Clinical trial NCT03378479: Posaconazole for the Prevention of Influenza-associated Aspergillosis in Critically Ill Patients
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
Overall status: COMPLETED
Phase: PHASE4
Conditions: Aspergillosis; Pulmonary, Invasive (Etiology)
Keywords: Influenza
Lead sponsor: Universitaire Ziekenhuizen KU Leuven
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2017-12-19
Enrollment: 88
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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 -

Primary outcomes:
measure: Number of Participants With IAA-infection at ICU Discharge
timeFrame: from date of admission in ICU assessed up to ICU discharge, approximately 21 days
Secondary outcomes:
measure: Time to IAPA Diagnosis
timeFrame: from date of inclusion to date of first sign/symptom of IAA infection, assessed up to ICU discharge, approximately 10 days
measure: Length of ICU Stay
timeFrame: from date of admission in ICU to date of discharge from ICU, approximately 20 days
measure: Length of Hospital Stay
timeFrame: from date of admission in hospital to date of discharge from hospital, approximately 25 days
measure: ICU Mortality - Number of Participant Deaths
timeFrame: At ICU discharge
measure: Hospital Mortality - Number of Participant Deaths
timeFrame: At hospital discharge
measure: 90-day Mortality - Number of Participant Deaths
timeFrame: At 90 days after ICU admission
Other outcomes:
Locations:
city: Brugge
country: Belgium
facility: AZ Sint Jan
city: Gent
country: Belgium
facility: UZ Gent
city: Leuven
country: Belgium
facility: UZ Leuven
city: Roeselare
country: Belgium
facility: AZ Delta
city: Lille
country: France
facility: CHU Lille
city: Paris
country: France
facility: Hospital Lariboisière
city: Paris
country: France
facility: Hospital Saint-Louis
city: Maastricht
country: Netherlands
facility: UMC Maastricht
city: Nijmegen
country: Netherlands
facility: UMC Radboud
city: Nijmegen
country: Netherlands
facility: Canisius Wilhelmina Hospital
city: Rotterdam
country: Netherlands
facility: MC Erasmus
city: Tilburg
country: Netherlands
facility: Elisabeth-TweeSteden Hospital
Study officials:
affiliation: UZ Leuven
name: Joost Wauters, Phd
role: PRINCIPAL_INVESTIGATOR
affiliation: Radboud University Medical Center
name: Paul Verweij, Phd
role: PRINCIPAL_INVESTIGATOR
References:
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.