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

Primary Purpose

Aspergillosis; Pulmonary, Invasive (Etiology)

Status
Completed
Phase
Phase 4
Locations
International
Study Type
Interventional
Intervention
SOC +Posaconazole 18 MG/ML (milligram/milliliter)
standard of care (SOC)
Sponsored by
Universitaire Ziekenhuizen KU Leuven
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Aspergillosis; Pulmonary, Invasive (Etiology) focused on measuring Influenza

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 -

Sites / Locations

  • AZ Sint Jan
  • UZ Gent
  • UZ Leuven
  • AZ Delta
  • Universitair Medisch Centrum
  • UMC Radboud
  • MC Erasmus

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Other

Arm Label

SOC + 'Posaconazole 18 MG/ML'

Standard of Care

Arm Description

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)

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

Outcomes

Primary Outcome Measures

The incidence of 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

Secondary Outcome Measures

Time to IAA diagnosis
days to IAA diagnosis
length of ICU stay
amount of days at ICU
length of hospital stay
admission days
mortality
survival status
identify changes in PK of posaconazole in critically ill patients
altered clearance of posaconazole in critically ill patients

Full Information

First Posted
October 30, 2017
Last Updated
June 29, 2022
Sponsor
Universitaire Ziekenhuizen KU Leuven
Collaborators
Merck Sharp & Dohme LLC
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1. Study Identification

Unique Protocol Identification Number
NCT03378479
Brief Title
Posaconazole for the Prevention of Influenza-associated Aspergillosis in Critically Ill Patients
Acronym
POSA-FLU
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
June 2022
Overall Recruitment Status
Completed
Study Start Date
December 27, 2017 (Actual)
Primary Completion Date
March 31, 2020 (Actual)
Study Completion Date
March 30, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Universitaire Ziekenhuizen KU Leuven
Collaborators
Merck Sharp & Dohme LLC

4. Oversight

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
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Aspergillosis; Pulmonary, Invasive (Etiology)
Keywords
Influenza

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
88 (Actual)

8. Arms, Groups, and Interventions

Arm Title
SOC + 'Posaconazole 18 MG/ML'
Arm Type
Other
Arm Description
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)
Arm Title
Standard of Care
Arm Type
Other
Arm Description
standard of care treatment for influenza pneumonia (at the investigators discretion)
Intervention Type
Drug
Intervention Name(s)
SOC +Posaconazole 18 MG/ML (milligram/milliliter)
Other Intervention Name(s)
Noxafil
Intervention Description
.2*300mg/d IV on day 1, followed by 1*300mg/d IV from day 2 for 7 days (total 7 days)
Intervention Type
Other
Intervention Name(s)
standard of care (SOC)
Intervention Description
treatment for influenza pneumonia at the investigators discretion
Primary Outcome Measure Information:
Title
The incidence of IAA-infection at ICU discharge
Description
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
Time Frame
from date of admission in ICU assessed up to ICU discharge, approximately 21 days
Secondary Outcome Measure Information:
Title
Time to IAA diagnosis
Description
days to IAA diagnosis
Time Frame
from date of inclusion to date of first sign/symptom of IAA infection, assessed up to ICU discharge, approximately 10 days
Title
length of ICU stay
Description
amount of days at ICU
Time Frame
from date of admission in ICU to date of discharge from ICU, approximately 20 days
Title
length of hospital stay
Description
admission days
Time Frame
from date of admission in hospital to date of discharge from hospital, approximately 25 days
Title
mortality
Description
survival status
Time Frame
at day 30 and at day 90
Title
identify changes in PK of posaconazole in critically ill patients
Description
altered clearance of posaconazole in critically ill patients
Time Frame
from day 1 until day 7

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Written informed consent must be obtained from the patient or his/her legal representative prior to any study procedures Adult patient (≥ 18 years) 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) Influenza symptoms present for no more than 10 days before ICU admission 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: Patients with age < 18 years Pregnant women (based on a positive serum sample) Expected survival on ICU admission ≤ 48h Patients having influenza symptoms for more than 10 days before ICU admission 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) Patients with known intolerance or hypersensitivity to posaconazole or other azole antifungal agents Patients that are being treated actively with antifungal agents for invasive aspergillosis Patients with a QTc (corrected QT interval) interval ≥500 msec Patients with liver cirrhosis (Child C) Participation in another interventional clinical trial -
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Joost Wauters, Phd
Organizational Affiliation
UZ Leuven
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Paul Verweij, Phd
Organizational Affiliation
Radboud University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
AZ Sint Jan
City
Brugge
ZIP/Postal Code
8000
Country
Belgium
Facility Name
UZ Gent
City
Gent
ZIP/Postal Code
9000
Country
Belgium
Facility Name
UZ Leuven
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Facility Name
AZ Delta
City
Roeselare
ZIP/Postal Code
8800
Country
Belgium
Facility Name
Universitair Medisch Centrum
City
Groningen
Country
Netherlands
Facility Name
UMC Radboud
City
Nijmegen
ZIP/Postal Code
6500
Country
Netherlands
Facility Name
MC Erasmus
City
Rotterdam
ZIP/Postal Code
3015
Country
Netherlands

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
34050768
Citation
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.
Results Reference
derived

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

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