Posaconazole for the Prevention of Influenza-associated Aspergillosis in Critically Ill Patients

NCT ID: NCT03378479

Last Updated: 2025-04-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 88 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-12-27
• Study Completion Date: 2021-03-30

Brief Summary

The objective of this study is to deliver proof of concept that antifungal prophylaxis can reduce the incidence of Influenza Associated Aspergillosis (IAA) in ICU (intensive care unit) patients with severe influenza.

The investigators will perform an interventional non-blinded randomized controlled multicentric proof-of-concept study in patients with severe influenza admitted to the ICU. Patients will be randomized to the posaconazole prophylaxis group or to the SOC (standard of care) group. Oseltamivir will be started at the discretion of the investigator. Patients in the posaconazole group will receive posaconazole prophylaxis for 7 days.

addendum: pharmacokinetics of posaconazole as prophylaxis for invasive fungal disease on ICU

Detailed Description

Critically ill patients with PCR-confirmed influenza criteria) are eligible for inclusion in this study and will be randomized to or the posaconazole prophylaxis group or the SOC group.

If a patient is randomized to the posaconazole prophylaxis group, posaconazole (Noxafil, MSD) will be started intravenously from day 1 of randomization (2*300mg( milligram) /d on day 1, followed by 1*300mg/d from day 2 for 7 days) In both patient groups (prophylaxis and SOC) oseltamivir (non-IMP) will be started at the discretion of the treating physician from the first day of ICU admission as 2*150 mg/day for 10 days. If oseltamivir had already been started up before ICU admission, oseltamivir treatment will be continued up to a total of 10 days.

Within 48 hours after influenza diagnosis a bronchoscopy with BAL (bronchoalveolar lavage) and a serum galactomannan will be performed as part of routine ICU care in this type of patients. If an IAA-infection is suspected based on the result of this BAL ((A) Aspergillus cultured from BAL, or (B) a galactomannan (GM)the patient will be withdrawn from the study and antifungal treatment will be started.

addendum: Extensive PK sampling (UZ Leuven and Radboud): full PK curve on day 2 and day 5 (predose, 1.5; 2,3,4,6,8,10,12,18,24 h post infusion).

on non PK days, until day 7, predose sample. PK in BAL fluid only in patients with mechanical ventilation and when medically indicated.

Limited PK sampling: on day 2 and day 5: 1.5-3h, 4-8 h;8-12h; 12-24h post dose. on non PK days: PK pre dose.

Conditions

Aspergillosis; Pulmonary, Invasive (Etiology)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

SOC + 'Posaconazole 18 MG/ML'

standard of care (SOC) treatment for influenza pneumonia +posaconazole 2\*300mg/d IV on day 1, followed by 1\*300mg/d IV from day 2 for 7 days; vials containing 18mg posaconazole /mL, 300mg posaconazole/vial in total)

Group Type: OTHER

SOC +Posaconazole 18 MG/ML (milligram/milliliter)

Intervention Type: DRUG

.2\*300mg/d IV on day 1, followed by 1\*300mg/d IV from day 2 for 7 days (total 7 days)

standard of care (SOC)

Intervention Type: OTHER

treatment for influenza pneumonia at the investigators discretion

Standard of Care

standard of care treatment for influenza pneumonia (at the investigators discretion)

Group Type: OTHER

standard of care (SOC)

Intervention Type: OTHER

treatment for influenza pneumonia at the investigators discretion

Interventions

SOC +Posaconazole 18 MG/ML (milligram/milliliter)

.2\*300mg/d IV on day 1, followed by 1\*300mg/d IV from day 2 for 7 days (total 7 days)

Intervention Type: DRUG

standard of care (SOC)

treatment for influenza pneumonia at the investigators discretion

Intervention Type: OTHER

Other Intervention Names

Noxafil

Eligibility Criteria

Inclusion Criteria

1. Written informed consent must be obtained from the patient or his/her legal representative prior to any study procedures

