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| Name | Class |
|---|---|
| Merck Sharp & Dohme LLC | INDUSTRY |
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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
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based on the result of this BAL ((A) Aspergillus cultured from BAL, or (B) a galactomannan (GM)the patient will be withdrawn from the study and antifungal treatment will be started.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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| SOC + 'Posaconazole 18 MG/ML' | Other | 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 | Other | standard of care treatment for influenza pneumonia (at the investigators discretion) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| SOC +Posaconazole 18 MG/ML (milligram/milliliter) | Drug | .2*300mg/d IV on day 1, followed by 1*300mg/d IV from day 2 for 7 days (total 7 days) |
|
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Joost Wauters, Phd | UZ Leuven | Principal Investigator |
| Paul Verweij, Phd | Radboud University Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| AZ Sint Jan | Bruges | 8000 | Belgium | |||
| UZ Gent |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38828958 | Derived | Elkayal O, Mertens B, Wauters J, Debaveye Y, Rijnders B, Verweij PE, Bruggemann RJ, Spriet I, Dreesen E. Dosing of IV posaconazole to treat critically ill patients with invasive pulmonary aspergillosis: a population pharmacokinetics modelling and simulation study. J Antimicrob Chemother. 2024 Jul 1;79(7):1645-1656. doi: 10.1093/jac/dkae160. | |
| 34050768 |
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| ID | Title | Description |
|---|---|---|
| FG000 | SOC + 'Posaconazole 18 Milligram/Milliliter' | standard of care (SOC) treatment for influenza pneumonia +posaconazole 2*300mg/d intravenously (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) 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) standard of care (SOC): treatment for influenza pneumonia at the investigators discretion |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jan 3, 2018 |
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|
| standard of care (SOC) | Other | treatment for influenza pneumonia at the investigators discretion |
|
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 |
| Ghent |
| 9000 |
| Belgium |
| UZ Leuven | Leuven | 3000 | Belgium |
| AZ Delta | Roeselare | 8800 | Belgium |
| CHU Lille | Lille | 59000 | France |
| Hospital Lariboisière | Paris | 75010 | France |
| Hospital Saint-Louis | Paris | 75010 | France |
| UMC Maastricht | Maastricht | 6229 | Netherlands |
| UMC Radboud | Nijmegen | 6500 | Netherlands |
| Canisius Wilhelmina Hospital | Nijmegen | 6532 | Netherlands |
| MC Erasmus | Rotterdam | 3015 | Netherlands |
| Elisabeth-TweeSteden Hospital | Tilburg | 5042 | Netherlands |
| 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. |
| FG001 | Standard of Care | standard of care treatment for influenza pneumonia (at the investigators discretion) standard of care (SOC): treatment for influenza pneumonia at the investigators discretion |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | 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) 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) standard of care (SOC): treatment for influenza pneumonia at the investigators discretion |
| BG001 | Standard of Care | standard of care treatment for influenza pneumonia (at the investigators discretion) standard of care (SOC): treatment for influenza pneumonia at the investigators discretion |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
| ||||||||||||||||||
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||||
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||||
| Region of Enrollment | Number | participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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 | Posted | Count of Participants | Participants | from date of admission in ICU assessed up to ICU discharge, approximately 21 days |
|
|
| ||||||||||||||||||||||||||||||
| Secondary | Time to IAPA Diagnosis | Days to influenza-associated pulmonary aspergillosis (IAPA) diagnosis | Calculated for the patients with IAPA 2 patients in SOC + 'Posaconazole 18 mg/ml' group 4 patients in SOC group | Posted | Median | Inter-Quartile Range | days | from date of inclusion to date of first sign/symptom of IAA infection, assessed up to ICU discharge, approximately 10 days |
|
| |||||||||||||||||||||||||||||
| Secondary | Length of ICU Stay | amount of days at ICU | Length of stay was defined as the time to discharge alive, while death was considered as a competing event. 7 patients died in SOC + POS group (37-7=30) 9 patient died in SOC group (36-9=27) | Posted | Median | Inter-Quartile Range | days | from date of admission in ICU to date of discharge from ICU, approximately 20 days |
|
| |||||||||||||||||||||||||||||
| Secondary | Length of Hospital Stay | Number of days in the hospital | Length of stay was defined as the time to discharge alive, while death was considered as a competing event. 9 patients died in SOC + POS group (37-9=28) 11 patients died in SOC group (37-11=25) | Posted | Median | Inter-Quartile Range | days | from date of admission in hospital to date of discharge from hospital, approximately 25 days |
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| |||||||||||||||||||||||||||||
| Secondary | ICU Mortality - Number of Participant Deaths | survival status | Posted | Count of Participants | Participants | At ICU discharge |
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| Secondary | Hospital Mortality - Number of Participant Deaths | Survival status at hospital discharge | Posted | Count of Participants | Participants | At hospital discharge |
|
| |||||||||||||||||||||||||||||||
| Secondary | 90-day Mortality - Number of Participant Deaths | Survival status at 90 days after ICU admission | Posted | Count of Participants | Participants | At 90 days after ICU admission |
|
|
90 days after ICU admission
Adverse events at the ICU department are very hard to define. SAE were documented. Other [Not Including Serious] Adverse Events were not monitored/assessed.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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) 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) standard of care (SOC): treatment for influenza pneumonia at the investigators discretion | 9 | 37 | 9 | 37 | 0 | 0 |
| EG001 | Standard of Care | standard of care treatment for influenza pneumonia (at the investigators discretion) standard of care (SOC): treatment for influenza pneumonia at the investigators discretion | 11 | 36 | 11 | 36 | 0 | 0 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Death | Infections and infestations | CTCAE (5.0) | Non-systematic Assessment | Not related to the study-medication |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Explanation | Infections and infestations | CTCAE (5.0) | Non-systematic Assessment | No AEs were reported due to the ICU setting, as patients admitted to the ICU are critically ill. It is not feasible to record AEs unrelated to the study under such circumstances. |
|
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Prof. Dr. Joost Wauters - Intensivist | UZ Leuven | 016344275 | joost.wauters@uzleuven.be |
| Jun 30, 2022 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D001228 | Aspergillosis |
| D007251 | Influenza, Human |
| ID | Term |
|---|---|
| D009181 | Mycoses |
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |
| D012141 | Respiratory Tract Infections |
| D009976 | Orthomyxoviridae Infections |
| D012327 | RNA Virus Infections |
| D014777 | Virus Diseases |
| D012140 | Respiratory Tract Diseases |
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| ID | Term |
|---|---|
| D008274 | Magnesium |
| C101425 | posaconazole |
| D059039 | Standard of Care |
| ID | Term |
|---|---|
| D008673 | Metals, Alkaline Earth |
| D004602 | Elements |
| D007287 | Inorganic Chemicals |
| D019565 | Metals, Light |
| D008670 | Metals |
| D019984 | Quality Indicators, Health Care |
| D011787 | Quality of Health Care |
| D006298 | Health Services Administration |
| D017530 | Health Care Quality, Access, and Evaluation |
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| >=65 years |
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| Male |
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| Not Hispanic or Latino |
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| Unknown or Not Reported |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| Belgium |
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| France |
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