CYP2C19 Genotype-Specific Dosing Plus TDM on Reaching Therapeutic Voriconazole Blood Levels

NCT03731169 | Completed Phase 4

• 1 other identifier: 15-9226
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 2

Brief Summary

Invasive aspergillosis is a fungal infection which left untreated, is a significant cause of morbidity and mortality. Immunocompromised patient populations such as solid organ transplant and malignant hematology patients are especially susceptible to invasive fungal infections. Voriconazole is an anti-fungal agent that is frontline therapy for invasive aspergillosis. Treatment success is highly dependent on maintaining therapeutic voriconazole concentrations. The current published literature has established that treatment failure is associated with sub- and supra-therapeutic voriconazole concentrations. Maintaining therapeutic voriconazole concentrations however, is challenging due to the high inter and intra-patient variability in voriconazole pharmacokinetics. The complex kinetics of voriconazole renders current manufacturers' dosing guidelines ineffective. Much of this complexity has been linked to genetic polymorphisms in the cytochrome P450 2C19 gene, and it has been found that CYP2C19 genotype plays an important role in determining voriconazole exposure levels. Therapeutic drug monitoring has been found to increase efficacy of voriconazole treatment through the monitoring of patients' voriconazole levels, allowing for dosage adjustments in response to supra- or sub-therapeutic levels. There are few robust studies that have examined the effect of CYP2C19 genotype on voriconazole treatment outcomes. They have been unable to determine relationships between CYP2C19 genetic status, and clinical efficacy and safety. No studies to our knowledge have made dosing adjustments based on CYP2C19 genetic status. The study aim is to explore the utility of voriconazole dosing that is based on the genetic status of the patient in conjunction with therapeutic drug monitoring. Over the course of one year, solid organ transplant recipients at Toronto General Hospital and malignant hematology patients at Princess Margaret Cancer Centre receiving voriconazole therapy will be randomized into one of two trial arms: a control arm receiving therapeutic drug monitoring only, or a treatment arm receiving genotype-specific dosing in conjunction with therapeutic drug monitoring. The investigators will compare the proportion of patients that achieve voriconazole therapeutic concentrations, the number of dose adjustments needed to achieve therapeutic voriconazole levels, and clinical outcomes between trial arms.

Conditions

Aspergillosis Invasive; Fungal Infection

Outcome Measures

Primary Outcomes (3)

• Voriconazole trough concentrations at steady-state

  To determine if the proportion of patients who achieve therapeutic voriconazole trough concentrations at steady-state through genotype-specific dosing in conjunction with TDM is greater than the proportion of patients who obtain therapeutic voriconazole concentrations via TDM alone.

  1 year

• Number of dose adjustments

  To determine if genotype-specific dosing in conjunction with TDM will result in a fewer number of dose adjustments needed to achieve therapeutic voriconazole levels, compared to TDM alone.

  1 year

• Genotype-specific dosages

  To evaluate the genotype-specific dosages suggested for the genotyping plus TDM trial arm.

  1 year

Secondary Outcomes (1)

• Genotype-specific dosing on treatment success/failure

  1 year

Study Arms (2)

TDM Only

ACTIVE COMPARATOR

This is the standard of care trial arm. Patients receive voriconazole dosages according to the product monograph. After day 4, dosing in both trial arms will adhere to the following in order to reach the target therapeutic window: 1.0-5.5 mg/L.

Drug: Standard of Care

Genotyping + TDM

EXPERIMENTAL

After ascertaining CYP2C19 genetic status, the participants will be categorized as having either the ultra-rapid metabolizer (URM), extensive metabolizer (EM), heterozygous extensive metabolizer (HEM) or poor metabolizer (PM) phenotype. They will receive an experimental dosage regimen based on their phenotype. receive the following dosing regimen until TDM is conducted on day 4. After day 4, dosing in both trial arms will adhere to the following in order to reach the target therapeutic window: 1.0-5.5 mg/L.

Genetic: Voriconazole genotype-specific dosing

Interventions

Voriconazole genotype-specific dosing GENETIC

Those in the intervention arm will receive an experimental dosage regimen of voriconazole based on their genetic status. URM: 6 mg/kg voriconazole twice on the first day followed by 5 mg/kg twice daily, rounded to the nearest 50mg for oral formulations up to day 4 post-start of voriconazole therapy. EM: 6 mg/kg voriconazole twice on the first day followed by 4 mg/kg twice daily, rounded to the nearest 50mg for oral formulations up to day 4 post-start of voriconazole therapy. HEM and PM: 6 mg/kg voriconazole twice on the first day followed by 2 mg/kg twice daily, rounded to the nearest 50mg for oral formulations up to day 4 post-start of voriconazole therapy.

Also known as: Genotype-guided dosing

Genotyping + TDM

Standard of Care DRUG

Participants are given 6 mg/kg voriconazole twice on the first day followed by 4 mg/kg twice daily, rounded to the nearest 50mg for oral formulations up to day 4 post-start of voriconazole therapy. After TDM is conducted on day 4 for all patients, dosing in both trial arms will adhere to the following in order to reach the target therapeutic window: 1.0-5.5 mg/L.

TDM Only

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All adult malignant hematology patients who are prescribed voriconazole.

You may not qualify if:

• Patients that have previously taken voriconazole within the last 2 weeks

Sponsors & Collaborators

• University Health Network, Toronto: lead

Study Sites (2)

Toronto General Hospital

Toronto, Ontario, M5G 2C4, Canada

Location

Princess Margaret Cancer Care Centre

Toronto, Ontario, M5G 2M9, Canada

Location

MeSH Terms

Conditions

Mycoses

Interventions

Standard of Care

Condition Hierarchy (Ancestors)

Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Study Officials

• Marisa Battistella, PharmD

  University Health Network, Toronto

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Pharmacy Clinician Scientist

Study Record Dates

• First Submitted: November 2, 2018
• First Posted: November 6, 2018
• Study Start: January 10, 2018
• Primary Completion: August 31, 2019
• Study Completion: August 28, 2020
• Last Updated: November 3, 2020

Record last verified: 2020-11

Data Sharing

• IPD Sharing: Will not share

Locations

CA (2)