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    Clinical Trial Results:
    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

    Summary
    EudraCT number
    		 2017-003270-14
    Trial protocol
    		 BE   NL   FR  
    Global end of trial date
    14 Jun 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Jul 2022
    First version publication date
    15 Jul 2022
    Other versions
    Summary report(s)
    		 Posaconazole for prevention of invasive pulmonary aspergillosis in critically ill influenza patients (POSA‑FLU): a randomised, open‑label, proof‑of‑concept trial

    Trial information

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    Trial identification
    Sponsor protocol code
    POSA-FLU
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03378479
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UZ Leuven
    Sponsor organisation address
    Herestraat 49, Leuven, Belgium, 3000
    Public contact
    Prof. Dr. Joost Wauters, UZ Leuven, joost.wauters@uzleuven.be
    Scientific contact
    Prof. Dr. Joost Wauters, UZ Leuven, joost.wauters@uzleuven.be
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Jun 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Jun 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Influenza-associated pulmonary aspergillosis (IAPA) is a frequent complication in critically ill influenza patients, associated with significant mortality. We investigated whether antifungal prophylaxis reduces the incidence of IAPA.
    Protection of trial subjects
    The Principal Investigator (PI) retains overall responsibility for the informed consent of participants at their site and must ensure that any person delegated responsibility to participate in the informed consent process is duly authorised, trained and competent to participate according to the ethically approved protocol, principles of Good Clinical Practice (GCP) and Declaration of Helsinki. Informed consent must be obtained prior to the participant undergoing procedures that are specifically for the purposes of the trial and are out-with standard routine care at the participating site (including the collection of identifiable participant). The right of a participant to refuse participation without giving reasons must be respected. The participant must remain free to withdraw at any time from the trial without giving reasons and without prejudicing his/her further treatment and must be provided with a contact point where he/she may obtain further information about the trial. Where a participant is required to re-consent or new information is required to be provided to a participant, it is the responsibility of the PI to ensure this is done in a timely manner. The PI takes responsibility for ensuring that all vulnerable subjects are protected and participate voluntarily in an environment free from coercion or undue influence. Where the participant population is likely to include a significant proportion of participants who cannot read or write, require translators or have cognitive impairment, appropriate alternative methods for supporting the informed consent process should be employed. This may include allowing a witness to sign on a participant’s behalf (in the case of problems with reading or writing), designate a legal representative , or providing Participant Information Sheets in other languages or in a format easily understood by the participant population (in the case of minors or cognitive impairment) providing they are approved by the EC.
    Background therapy
    		 Oseltamivir (non-IMP) will be started at the discretion of the treating physician from the first day of ICU admission as 2x150mg for a duration of 10 days.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Dec 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 3 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 11
    Country: Number of subjects enrolled
    Belgium: 69
    Country: Number of subjects enrolled
    France: 8
    Worldwide total number of subjects
    88
    EEA total number of subjects
    88
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    56
    From 65 to 84 years
    26
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients admitted to intensive care unit (ICU) with a severe influenza pneumonia will be screened. When all eligibility criteria are met, the principle investigator (PI) or the treating physician will approach the patient or his/her relatives in order to give study information and request informed consent.

    Pre-assignment
    Screening details
    		 After eligibility screening, the following screening assessments will be done: - Patient demographics and baseline parameters - Medical History

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Posaconazole prophylaxis group + standard-of-care
    Arm description
    		 Posaconazole (Noxafil) will be started intravenously from day 1 of randomisation (2x300mg on day 1, followed by 1x300mg from day 2 for 7 days). Noxafil concentrate injections (vials made of type I glass containing 18mg posaconazole/mL, 300mg posaconazole/vial in total) for intravenous use will be provided by MSD.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Posaconazole, noxafil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    2x300mg on day 1 1x300mg on day 2 for 7 days Intravenously

    Arm title
    		 Standard-of-care
    Arm description
    		 The treating physician can decide to perform an additional bronchoscopy with BAL between day 2 after randomisation and ICU discharge in case of respiratory deterioration and clinical suspicion of an IAA-infection. Any bronchoscopy will only be performed if the safety of the patient will not be compromised. In case of positive mycological evidence of an IAA-infection, a CT thorax without IV contrast is performed if possible. If an IAA-infection is documented, antifungal treatment will be started and - in case the IAA-infection is diagnosed before the ending of the study drug - the patient will be withdrawn from the study. Again, type and duration of antifungal therapy will be at the discretion of the treating physician. Oseltamivir will be started at the discretion of the treating physician from the first day of ICU admission as 2x150 mg/day for a duration of 10 days. If oseltamivir had already been started up before ICU admission, oseltamivir treatment will be continued up to 10 days
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Posaconazole prophylaxis group + standard-of-care Standard-of-care
    Started
    43
    45
    Completed
    37
    36
    Not completed
    6
    9
         IAPA at ICU admission
    6
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 Overall

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 88 88
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 56 56
        From 65-84 years
    		 26 26
        85 years and over
    		 6 6
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61 ± 15 -
    Gender categorical
    Units: Subjects
        Female
    		 38 38
        Male
    		 50 50

    End points

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    End points reporting groups
    Reporting group title
    Posaconazole prophylaxis group + standard-of-care
    Reporting group description
    		 Posaconazole (Noxafil) will be started intravenously from day 1 of randomisation (2x300mg on day 1, followed by 1x300mg from day 2 for 7 days). Noxafil concentrate injections (vials made of type I glass containing 18mg posaconazole/mL, 300mg posaconazole/vial in total) for intravenous use will be provided by MSD.

    Reporting group title
    Standard-of-care
    Reporting group description
    		 The treating physician can decide to perform an additional bronchoscopy with BAL between day 2 after randomisation and ICU discharge in case of respiratory deterioration and clinical suspicion of an IAA-infection. Any bronchoscopy will only be performed if the safety of the patient will not be compromised. In case of positive mycological evidence of an IAA-infection, a CT thorax without IV contrast is performed if possible. If an IAA-infection is documented, antifungal treatment will be started and - in case the IAA-infection is diagnosed before the ending of the study drug - the patient will be withdrawn from the study. Again, type and duration of antifungal therapy will be at the discretion of the treating physician. Oseltamivir will be started at the discretion of the treating physician from the first day of ICU admission as 2x150 mg/day for a duration of 10 days. If oseltamivir had already been started up before ICU admission, oseltamivir treatment will be continued up to 10 days

    Primary: IAPA incidence

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    End point title
    		 IAPA incidence
    End point description
    End point type
    Primary
    End point timeframe
    During ICU stay
    End point values
    		 Posaconazole prophylaxis group + standard-of-care Standard-of-care
    Number of subjects analysed
    37
    36
    Units: number of patients
        number (not applicable)
    2
    4
    Statistical analysis title
    		 One-sided Fisher's Exact test
    Comparison groups
    Posaconazole prophylaxis group + standard-of-care v Standard-of-care
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05 [1]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [1] - Significance was defined as p values <0.05

    Secondary: Time to IAPA diagnosis

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    End point title
    		 Time to IAPA diagnosis
    End point description
    End point type
    Secondary
    End point timeframe
    Time to IAPA diagnosis
    End point values
    		 Posaconazole prophylaxis group + standard-of-care Standard-of-care
    Number of subjects analysed
    37
    36
    Units: days
        median (inter-quartile range (Q1-Q3))
    10 (8 to 12)
    5 (3 to 8)
    No statistical analyses for this end point

    Secondary: Length of ICU stay

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    End point title
    		 Length of ICU stay
    End point description
    End point type
    Secondary
    End point timeframe
    Length of ICU stay
    End point values
    		 Posaconazole prophylaxis group + standard-of-care Standard-of-care
    Number of subjects analysed
    30
    27
    Units: days
        median (inter-quartile range (Q1-Q3))
    16 (8 to 29)
    6 (3 to 12)
    No statistical analyses for this end point

    Secondary: Length of hospital stay

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    End point title
    		 Length of hospital stay
    End point description
    End point type
    Secondary
    End point timeframe
    Length of hospital stay
    End point values
    		 Posaconazole prophylaxis group + standard-of-care Standard-of-care
    Number of subjects analysed
    28
    25
    Units: days
        median (inter-quartile range (Q1-Q3))
    25 (18 to 45)
    12 (9 to 35)
    No statistical analyses for this end point

    Secondary: ICU mortality

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    End point title
    		 ICU mortality
    End point description
    End point type
    Secondary
    End point timeframe
    ICU mortality
    End point values
    		 Posaconazole prophylaxis group + standard-of-care Standard-of-care
    Number of subjects analysed
    37
    36
    Units: Number of patients
        number (not applicable)
    7
    9
    No statistical analyses for this end point

    Secondary: Hospital mortality

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    End point title
    		 Hospital mortality
    End point description
    End point type
    Secondary
    End point timeframe
    Hospital mortality
    End point values
    		 Posaconazole prophylaxis group + standard-of-care Standard-of-care
    Number of subjects analysed
    37
    36
    Units: Number of patients
        number (not applicable)
    8
    10
    No statistical analyses for this end point

    Secondary: 90-day mortality

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    End point title
    		 90-day mortality
    End point description
    End point type
    Secondary
    End point timeframe
    90-day mortality
    End point values
    		 Posaconazole prophylaxis group + standard-of-care Standard-of-care
    Number of subjects analysed
    37
    36
    Units: Number of patients
        number (not applicable)
    9
    11
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Adverse events should be reported in the eCRF. SAE should be reported to the sponsor immediately (within 24h of becoming aware of the event)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    5.0
    Reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 Adverse event at the ICU department are very hard to define.

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Adverse events are very hard to define at the intensive care unit. Therefore, we only reported SAE's.
    Serious adverse events
    		 Overall trial
    Total subjects affected by serious adverse events
         subjects affected / exposed
    29 / 88 (32.95%)
         number of deaths (all causes)
    29
         number of deaths resulting from adverse events
    0
    Infections and infestations
    Death
    Additional description: 29 patients died during the study (until 90 days)
         subjects affected / exposed
    29 / 88 (32.95%)
         occurrences causally related to treatment / all
    0 / 29
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Overall trial
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 88 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jan 2018
    PK substudy

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34050768
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