exposure from Day 8 to Day 30
timeFrame: Day 8 to Day 30
measure: Days to achieve first measured therapeutic trough voriconazole exposure
timeFrame: Assessed over 30 days
measure: Doses to achieve first measured therapeutic trough voriconazole exposure.
timeFrame: Assessed over 30 days
measure: Percent difference in dose when dose adjustment is performed
timeFrame: Assessed over 30 days
measure: Number of days of antifungal therapy
timeFrame: Assessed over 30 days
measure: Number of doses of antifungal therapy
timeFrame: Assessed over 30 days
measure: Clinical cure or stable disease
timeFrame: Assessed over 30 days
measure: Patients with no reported fungal infection during course
timeFrame: Assessed over 30 days
measure: Hospital free days
timeFrame: Day 30
measure: Length of hospital stay post-randomisation
timeFrame: Assessed over 30 days
measure: Number of patients experiencing at least one adverse event
timeFrame: Assessed over 30 days
measure: Number and type of adverse events
timeFrame: Assessed over 30 days
measure: All-cause mortality at 30 days
timeFrame: Assessed over 30 days
measure: Clinical success
timeFrame: Assessed over 30 days
Other outcomes:
Locations:
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Centre
state: Washington
city: Sydney
country: Australia
facility: Sydney Children's Hospital Network
state: New South Wales
city: Sydney
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Brisbane
country: Australia
facility: Royal Brisbane & Women's Hospital
state: Queensland
city: South Brisbane
country: Australia
facility: Children's Hospital Queensland
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
Study officials:
References: