Pharmacokinetics of Voriconazole in Adult ECMO Patients

An Observational Pharmacokinetic Study of Intravenous Voriconazole Used for Treatment of Invasive Aspergillosis in Adult Patients With Severe Influenza / COVID-19 Supported With Extra-corporeal Membrane Oxygenation (ECMO)

Given the high burden of fungal co-infection in patients admitted to ICU and improved outcomes with prompt anti-fungal treatment, it is of vital importance that the doses of anti-fungal are optimum to improve the dismal outcome of influenza/Covid-19 Associated Pulmonary Aspergillosis.

Due to the reported difficulties in dosing appropriately in ECMO patients, a prospective observational study is required to accurately evaluate the pharmacokinetics of voriconazole in patients supported on ECMO. This is to ensure that the dose of voriconazole is optimised to improve efficacy and reduce toxicity.

Study Overview

• Status: Recruiting
• Conditions: Covid19; Influenza; Aspergillosis
• Intervention / Treatment: Other: 5 blood samples; Genetic: Determination of CYP2C19 genotype

Detailed Description

A single centre, open label, prospective, observational, pharmacokinetic study of voriconazole administered to adults (aged > 18 years) supported on ECMO. This is a low-interventional study. There will be no treatment changes as a result of participation in this study. The decision to initiate voriconazole therapy will be taken independent of this study protocol. Intravenous voriconazole will be prescribed according to the approved dose in the SmPC. All adults requiring voriconazole therapy will be eligible for recruitment into the study.

The only additional procedure in this study will be to take a total of 5 blood samples across 3 occasions/sampling windows (Day 1-4, Day 6-9 and Day 11-14) to determine plasma concentrations of voriconazole. In addition, a single buccal swab to determine the CYP2C19 genotype will be undertaken during the course of ICU stay.

• Study Type: Observational
• Enrollment (Estimated): 50

Contacts and Locations

• Study Contact: Name: Hakeem Yusuff, MD; Phone Number: 07789 880920; Email: hakeem.yusuff@uhl-tr.nhs.uk
• Study Contact Backup: Name: Hussain Mulla, PhD; Phone Number: 2708 07702 559537; Email: hussain.mulla@uhl-tr.nhs.uk

Study Locations

• United Kingdom
  • Leicester, United Kingdom
    • Recruiting
    • University Hospitals of Leicester
    • Contact: Hakeem Yusuff

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Adult patients (≥18 years) with acute (cardio-)respiratory failure, inadequately supported by mechanical ventilation, requiring additional support with ECMO, and in the opinion of the direct care team requires intravenous voriconazole therapy for treatment of confirmed or suspected invasive aspergillosis, will be eligible to be recruited.

Description

Inclusion Criteria:

1. Adults aged ≥18 years
2. Admitted to ICU on ECMO support
3. Positive influenza or SARS-CoV-2 PCR from nasal, throat swab, BAL or other respiratory specimen.
4. Positive invasive aspergillosis infection (positive Aspergillus species culture from respiratory specimen or positive serum galactomannan) or strong clinical suspicion of invasive aspergillosis infection based on symptoms, CT, CXR.

Exclusion Criteria:

1. No participants < 18 years of age
2. Not requiring ECMO support
3. No positive influenza or SARS-CoV-2 results
4. Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant's ability to participate in the trial.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Voriconazole administration to adult patients with suspected fungal disease, receiving ECMO support; Adult (>18 years) patients with severe influenza / Covid-19 supported on ECMO and with confirmed or suspected aspergillosis infection.	Other: 5 blood samples; 5 blood samples across 3 occasions/sampling windows (Day 1-4, Day 6-9 and Day 11-14) to determine plasma concentrations of voriconazole; Genetic: Determination of CYP2C19 genotype; A single buccal swab to determine the CYP2C19 genotype will be undertaken during the course of ICU stay.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma levels of voriconazole administered to critically ill adult patients with suspected fungal disease, receiving ECMO support.	Primary parameter: Clearance (CL)	14 days
Plasma levels of voriconazole administered to critically ill adult patients with suspected fungal disease, receiving ECMO support.	Primary parameter: Volume of distribution (V)	14 days
Plasma levels of voriconazole administered to critically ill adult patients with suspected fungal disease, receiving ECMO support.	Secondary parameters: Maximum plasma concentration (Cmax)	14 days
Plasma levels of voriconazole administered to critically ill adult patients with suspected fungal disease, receiving ECMO support.	Secondary parameters: Area under plasma concentration time curve (AUC)	14 days
Plasma levels of voriconazole administered to critically ill adult patients with suspected fungal disease, receiving ECMO support.	Secondary parameters: Half-life (t1/2)	14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To assess the influence of CYP2C19 genotype on the plasma levels of voriconazole	CYP2C19 genotype: identify *2, *3, and *17 mutations and any influence on plasma levels of voriconazole	14 days

Collaborators and Investigators

• Sponsor: University Hospitals, Leicester
• Investigators: Principal Investigator: Hakeem Yusuff, MD, University Hospitals, Leicester

Study record dates

Study Major Dates

• Study Start (Actual): August 24, 2021
• Primary Completion (Estimated): June 30, 2024
• Study Completion (Estimated): June 30, 2024

Study Registration Dates

• First Submitted: February 18, 2021
• First Submitted That Met QC Criteria: April 27, 2021
• First Posted (Actual): April 30, 2021

Study Record Updates

• Last Update Posted (Actual): November 30, 2023
• Last Update Submitted That Met QC Criteria: November 29, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Voriconazole; Extracorporeal Membrane Oxygenation
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Bacterial Infections and Mycoses; Mycoses; Orthomyxoviridae Infections; COVID-19; Influenza, Human; Aspergillosis
• Other Study ID Numbers: 136965 V1.0

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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