Invasive Fungal InfectionsICONICNCT04777058
Pharmacokinetics of Isavuconazole in Patients in the Intensive Care Unit
An observational study of Invasive Fungal Infections and Pharmacokinetics, run by Radboud University Medical Center at 4 sites in 2 countries.
Trial summary
20 patients admitted to the ICU department and receiving isavuconazole as part of standard care for the treatment of fungal infections will be included in the study. Between day 3 and 7, 8 samples will be collected at t = 0 (pre-dose), and t = 0.5, 1, 2, 4, 6, 8 and 12 hours after end of infusion to obtain a PK curve. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Invasive Fungal Infections, Pharmacokinetics, Intensive Care Unit
- Type of treatment
- Injection or infusion
- How many people
- 20 participants
- Where
- 4 sitesin 2 countries
- Study dates
- 1 Mar 2021to 29 Sep 2022
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Twenty ICU patients treated with isavuconazole for a fungal infection are eligible for inclusion. These patients are admitted to the ICU of Radboudumc and UZ Leuven. Since the objective is to evaluate the pharmacokinetics of isavuconazole in a real-life cohort of patients admitted to the ICU, exclusion criteria are minimal on purpose, to give a good reflection of this heterogenic cohort. The possible inclusion of patients with for example hepatic insufficiencies, continuous renal replacement therapy (CRRT), extracorporeal membrane oxygenation (ECMO) et cetera, is considered. High variability between subjects in this highly heterogenetic patient population is expected and will be considered in the analyses.
Who may be able to join
- Patient is admitted to an ICU
- Is treated with isavuconazole intravenously (iv)
- Subject is at least 18 years on the day of the first dosing
- Is managed with a central venous catheter or arterial line
Who cannot join
- Patient has previously participated in this study
Trial locations and contacts
4 sites in 2 countries.
4 sites in 2 countries
Netherlands3 sites
Jeroen Bosch Hospital
's-Hertogenbosch
Radboud University Medical Centre
Nijmegen
University Medical Center Utrecht
Utrecht
About this study
Official title: Pharmacokinetics of Isavuconazole (Cresemba®) Given as Treatment of Invasive Fungal Infections in Patients in the Intensive Care Unit
20 patients admitted to the ICU department and receiving isavuconazole as part of standard care for the treatment of fungal infections will be included in the study. Between day 3 and 7, 8 samples will be collected at t = 0 (pre-dose), and t = 0.5, 1, 2, 4, 6, 8 and 12 hours after end of infusion to obtain a PK curve. An optional, additional sample can be collected after discontinuation of isavuconazole therapy if possible. Total and free isavuconazole concentrations will be determined. A pharmacokinetic model will be fitted to the data from all individuals simultaneously. Data will be analysed using non-linear mixed effects modelling (NONMEM).
Read the detailed description
Fungal infections are a serious threat to immunocompromised patients and represent a major burden in the critical care setting. The azole antifungal drugs are the most important drugs for managing infections caused by Aspergillus moulds and the prevention of invasive fungal infections in general. Azoles are currently used as first line prophylaxis and treatment of invasive aspergillosis and their use has substantially improved the survival of the overall population. Recently, there has been increased awareness for invasive aspergillosis cases in critically ill patients, including patients with severe influenza (influenza associated pulmonary aspergillosis, IAPA), and recently COVID-19 associated pulmonary aspergillosis (CAPA). These patients require azole-based therapy, for which voriconazole and isavuconazole are recommended first choice drugs.
