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

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based on the result of this BAL ((A) Aspergillus cultured from BAL, or (B) a galactomannan (GM)the patient will be withdrawn from the study and antifungal treatment will be started.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

Official Title
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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

Conditions
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Aspergillosis; Pulmonary, Invasive (Etiology)

Intervention / Treatment
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* Drug: SOC +Posaconazole 18 MG/ML (milligram/milliliter)
* Other: standard of care (SOC)


Participation Criteria
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Eligibility Criteria
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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 -

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: SOC + 'Posaconazole 18 MG/ML'<br>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)<br>* .2*300mg/d IV on day 1, followed by 1*300mg/d IV from day 2 for 7 days (total 7 days)<br>* Other names: Noxafil;Other: standard of care (SOC)<br>* treatment for influenza pneumonia at the investigators discretion<br>|
| Other: Standard of Care<br>standard of care treatment for influenza pneumonia (at the investigators discretion) | Other: standard of care (SOC)<br>* treatment for influenza pneumonia at the investigators discretion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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 IAA diagnosis | days to IAA 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 | admission days | from date of admission in hospital to date of discharge from hospital, approximately 25 days | 
| mortality | survival status | at day 30 and at day 90 | 
| identify changes in PK of posaconazole in critically ill patients | altered clearance of posaconazole in critically ill patients | from day 1 until day 7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Influenza