Personalized Dosing for Fungal Infections

(PRAGMATIC Trial)

Recruiting at 6 trial locations

Overseen By Julian Lindsay

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: The University of Queensland

Must be taking: Voriconazole

Disqualifiers: Post-HCT without DNA, Imminent death, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 4 weeks

104 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It focuses on dosing voriconazole for fungal infections, so it's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug Voriconazole for fungal infections?

Research shows that using software to personalize Voriconazole dosing can help achieve safe and effective drug levels in patients, improving treatment outcomes for fungal infections. Studies also indicate that integrating patient-specific data and pathogen susceptibility can predict the success of Voriconazole treatment. ^{1 2 3 4 5}

Is voriconazole generally safe for humans?

Voriconazole is generally safe for humans, but it has a narrow therapeutic window, meaning the difference between an effective dose and a harmful dose is small. It can cause side effects if blood levels are too high, so monitoring is important to ensure safe and effective use. ^{3 4 6 7 8}

How is the drug Voriconazole used differently in this clinical trial for fungal infections?

This clinical trial uses personalized dosing of Voriconazole by integrating individual patient data and pathogen susceptibility to optimize treatment outcomes, which is different from standard dosing that doesn't account for these individual variations. ^{1 2 4 9 10}

Eligibility Criteria

This trial is for kids and adults with blood cancer who are dealing with invasive fungal infections. Participants must be able to undergo genotype testing, which will guide the dosing of voriconazole treatment.

Inclusion Criteria

Written informed consent obtained

My doctor has decided to treat me with voriconazole.

I am at least 2 years old.

Exclusion Criteria

I had a stem cell transplant but don't have access to the DNA from before the transplant.

Death is likely imminent within 7 days

Previously randomised to this trial

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline and Randomisation

Baseline data collection and randomisation of participants into standard care or precision care groups

1 week

1 visit (in-person)

Treatment

Participants receive voriconazole with dose adjustments based on TDM and genotype testing

4 weeks

Multiple visits for blood sampling and dose adjustments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Voriconazole

Trial Overview The study tests if personalized dosing of voriconazole, guided by genetic testing and special software, can better control fungal infections in blood cancer patients compared to standard care. It's a randomized trial where participants are split into groups by chance.

Participant Groups

Group I: Precision Care Experimental Treatment 1 Intervention

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.

Group II: Standard Care Active Control 1 Intervention

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.

Who Is Running the Clinical Trial?

The University of Queensland

Lead Sponsor

Trials

149

Recruited

71,700+

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Collaborator

Trials

10

Recruited

2,100+

University of Sydney

Collaborator

Trials

208

Recruited

417,000+

Royal Adelaide Hospital

Collaborator

Trials

23

Recruited

4,900+

Metro North Hospital and Health Service

Collaborator

Trials

2

Recruited

200+

Sydney Children's Hospitals Network

Collaborator

Trials

37

Recruited

43,300+

Royal Brisbane and Women's Hospital

Collaborator

Trials

33

Recruited

22,900+

Pathology Queensland

Collaborator

Trials

2

Recruited

200+

Western Sydney Local Health District

Collaborator

Trials

42

Recruited

18,600+

University of Melbourne

Collaborator

Trials

193

Recruited

1,287,000+

Findings from Research

Voriconazole is an effective antifungal agent, showing at least equal efficacy to amphotericin B for treating acute invasive aspergillosis in immunocompromised patients, and similar effectiveness to fluconazole for esophageal candidiasis.

The drug is well-absorbed when taken orally and can penetrate the central nervous system, but it may cause side effects like visual disturbances and liver function test elevations, and it has potential drug interactions due to its metabolism through specific liver enzymes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Voriconazole: a new triazole antifungal agent. Pearson, MM., Rogers, PD., Cleary, JD., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Software for dosage individualization of voriconazole for immunocompromised patients. [2022]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Predicting the Outcome of Voriconazole Individualized Medication Using Integrated Pharmacokinetic/Pharmacodynamic Model. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Software for Dosage Individualization of Voriconazole: a Prospective Clinical Study. [2022]

4. Germany pubmed.ncbi.nlm.nih.gov

A pharmacokinetic/pharmacodynamic analysis of a standard voriconazole regimen in different CYP2C19 genotypes by Monte Carlo simulation. [2016]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Systematic Evaluation of Voriconazole Pharmacokinetic Models without Pharmacogenetic Information for Bayesian Forecasting in Critically Ill Patients. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Voriconazole in clinical practice. [2014]

7. United States pubmed.ncbi.nlm.nih.gov

Voriconazole: a new triazole antifungal agent. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Therapeutic drug monitoring of voriconazole. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Neurological adverse events to voriconazole: evidence for therapeutic drug monitoring. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Population pharmacokinetics of voriconazole in adults. [2021]