2. Adult patient (≥ 18 years)

3. PCR-confirmed influenza based on nasopharyngeal swab (NS), bronchial aspirate (BA) or broncho-alveolar lavage (BAL) within 7 days before ICU admission or within 48 hours after ICU admission. If PCR is not available a positive result of a rapid test is required (a negative rapid test does not imply absence of influenza and thus requires confirmation by PCR)

4. Influenza symptoms present for no more than 10 days before ICU admission

5. Respiratory distress as the main reason for ICU admission. Respiratory distress will be defined as tachypnea with an respiratory rate ≥ 25x/min and a paO2/fiO2-ratio (fraction of inspired oxygen) ≤ 300 with or without (bilateral) infiltrates.

Exclusion Criteria

1. Patients with age < 18 years

2. Pregnant women (based on a positive serum sample)

3. Expected survival on ICU admission ≤ 48h

4. Patients having influenza symptoms for more than 10 days before ICU admission

5. Patients being transferred from another hospital ward or another hospital who already have mycological evidence for an IAA-infection (based on sputum, BA or BAL culture, BAL or serum GM)

6. Patients with known intolerance or hypersensitivity to posaconazole or other azole antifungal agents

7. Patients that are being treated actively with antifungal agents for invasive aspergillosis

8. Patients with a QTc (corrected QT interval) interval ≥500 msec

9. Patients with liver cirrhosis (Child C)

10. Participation in another interventional clinical trial -

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

Universitaire Ziekenhuizen KU Leuven

OTHER

Sponsor Role: lead

Responsible Party

Joost Wauters, prof. dr.

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Joost Wauters, Phd

Role: PRINCIPAL_INVESTIGATOR

UZ Leuven

Paul Verweij, Phd

Role: PRINCIPAL_INVESTIGATOR

Radboud University Medical Center

Locations

AZ Sint Jan

Bruges, , Belgium

UZ Gent

Ghent, , Belgium

UZ Leuven

Leuven, , Belgium

AZ Delta

Roeselare, , Belgium

CHU Lille

Lille, , France

Hospital Lariboisière

Paris, , France

Hospital Saint-Louis

Paris, , France

UMC Maastricht

Maastricht, , Netherlands

UMC Radboud

Nijmegen, , Netherlands

Canisius Wilhelmina Hospital

Nijmegen, , Netherlands

MC Erasmus

Rotterdam, , Netherlands

Elisabeth-TweeSteden Hospital

Tilburg, , Netherlands

Countries

Belgium; France; Netherlands

References

Elkayal O, Mertens B, Wauters J, Debaveye Y, Rijnders B, Verweij PE, Bruggemann RJ, Spriet I, Dreesen E. Dosing of IV posaconazole to treat critically ill patients with invasive pulmonary aspergillosis: a population pharmacokinetics modelling and simulation study. J Antimicrob Chemother. 2024 Jul 1;79(7):1645-1656. doi: 10.1093/jac/dkae160.

Reference Type: DERIVED

PMID: 38828958 (View on PubMed)

Vanderbeke L, Janssen NAF, Bergmans DCJJ, Bourgeois M, Buil JB, Debaveye Y, Depuydt P, Feys S, Hermans G, Hoiting O, van der Hoven B, Jacobs C, Lagrou K, Lemiale V, Lormans P, Maertens J, Meersseman P, Megarbane B, Nseir S, van Oers JAH, Reynders M, Rijnders BJA, Schouten JA, Spriet I, Thevissen K, Thille AW, Van Daele R, van de Veerdonk FL, Verweij PE, Wilmer A, Bruggemann RJM, Wauters J; Dutch-Belgian Mycosis Study Group. Posaconazole for prevention of invasive pulmonary aspergillosis in critically ill influenza patients (POSA-FLU): a randomised, open-label, proof-of-concept trial. Intensive Care Med. 2021 Jun;47(6):674-686. doi: 10.1007/s00134-021-06431-0. Epub 2021 May 29.

Reference Type: DERIVED

PMID: 34050768 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

POSA-FLU

Identifier Type: -

Identifier Source: org_study_id