Isavuconazole is a relatively novel azole drug with promising efficacy, a broad antifungal spectrum, favourable side effect profile and limited drug-drug interactions compared to other azole agents. Isavuconazole is registered for the primary treatment of adults with invasive aspergillosis, and patients with mucormycosis where amphotericin B is not suitable. Efficacy and safety information in the isavuconazole label is mostly derived from clinical studies in healthy volunteers. However, the pharmacokinetics in some specific patient populations may differ greatly from those in the healthy population. Changes in pharmacokinetics of isavuconazole in ICU patients are to be expected due to a wide variety of factors, e.g. changes in protein binding and changes in fluid distribution. Therefore, it is likely that the present standard dosing regimens of isavuconazole lead to suboptimal outcomes for ICU patients, similar to observations made for fluconazole and echinocandins. Optimizing dosing regimens in ICU patients for existing antifungal agents such as isavuconazole is important to improve clinical outcome rates. To date, limited information on the pharmacokinetics of isavuconazole in critically ill patients is available and optimal dosing regimens remain uncertain. With this study we aim to describe isavuconazole pharmacokinetics in ICU admitted patients.
20 patients admitted to the ICU department and receiving isavuconazole as part of standard care for the treatment of fungal infections will be included in the study. Between day 3 and 7, 8 samples will be collected at t = 0 (pre-dose), and t = 0.5, 1, 2, 4, 6, 8 and 12 hours after end of infusion to obtain a PK curve. An optional, additional sample can be collected after discontinuation of isavuconazole therapy if possible. Total and free isavuconazole concentrations will be determined. A pharmacokinetic model will be fitted to the data from all individuals simultaneously. Data will be analysed using non-linear mixed effects modelling (NONMEM). NONMEM is a one-stage analysis that simultaneously estimates mean parameters, fixed effect parameters, interindividual variability, and residual random effects. Since allowance can be made for individual differences, this method can be used with both intensive sampling and sparse data (and in the occasion of missing values: an unbalanced number of data points per patients).
Primary objective:
- To determine the pharmacokinetics of isavuconazole given as treatment of invasive fungal infections in ICU patients as part of standard care.
Secondary objectives:
- To investigate the protein binding of isavuconazole in ICU patients and the variability in protein binding between patients in the ICU population.
- To explore if unbound isavuconazole concentrations can be predicted from total isavuconazole concentrations.
- To assess pharmacokinetic/pharmacodynamic target attainment in the ICU patient population.
- Keywords
- isavuconazole, population pharmacokinetics, protein binding
- Medical subject headings
- Invasive Fungal Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Patients | Patients admitted to the intensive care unit, treated with isavuconazole intravenously for treatment of invasive fungal infections |
What is being measured
The primary outcome is the main question the study is designed to answer.
Isavuconazole clearance in ICU patients.
Isavuconazole clearance in ICU patients in liters/hour. Full pharmacokinetic curves will be taken and an optional sample during the elimination phase of isavuconazole.
Measured: Day 3-7 after start of treatment and optional: 96-300 hours after discontinuation of treatment
Isavuconazole volume of distribution in ICU patients
Isavuconazole volume of distribution in ICU patients in liters. Full pharmacokinetic curves will be taken and an optional sample during the elimination phase of isavuconazole.
Measured: Day 3-7 after start of treatment and optional: 96-300 hours after discontinuation of treatment
Secondary outcomes (3)
Isavuconazole proteinbinding in ICU patients.
Isavuconazole proteinbinding in ICU patients described by unbound isavuconazole fraction (fu).
Measured: Day 3-7 after start of treatment and optional: 96-300 hours after discontinuation of treatment
Predictability of unbound isavuconazole concentrations
To compare the predicted and observed unbound isavuconazole concentrations in ICU patients: percentage of deviation from predicted.
Measured: Day 3-7 after start of treatment and optional: 96-300 hours after discontinuation of treatment
Target attainment of isavuconazole in ICU patients
Percentage of patients reaching the predetermined adequate PK/PD target (isavuconazole trough concentration in mg/l)
Measured: At steady state (day 3-7 after start of treatment)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Mar 2021
- Study start1 Mar 2021
- Primary completion29 Sep 2022
- Study completion29 Sep 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Invasive Fungal InfectionsStudies of the same condition, open and under way.
