Aspergillosis; Pulmonary, Invasive (Etiology)
Conditions
Keywords
Influenza
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based on the result of this BAL ((A) Aspergillus cultured from BAL, or (B) a galactomannan (GM)the patient will be withdrawn from the study and antifungal treatment will be started.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.
Interventions
DRUGSOC +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)
OTHERstandard of care (SOC)
treatment for influenza pneumonia at the investigators discretion
Sponsors
Merck Sharp & Dohme LLC
Universitaire Ziekenhuizen KU Leuven
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 -
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With IAA-infection at ICU Discharge | 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
| Measure | Time frame | Description |
|---|---|---|
| Length of ICU Stay | from date of admission in ICU to date of discharge from ICU, approximately 20 days | amount of days at ICU |
| Length of Hospital Stay | from date of admission in hospital to date of discharge from hospital, approximately 25 days | Number of days in the hospital |
| Time to IAPA Diagnosis | from date of inclusion to date of first sign/symptom of IAA infection, assessed up to ICU discharge, approximately 10 days | Days to influenza-associated pulmonary aspergillosis (IAPA) diagnosis |
| Hospital Mortality - Number of Participant Deaths | At hospital discharge | Survival status at hospital discharge |
| 90-day Mortality - Number of Participant Deaths | At 90 days after ICU admission | Survival status at 90 days after ICU admission |
| ICU Mortality - Number of Participant Deaths | At ICU discharge | survival status |
Countries
Belgium, France, Netherlands
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 | 37 |
| 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 | 36 |
| Total | 73 |
Baseline characteristics
| Characteristic | SOC + 'Posaconazole 18 MG/ML' | Standard of Care | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 12 Participants | 16 Participants | 28 Participants |
| Age, Categorical Between 18 and 65 years | 25 Participants | 20 Participants | 45 Participants |
| Age, Continuous | 59 years STANDARD_DEVIATION 16 | 63 years STANDARD_DEVIATION 15 | 61 years STANDARD_DEVIATION 15 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 37 Participants | 36 Participants | 73 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 11 Participants | 9 Participants | 20 Participants |
| Race (NIH/OMB) White | 25 Participants | 25 Participants | 50 Participants |
| Region of Enrollment Belgium | 34 participants | 27 participants | 61 participants |
| Region of Enrollment France | 2 participants | 5 participants | 7 participants |
| Region of Enrollment Netherlands | 1 participants | 4 participants | 5 participants |
| Sex: Female, Male Female | 14 Participants | 18 Participants | 32 Participants |
| Sex: Female, Male Male | 23 Participants | 18 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 9 / 37 | 11 / 36 |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 9 / 37 | 11 / 36 |
Outcome results
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
Time frame: from date of admission in ICU assessed up to ICU discharge, approximately 21 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SOC + 'Posaconazole 18 MG/ML' | Number of Participants With IAA-infection at ICU Discharge | 2 Participants |
| Standard of Care | Number of Participants With IAA-infection at ICU Discharge | 4 Participants |
Secondary
90-day Mortality - Number of Participant Deaths
Survival status at 90 days after ICU admission
Time frame: At 90 days after ICU admission
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SOC + 'Posaconazole 18 MG/ML' | 90-day Mortality - Number of Participant Deaths | 9 Participants |
| Standard of Care | 90-day Mortality - Number of Participant Deaths | 11 Participants |
Secondary
Hospital Mortality - Number of Participant Deaths
Survival status at hospital discharge
Time frame: At hospital discharge
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SOC + 'Posaconazole 18 MG/ML' | Hospital Mortality - Number of Participant Deaths | 8 Participants |
| Standard of Care | Hospital Mortality - Number of Participant Deaths | 10 Participants |
Secondary
ICU Mortality - Number of Participant Deaths
survival status
Time frame: At ICU discharge
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SOC + 'Posaconazole 18 MG/ML' | ICU Mortality - Number of Participant Deaths | 7 Participants |
| Standard of Care | ICU Mortality - Number of Participant Deaths | 9 Participants |
Secondary
Length of Hospital Stay
Number of days in the hospital
Time frame: from date of admission in hospital to date of discharge from hospital, approximately 25 days
Population: 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)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| SOC + 'Posaconazole 18 MG/ML' | Length of Hospital Stay | 25 days |
| Standard of Care | Length of Hospital Stay | 12 days |
Secondary
Length of ICU Stay
amount of days at ICU
Time frame: from date of admission in ICU to date of discharge from ICU, approximately 20 days
Population: 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)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| SOC + 'Posaconazole 18 MG/ML' | Length of ICU Stay | 16 days |
| Standard of Care | Length of ICU Stay | 6 days |
Secondary
Time to IAPA Diagnosis
Days to influenza-associated pulmonary aspergillosis (IAPA) diagnosis
Time frame: from date of inclusion to date of first sign/symptom of IAA infection, assessed up to ICU discharge, approximately 10 days
Population: Calculated for the patients with IAPA 2 patients in SOC + 'Posaconazole 18 mg/ml' group 4 patients in SOC group
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| SOC + 'Posaconazole 18 MG/ML' | Time to IAPA Diagnosis | 10 days |
| Standard of Care | Time to IAPA Diagnosis | 5 days |