Randomized Clinical Trial to Evaluate the Use of Genotype-based Dosing of Voriconazole
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 104
- 试验地点
- 12
- 主要终点
- Therapeutic trough voriconazole concentration at Day 8
研究概览
简要总结
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.
详细描述
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:
- 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.
- Antifungal exposure: to compare antifungal exposure over the first 28 days of therapy between precision care and standard care groups.
- 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.
- 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.
- Genotype: describe clinical success of voriconazole between genotypes.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 2 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Age ≥ 2 years.
- •Written informed consent obtained.
- •Decision to prescribe voriconazole.
- •Admitted to a trial site, or sufficient outpatient follow-up appointments are feasible
排除标准
- •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
研究组 & 干预措施
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.
干预措施: genotype-directed dosing with dosing software based on therapeutic drug monitoring (Other)
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.
结局指标
主要结局
Therapeutic trough voriconazole concentration at Day 8
时间窗: Day 8
Proportion of patients with measured therapeutic trough voriconazole concentration at Day 9 (+/- 1 day)
次要结局
- Number of days of antifungal therapy(Assessed over 30 days)
- Simulated therapeutic trough voriconazole exposure at Day 14(Day 14)
- Measured therapeutic trough voriconazole exposure at both Days 8 and 14(Days 8 and 14)
- Days to achieve first measured therapeutic trough voriconazole exposure(Assessed over 30 days)
- Measured therapeutic trough voriconazole exposure at Day 14.(Day 14)
- 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(Day 8 to Day 30)
- Simulated therapeutic trough voriconazole exposure at Day 8(Day 8)
- Doses to achieve first measured therapeutic trough voriconazole exposure.(Assessed over 30 days)
- Number of doses of antifungal therapy(Assessed over 30 days)
- Percent difference in dose when dose adjustment is performed(Assessed over 30 days)
- Length of hospital stay post-randomisation(Assessed over 30 days)
- Number of patients experiencing at least one adverse event(Assessed over 30 days)
- Number and type of adverse events(Assessed over 30 days)
- Clinical cure or stable disease(Assessed over 30 days)
- Patients with no reported fungal infection during course(Assessed over 30 days)
- All-cause mortality at 30 days(Assessed over 30 days)
- Clinical success(Assessed over 30 days)
- Hospital free days(Day 30)