- More trials run by Radboud University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- Radboud University Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04777058
- Sponsor's protocol ID
- UMCN-AKF-21.02
- Acronym
- ICONIC
- Status last verified
- Oct 2022
- First submitted
- 11 Feb 2021
- Last updated
- 26 Oct 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Jansen AME, Mertens B, Spriet I, Verweij PE, Schouten J, Wauters J, Debaveye Y, Ter Heine R, Bruggemann RJM. Population Pharmacokinetics of Total and Unbound Isavuconazole in Critically Ill Patients: Implications for Adaptive Dosing Strategies. Clin Pharmacokinet. 2023 Dec;62(12):1701-1711. doi: 10.1007/s40262-023-01305-8. Epub 2023 Oct 11.
PubMed 37819503
Study at a glance
From the registry record, last updated by the sponsor on 26 Oct 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pharmacokinetics of Isavuconazole (Cresemba®) Given as Treatment of Invasive Fungal Infections in Patients in the Intensive Care Unit
- ClinicalTrials.gov ID
- NCT04777058
- Acronym / sponsor ID
- ICONIC / UMCN-AKF-21.02
- Keywords
- isavuconazole, population pharmacokinetics, protein binding
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 20 participants (actual)
- Lead sponsor
- Radboud University Medical CenterUniversity, hospital or other
- Study start
- 1 Mar 2021 (actual)
- Primary completion
- 29 Sep 2022 (actual)
- Study completion
- 29 Sep 2022 (actual)
- First posted
- 2 Mar 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
20 patients admitted to the ICU department and receiving isavuconazole as part of standard care for the treatment of fungal infections will be included in the study. Between day 3 and 7, 8 samples will be collected at t = 0 (pre-dose), and t = 0.5, 1, 2, 4, 6, 8 and 12 hours after end of infusion to obtain a PK curve. An optional, additional sample can be collected after discontinuation of isavuconazole therapy if possible. Total and free isavuconazole concentrations will be determined. A pharmacokinetic model will be fitted to the data from all individuals simultaneously. Data will be analysed using non-linear mixed effects modelling (NONMEM).
Detailed description
Fungal infections are a serious threat to immunocompromised patients and represent a major burden in the critical care setting. The azole antifungal drugs are the most important drugs for managing infections caused by Aspergillus moulds and the prevention of invasive fungal infections in general. Azoles are currently used as first line prophylaxis and treatment of invasive aspergillosis and their use has substantially improved the survival of the overall population. Recently, there has been increased awareness for invasive aspergillosis cases in critically ill patients, including patients with severe influenza (influenza associated pulmonary aspergillosis, IAPA), and recently COVID-19 associated pulmonary aspergillosis (CAPA). These patients require azole-based therapy, for which voriconazole and isavuconazole are recommended first choice drugs.
Isavuconazole is a relatively novel azole drug with promising efficacy, a broad antifungal spectrum, favourable side effect profile and limited drug-drug interactions compared to other azole agents. Isavuconazole is registered for the primary treatment of adults with invasive aspergillosis, and patients with mucormycosis where amphotericin B is not suitable. Efficacy and safety information in the isavuconazole label is mostly derived from clinical studies in healthy volunteers. However, the pharmacokinetics in some specific patient populations may differ greatly from those in the healthy population. Changes in pharmacokinetics of isavuconazole in ICU patients are to be expected due to a wide variety of factors, e.g. changes in protein binding and changes in fluid distribution. Therefore, it is likely that the present standard dosing regimens of isavuconazole lead to suboptimal outcomes for ICU patients, similar to observations made for fluconazole and echinocandins. Optimizing dosing regimens in ICU patients for existing antifungal agents such as isavuconazole is important to improve clinical outcome rates. To date, limited information on the pharmacokinetics of isavuconazole in critically ill patients is available and optimal dosing regimens remain uncertain. With this study we aim to describe isavuconazole pharmacokinetics in ICU admitted patients.
