Posaconazole for the Prevention of Influenza-associated Aspergillosis in Critically Ill Patients (POSA-FLU)

A Phase iv, Interventional, Non-blinded, Randomized Controlled Multicenter Study of Posaconazole Prophylaxis for the Prevention of Influenza-associated Aspergillosis (IAA) in Critically Ill Patients

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

Study Overview

• Status: Completed
• Conditions: Aspergillosis; Pulmonary, Invasive (Etiology)
• Intervention / Treatment: Drug: SOC +Posaconazole 18 MG/ML (milligram/milliliter); Other: standard of care (SOC)

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based on the result of this BAL ((A) Aspergillus cultured from BAL, or (B) a galactomannan (GM)the patient will be withdrawn from the study and antifungal treatment will be started.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.

• Study Type: Interventional
• Enrollment (Actual): 88
• Phase: Phase 4

Contacts and Locations

Study Locations

• Belgium
  • Brugge, Belgium, 8000
    • AZ Sint Jan
  • Gent, Belgium, 9000
    • UZ Gent
  • Leuven, Belgium, 3000
    • UZ Leuven
  • Roeselare, Belgium, 8800
    • AZ Delta
• France
  • Lille, France, 59000
    • Chu Lille
  • Paris, France, 75010
    • Hospital Saint-Louis
  • Paris, France, 75010
    • Hospital Lariboisière
• Netherlands
  • Maastricht, Netherlands, 6229
    • UMC Maastricht
  • Nijmegen, Netherlands, 6500
    • UMC Radboud
  • Nijmegen, Netherlands, 6532
    • Canisius Wilhelmina Hospital
  • Rotterdam, Netherlands, 3015
    • MC Erasmus
  • Tilburg, Netherlands, 5042
    • Elisabeth-Tweesteden Hospital

Participation Criteria

Eligibility Criteria

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

Description

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 -

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: 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)	Drug: 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); Other Names: Noxafil; Other: standard of care (SOC); treatment for influenza pneumonia at the investigators discretion
Other: Standard of Care; standard of care treatment for influenza pneumonia (at the investigators discretion)	Other: standard of care (SOC); treatment for influenza pneumonia at the investigators discretion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With IAA-infection at ICU Discharge	A patient with IAA-infection is defined as a patient having mycological evidence of Aspergillus and at least one Aspergillus compatible sign or symptom and radiological abnormalities	from date of admission in ICU assessed up to ICU discharge, approximately 21 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to IAPA Diagnosis	Days to influenza-associated pulmonary aspergillosis (IAPA) diagnosis	from date of inclusion to date of first sign/symptom of IAA infection, assessed up to ICU discharge, approximately 10 days
Length of ICU Stay	amount of days at ICU	from date of admission in ICU to date of discharge from ICU, approximately 20 days
Length of Hospital Stay	Number of days in the hospital	from date of admission in hospital to date of discharge from hospital, approximately 25 days
ICU Mortality - Number of Participant Deaths	survival status	At ICU discharge
Hospital Mortality - Number of Participant Deaths	Survival status at hospital discharge	At hospital discharge
90-day Mortality - Number of Participant Deaths	Survival status at 90 days after ICU admission	At 90 days after ICU admission

Collaborators and Investigators

• Sponsor: Universitaire Ziekenhuizen KU Leuven
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Joost Wauters, PhD, UZ Leuven; Principal Investigator: Paul Verweij, Phd, Radboud University Medical Center

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 27, 2017
• Primary Completion (Actual): March 31, 2020
• Study Completion (Actual): March 30, 2021

Study Registration Dates

• First Submitted: October 30, 2017
• First Submitted That Met QC Criteria: December 18, 2017
• First Posted (Actual): December 19, 2017

Study Record Updates

• Last Update Posted (Actual): April 8, 2025
• Last Update Submitted That Met QC Criteria: March 25, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Influenza
• Additional Relevant MeSH Terms: Respiratory Tract Infections; Infections; Orthomyxoviridae Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Bacterial Infections and Mycoses; Mycoses; Influenza, Human; Aspergillosis; Anti-Infective Agents; Antifungal Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones, Hormone Substitutes, and Hormone Antagonists; Enzyme Inhibitors; Steroid Synthesis Inhibitors; Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; 14-alpha Demethylase Inhibitors; Trypanocidal Agents; Posaconazole
• Other Study ID Numbers: POSA-FLU

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

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.: No