Pharmacogenomics for Better Treatment of Fungal Infections Clinical Trial (PRAGMATIC)

Randomized Clinical Trial to Evaluate the Use of Genotype-based Dosing of Voriconazole

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.

Study Overview

• Status: Recruiting
• Conditions: Infectious Disease; Fungal Infection; Blood Cancer; Haematological Malignancy
• Intervention / Treatment: Other: genotype-directed dosing with dosing software based on therapeutic drug monitoring

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.

• Study Type: Interventional
• Enrollment (Estimated): 104
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jason A Roberts, PhD; Phone Number: 65032 +61 7 3346 5032; Email: j.roberts2@uq.edu.au
• Study Contact Backup: Name: Luminita Vlad; Phone Number: 61 7 3346 5045; Email: l.vlad@uq.edu.au

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2145
      • Recruiting
      • Westmead Hospital
      • Contact: Johannes Alffenaar; Phone Number: +61 2 8627 0019; Email: johannes.alffenaar@sydney.edu.au
      • Contact: Catherine Linh; Email: catherine.linh@health.nsw.gov.au
      • Sub-Investigator: Johannes Alffernaar, PhD, PharmD, Clinical Pharmaco
    • Sydney, New South Wales, Australia, 21452031
      • Recruiting
      • Sydney Children's Hospital Network
      • Contact: Tony Lai; Phone Number: +61 2 9845 2700; Email: tony.lai@health.nsw.gov.au
      • Contact: Shirley Wong; Email: shirley.wong@health.nsw.gov.au
  • Queensland
    • Brisbane, Queensland, Australia, 4029
      • Recruiting
      • Royal Brisbane & Women's Hospital
      • Contact: Amy Legg; Phone Number: +61 7 3647 0802; Email: amy.legg@health.qld.gov.au
      • Contact: Midori Nakagaki, PhD; Phone Number: +61 7 3647 0185; Email: midori.nakagaki@health.qld.gov.au
    • South Brisbane, Queensland, Australia, 4029
      • Recruiting
      • Children's Hospital Queensland
      • Contact: Adam D Irwin, MBBS, PhD; Phone Number: 07 3346 5075; Email: a.irwin@uq.edu.au
      • Contact: Rachael Lawson, PhD; Email: rachael.lawson@health.qld.gov.au
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Recruiting
      • Royal Adelaide Hospital
      • Contact: Philip R Selby; Phone Number: 08 7074 0000; Email: philip.selby@sa.gov.au
      • Contact: Jane Rose; Email: Jane.rose@sa.gov.au
  • Victoria
    • Melbourne, Victoria, Australia, 3053
      • Recruiting
      • Peter Maccallum Cancer Centre
      • Contact: Rachel Wolstencroft; Phone Number: +61 3 8559 7973; Email: infectiousdiseases.clinicaltrials@petermac.org
      • Contact: Monica Slavin, MBBS, FRACP, MD, FAAHMS, FECMM; Phone Number: +61 3 8559 5000; Email: monica.slavin@petermac.org
      • Sub-Investigator: Monica Slavin, MBBS, PHD
• United States
  • Washington
    • Seattle, Washington, United States, 908109-1024
      • Recruiting
      • Fred Hutchinson Cancer Centre
      • Contact: Ashleigh Miller; Phone Number: 206-667-1994; Email: amiller3@fredhutch.org
      • Contact: Catherine Professor Liu, MD; Phone Number: 206-667-2729; Email: catherine.liu@fredhutch.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Precision Care; 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.	Other: genotype-directed dosing with dosing software based on therapeutic drug monitoring; Genotype-directed dosing with dosing software based on therapeutic drug monitoring; Other Names: genotype directed with dosing software
No Intervention: Standard 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 and based on clinical judgement.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Therapeutic trough voriconazole concentration at Day 8	Proportion of patients with measured therapeutic trough voriconazole concentration at Day 9 (+/- 1 day)	Day 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Simulated therapeutic trough voriconazole exposure at Day 8	Proportion of patients with simulated therapeutic trough voriconazole exposure at Day 8	Day 8
