To deliver proof of concept that antifungal prophylaxis with posaconazole in addition to standard of care (SOC) can reduce the incidence of IAA in ICU patients with severe influenza, in comparison with SOC alone.To assess differences in cytokine…
ID
Source
Brief title
POSA-FLU
Condition
- Immunodeficiency syndromes
- Fungal infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The difference in IAA incidence at ICU discharge between the intervention and
control group.
Secondary outcome
- Time to IAA diagnosis
- Length of ICU stay
- Length of hospital stay
- Overall mortality
- 30-day mortality
- 90-day mortality
- Presence of markers of MAS in blood
- Cytokine production by peripheral blood mononuclear cells (Nijmegen site only)
- Reactive oxygen species (ROS) production by peripheral blood
polymorphonuclear cells/neutrophils (Nijmegen site only)
- Frequencies in single nucleotide polymorphisms/mutations in relevant genes
(Nijmegen site only)
Background summary
Invasive aspergillosis (IA) has classically been viewed as an opportunistic
infection in patients with specific forms of immunosuppression. Recently,
however, IA has been found to occur as a complication of influenza pneumonia in
patients admitted to the Intensive Care Unit (ICU) on account of respiratory
insufficiency due to their influenza pneumonia, a condition known as
influenza-associated aspergillosis (IAA). In the 2015/2016 influenza season, an
incidence of 16% of IAA was observed with a mortality rate of 61%, including
previously healthy patients. Furthermore, time to initiation of antifungal
therapy was significantly shorter in survivors versus non-survivors,
emphasizing the importance of early treatment. The antifungal drug posaconazole
is the drug of choice for antifungal prophylaxis in neutropenic patients with
acute myeloid leukaemia and patients with graft-versus-host disease after
allogeneic haematopoietic stem cell transplantation, effectively reducing the
incidence of IA. Therefore, we hypothesize that prophylactic use of
posaconazole can reduce the incidence of IAA in ICU patients admitted with
severe influenza pneumonia.
Study objective
To deliver proof of concept that antifungal prophylaxis with posaconazole in
addition to standard of care (SOC) can reduce the incidence of IAA in ICU
patients with severe influenza, in comparison with SOC alone.
To assess differences in cytokine production, reactive oxygen species (ROS)
production and frequencies in single nucleotide polymorphisms/mutations in
relevant genes between patients with severe influenza pneumonia who develop IAA
and those who do not develop IAA (Nijmegen site only). Furthermore, to assess
differences in presence of markers of macrophage activation syndrome (MAS)
between patients with severe influenza pneumonia who develop IAA and those who
do not develop IAA.
Study design
A phase IV, interventional, non-blinded, randomized controlled trial.
Intervention
The intervention group receives 300 mg posaconazole once daily intravenously
(after a loading dose of 300 mg twice daily) during 7 days, in addition to
standard of care (SOC). The control group receives SOC (including, but not
limited to, treatment with oseltamivir).
Study burden and risks
The risk classification is regarded as negligible to the patient population
receiving the study drug at the current regimens. The study drug has a market
authorisation. Patients will be assessed for the most common side effects,
including liver enzyme testing by drawing blood and performing
electrocardiography (ECG). For the pathophysiological portion of the study,
20-30 ml of blood sample will be collected once (Nijmegen site only). Before
inclusion, women of child-bearing age will undergo pregnancy testing in urine.
Liver enzyme, pregnancy testing and taking blood samples for the
pathophysiological portion of the study can probably be imbedded in standard of
care diagnostic work-up, leading to only a minimum of additional blood samples
taken as compared to routine standard of care. 30 and 90 days after inclusion,
patients will be contacted by telephone for follow-up. Potentially, patients
receiving study drug may experience benefit, if this and future studies
indicate that prophylactic use of posaconazole can reduce the incidence of IAA
in this group of patients.
Geert Grooteplein-Zuid 10
Nijmegen 6525 GA
NL
Geert Grooteplein-Zuid 10
Nijmegen 6525 GA
NL
Listed location countries
Age
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 in nasopharyngeal swab (NS), bronchial aspirate (BA) or broncho-alveolar lavage (BAL) fluid within 7 days prior to 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 means of PCR);
4. Influenza symptoms present for no more than 10 days prior to ICU admission;
5. Respiratory distress as the main reason for ICU admission. Respiratory distress will be defined as tachypnea with a respiratory rate >= 25/min. and a PaO2/FiO2 ratio <= 300 with or without (bilateral) infiltrates on radiographic chest studies
Exclusion criteria
1. Pregnant women (based on a positive serum sample);
2. Expected survival on ICU admission <= 48 hours;
3. Patients being transferred from another hospital ward or another hospital who already have mycological evidence of invasive aspergillosis (based on sputum, BA or BAL fluid culture; BAL fluid or serum galactomannan);
4. Patients with known intolerance of or hypersensitivity to posaconazole;
5. Patients actively treated with antifungal agents active against Aspergillus species;
6. Patients actively treated with rifampicin or rifabutin
7. Patients with a QTc interval >= 500 milliseconds on electrocardiography (ECG);
8. Patients with liver cirrhosis (Child-Pugh classification C);
9. Participation in another investigational clinical trial;
10. Any disorder which, in the investigator's opinion, might jeopardize subject's safety or compliance with the protocol
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-003270-14-NL |
| ClinicalTrials.gov | NCT03378479 |
| CCMO | NL64151.091.18 |