20 patients admitted to the ICU department and receiving isavuconazole as part of standard care for the treatment of fungal infections will be included in the study. Between day 3 and 7, 8 samples will be collected at t = 0 (pre-dose), and t = 0.5, 1, 2, 4, 6, 8 and 12 hours after end of infusion to obtain a PK curve. An optional, additional sample can be collected after discontinuation of isavuconazole therapy if possible. Total and free isavuconazole concentrations will be determined. A pharmacokinetic model will be fitted to the data from all individuals simultaneously. Data will be analysed using non-linear mixed effects modelling (NONMEM). NONMEM is a one-stage analysis that simultaneously estimates mean parameters, fixed effect parameters, interindividual variability, and residual random effects. Since allowance can be made for individual differences, this method can be used with both intensive sampling and sparse data (and in the occasion of missing values: an unbalanced number of data points per patients).
Primary objective:
- To determine the pharmacokinetics of isavuconazole given as treatment of invasive fungal infections in ICU patients as part of standard care.
Secondary objectives:
- To investigate the protein binding of isavuconazole in ICU patients and the variability in protein binding between patients in the ICU population.
- To explore if unbound isavuconazole concentrations can be predicted from total isavuconazole concentrations.
- To assess pharmacokinetic/pharmacodynamic target attainment in the ICU patient population.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Patients | – | –Patients admitted to the intensive care unit, treated with isavuconazole intravenously for treatment of invasive fungal infections |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Twenty ICU patients treated with isavuconazole for a fungal infection are eligible for inclusion. These patients are admitted to the ICU of Radboudumc and UZ Leuven. Since the objective is to evaluate the pharmacokinetics of isavuconazole in a real-life cohort of patients admitted to the ICU, exclusion criteria are minimal on purpose, to give a good reflection of this heterogenic cohort. The possible inclusion of patients with for example hepatic insufficiencies, continuous renal replacement therapy (CRRT), extracorporeal membrane oxygenation (ECMO) et cetera, is considered. High variability between subjects in this highly heterogenetic patient population is expected and will be considered in the analyses.
Key inclusion criteria (4 listed)
- Patient is admitted to an ICU
- Is treated with isavuconazole intravenously (iv)
- Subject is at least 18 years on the day of the first dosing
- Is managed with a central venous catheter or arterial line
Key exclusion criteria (1 listed)
- Patient has previously participated in this study
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Isavuconazole clearance in ICU patients.
Time frame: Day 3-7 after start of treatment and optional: 96-300 hours after discontinuation of treatment
Isavuconazole clearance in ICU patients in liters/hour. Full pharmacokinetic curves will be taken and an optional sample during the elimination phase of isavuconazole.
Isavuconazole volume of distribution in ICU patients
Time frame: Day 3-7 after start of treatment and optional: 96-300 hours after discontinuation of treatment
Isavuconazole volume of distribution in ICU patients in liters. Full pharmacokinetic curves will be taken and an optional sample during the elimination phase of isavuconazole.
3 secondary outcomes
Isavuconazole proteinbinding in ICU patients.
Time frame: Day 3-7 after start of treatment and optional: 96-300 hours after discontinuation of treatment
Predictability of unbound isavuconazole concentrations
Time frame: Day 3-7 after start of treatment and optional: 96-300 hours after discontinuation of treatment
Target attainment of isavuconazole in ICU patients
Time frame: At steady state (day 3-7 after start of treatment)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Oct 2022.
- Derived from this study: PubMed 37819503Jansen AME, Mertens B, Spriet I, Verweij PE, Schouten J, Wauters J, Debaveye Y, Ter Heine R, Bruggemann RJM. Population Pharmacokinetics of Total and Unbound Isavuconazole in Critically Ill Patients: Implications for Adaptive Dosing Strategies. Clin Pharmacokinet. 2023 Dec;62(12):1701-1711. doi: 10.1007/s40262-023-01305-8. Epub 2023 Oct 11.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
4 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Invasive Fungal Infections and Pharmacokinetics, run by Radboud University Medical Center at 4 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 26 Oct 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in Netherlands, Belgium. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Isavuconazole clearance in ICU patients. (time frame: Day 3-7 after start of treatment and optional: 96-300 hours after discontinuation of treatment). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04777058, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Oct 2022.