Measured therapeutic trough voriconazole exposure at Day 14.	Proportion of patients with measured therapeutic trough voriconazole exposure at Day 14.	Day 14
Simulated therapeutic trough voriconazole exposure at Day 14	Proportion of patients with simulated therapeutic trough voriconazole exposure at Day 14	Day 14
Measured therapeutic trough voriconazole exposure at both Days 8 and 14	Proportion of patients with measured therapeutic trough voriconazole exposure at both Days 8 and 14	Days 8 and 14
Simulated therapeutic trough voriconazole exposure at both Days 8 and 14	Proportion of patients with simulated therapeutic trough voriconazole exposure at both Days 8 and 14	Days 8 and 14
Simulated therapeutic trough voriconazole exposure from Day 8 to Day 30	Proportion of patients with simulated therapeutic trough voriconazole exposure from Day 8 to Day 30	Day 8 to Day 30
Days to achieve first measured therapeutic trough voriconazole exposure	Number of days to achieve first measured therapeutic trough voriconazole exposure	Assessed over 30 days
Doses to achieve first measured therapeutic trough voriconazole exposure.	Number of doses to achieve first measured therapeutic trough voriconazole exposure.	Assessed over 30 days
Percent difference in dose when dose adjustment is performed	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).	Assessed over 30 days
Number of days of antifungal therapy	Number of days of antifungal therapy	Assessed over 30 days
Number of doses of antifungal therapy	Number of doses of antifungal therapy	Assessed over 30 days
Clinical cure or stable disease	Proportion of patients achieving invasive fungal disease (IFD) clinical cure or stable disease; defined by treating team, if indication is IFD treatment	Assessed over 30 days
Patients with no reported fungal infection during course	Proportion of patients with no reported fungal infection during course, if indication is IFD prophylaxis.	Assessed over 30 days
Hospital free days	Number of hospital free days at day 30	Day 30
Length of hospital stay post-randomisation	Length of hospital stay post-randomisation	Assessed over 30 days
Number of patients experiencing at least one adverse event	Number of patients experiencing at least one adverse event	Assessed over 30 days
Number and type of adverse events	Number and type of adverse events	Assessed over 30 days
All-cause mortality at 30 days	All-cause mortality at 30 days	Assessed over 30 days
Clinical success	Proportion of patients achieving clinical success, defined as an absence of a clinical deterioration or event that requires a change of therapy	Assessed over 30 days

Collaborators and Investigators

• Sponsor: The University of Queensland
• Collaborators: University of Sydney; Sydney Children's Hospitals Network; Peter MacCallum Cancer Centre, Australia; Western Sydney Local Health District; University of Melbourne; Royal Brisbane and Women's Hospital; Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium; Royal Adelaide Hospital; Lady Cilento Children's Hospital, Brisbane; Metro North Hospital and Health Service; Pathology Queensland
• Investigators: Principal Investigator: Jason A Roberts, PhD, The University of Queensland

Study record dates

Study Major Dates

• Study Start (Actual): April 14, 2025
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): March 26, 2027

Study Registration Dates

• First Submitted: July 14, 2024
• First Submitted That Met QC Criteria: July 18, 2024
• First Posted (Actual): July 19, 2024

Study Record Updates

• Last Update Posted (Actual): April 16, 2026
• Last Update Submitted That Met QC Criteria: April 13, 2026
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: cancer; infection; pharmacogenomic; CYP2C19; genotype-based dosing
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Disease Attributes; Hematologic Diseases; Bacterial Infections and Mycoses; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Neoplasms; Hematologic Neoplasms; Infections; Communicable Diseases; Mycoses
• Other Study ID Numbers: PRAGMATIC 02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes