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

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ClinicalTrials.gov Identifier: NCT03378479
Recruitment Status : Recruiting
First Posted : December 19, 2017
Last Update Posted : December 10, 2018
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Joost Wauters, prof. dr., Universitaire Ziekenhuizen Leuven

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


Condition or disease Intervention/treatment Phase
Aspergillosis; Pulmonary, Invasive (Etiology) Drug: SOC +Posaconazole 18 MG/ML (milligram/milliliter) Other: standard of care (SOC) Phase 4

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  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
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
Actual Study Start Date : December 27, 2017
Estimated Primary Completion Date : March 30, 2019
Estimated Study Completion Date : March 30, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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 Name: Noxafil

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

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




Primary Outcome Measures :
  1. The incidence of IAA-infection at ICU discharge [ Time Frame: from date of admission in ICU assessed up to ICU discharge, approximately 21 days ]
    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 :
  1. Time 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 ]
    days to IAA diagnosis

  2. length of ICU stay [ Time Frame: from date of admission in ICU to date of discharge from ICU, approximately 20 days ]
    amount of days at ICU

  3. length of hospital stay [ Time Frame: from date of admission in hospital to date of discharge from hospital, approximately 25 days ]
    admission days

  4. mortality [ Time Frame: at day 30 and at day 90 ]
    survival status

  5. identify changes in PK of posaconazole in critically ill patients [ Time Frame: from day 1 until day 7 ]
    altered clearance of posaconazole in critically ill patients



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 -

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03378479


Contacts
Contact: Joost Wauters, Phd +32 16 344275 joost.wauters@uzleuven.be
Contact: Paul Verweij, Phd +31 24 3614356 paul.verweij@radboudumc.nl

Locations
Belgium
AZ Sint Jan Recruiting
Brugge, Belgium, 8000
Contact: Marc Bourgeois, Phd       marc.bourgeois@azsintjan.be   
UZ Gent Recruiting
Gent, Belgium, 9000
Contact: Pieter Depuydt, Phd         
Contact       pieter.depuydt@uzgent.be   
UZ Leuven Recruiting
Leuven, Belgium, 3000
Contact: Joost Wauters, Phd       joost.wauters@uzleuven.be   
AZ Delta Recruiting
Roeselare, Belgium, 8800
Contact: Piet Lormans, PhD    +3251237039    piet.lormans@azdelta.be   
Netherlands
Universitair Medisch Centrum Not yet recruiting
Groningen, Netherlands
Contact: Greetje A Kampinga, Phd       g.a.kampinga@umcg.nl   
UMC Radboud Not yet recruiting
Nijmegen, Netherlands, 6500
Contact: Paul Verweij, Phd    +31-24-3614356    Paul.verweij@radboudumc.nl   
MC Erasmus Not yet recruiting
Rotterdam, Netherlands, 3015
Contact: Bart Rijnders, Phd       b.rijnders@erasmusmc.nl   
Sponsors and Collaborators
Universitaire Ziekenhuizen Leuven
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Joost Wauters, Phd UZ Leuven
Principal Investigator: Paul Verweij, Phd Radboud UMC

Responsible Party: Joost Wauters, prof. dr., Principal Investigator, Universitaire Ziekenhuizen Leuven
ClinicalTrials.gov Identifier: NCT03378479     History of Changes
Other Study ID Numbers: POSA-FLU
First Posted: December 19, 2017    Key Record Dates
Last Update Posted: December 10, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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

Keywords provided by Joost Wauters, prof. dr., Universitaire Ziekenhuizen Leuven:
Influenza

Additional relevant MeSH terms:
Aspergillosis
Influenza, Human
Critical Illness
Orthomyxoviridae Infections
RNA Virus Infections
Virus Diseases
Respiratory Tract Infections
Respiratory Tract Diseases
Disease Attributes
Pathologic Processes
Mycoses
Hyalohyphomycosis
Dermatomycoses
Lung Diseases, Fungal
Skin Diseases, Infectious
Skin Diseases
Posaconazole
Antifungal Agents
Anti-Infective Agents
Trypanocidal Agents
Antiprotozoal Agents
Antiparasitic Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Steroid Synthesis Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs