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    Clinical Trial Results:
    Proof of concept study in male and female intensive care patients to investigate the clinical effect of repetitive orally inhaled doses of AP301 on alveolar liquid clearance in acute lung injury

    Summary
    EudraCT number
    2012-001863-64
    Trial protocol
    AT  
    Global end of trial date
    11 Aug 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    26 Mar 2016
    First version publication date
    09 Aug 2015
    Other versions
    v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    according to EudraCT requirement, study results have been reviewed again, no corrections needed.

    Trial information

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    Trial identification
    Sponsor protocol code
    AP301-II-001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01627613
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Apeptico GmbH
    Sponsor organisation address
    Mariahilfer Straße 136, Top 1.15, Vienna, Austria, 1060
    Public contact
    Doz. Dr. Bernhard Fischer, Apeptico Forschung und Entwicklung GmbH, 0043 6641432919, b.fischer@apeptico.com
    Scientific contact
    Doz. Dr. Bernhard Fischer, Apeptico Forschung und Entwicklung GmbH, 0043 6641432919, b.fischer@apeptico.com
    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
    11 Jul 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Aug 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Aug 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of orally inhaled AP301 on alveolar liquid clearance in ALI patients with the purpose to assess the treatment associated changes of extravascular lung water (EVLW) within 7 days of treatment.
    Protection of trial subjects
    Patients have been treated according to standard of care to minimize any pain and suffering in connection to their initial disease/condition leading to ICU admission and development of ALI.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Jul 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 40
    Worldwide total number of subjects
    40
    EEA total number of subjects
    40
    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)
    33
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    To be eligible, subjects had to be mechanically ventilated adult male and female patients at AKH, Vienna, Austria, with an onset of the ALI within the last 48 hours, present with a paO2/FiO2 ratio ≤300 mmHg, bilateral pulmonary infiltrates in the frontal chest X-ray, have absence of cardiac failure, and an EVLWI ≥8ml/kg PBW.

    Pre-assignment
    Screening details
    Demographic data , vital signs the medical history as well as concomitant medication has been documented. Blood gases, clinical chemistry and hematology were determined. The following scores were obtained: GOCA, SOFA, EVLW and lung injury scores were measured. Hemodyn. parameters were analyzed. For childbearing women, pregnancy test was performed

    Period 1
    Period 1 title
    Overall study participation (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Treatment
    Arm description
    In this arm, patientes received the IMP.
    Arm type
    Experimental

    Investigational medicinal product name
    AP-301
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    After patients met inclusion criteria, in study group I orally delivered doses of 87.6 mg AP301 (dose per subject, 5 ml nebuliser filling dose) were inhaled every 12 hours (± 30 min), for a total of 7 days. 87,6 mg AP301 are based on 125 mg nebuliser filling dose. This dose level is well below the highest dose level used in the phase I study. It represents a dose level corresponding to the most effective dose levels used in pharmacologic studies. To enable oral inhalation, reconstituted AP301 in WFI wasconverted into an inhalable aerosol by the Aeroneb Solo medicinal device. The Aeroneb Solo medicinal device is a product of Aerogen, Galway, Ireland and is a commercially available liquid nebuliser.

    Arm title
    Placebo
    Arm description
    in this arm, patients received Placebo treatment without active substance
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    After patients meet inclusion criteria, in study group II Placebo solution (0.9% physiologic NaCl, / 5 ml nebuliser filling dose) was inhaled every 12 hours (± 30 min), for a total of 7 days. To enable oral inhalation, reconstituted AP301 in WFI was converted into an inhalable aerosol by the Aeroneb Solo medicinal device. The Aeroneb Solo medicinal device is a product of Aerogen, Galway, Ireland and is a commercially available liquid nebuliser.

    Number of subjects in period 1
    Treatment Placebo
    Started
    20
    20
    Completed
    14
    16
    Not completed
    6
    4
         Adverse event, serious fatal
    6
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall study participation
    Reporting group description
    -

    Reporting group values
    Overall study participation Total
    Number of subjects
    40 40
    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)
    33 33
        From 65-84 years
    7 7
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    48.88 ± 16.04 -
    Gender categorical
    Units: Subjects
        Female
    14 14
        Male
    26 26
    Subject analysis sets

    Subject analysis set title
    AP-301
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Here, all patients received the IMP, AP-301

    Subject analysis set title
    Placebo
    Subject analysis set type
    Full analysis
    Subject analysis set description
    In this arm, patients received Placebo treatment

    Subject analysis sets values
    AP-301 Placebo
    Number of subjects
    19
    20
    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)
    14
    18
        From 65-84 years
    5
    2
        85 years and over
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    47.55 ± 17.39
    50.2 ± 14.91
    Gender categorical
    Units: Subjects
        Female
    5
    8
        Male
    14
    12

    End points

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    End points reporting groups
    Reporting group title
    Treatment
    Reporting group description
    In this arm, patientes received the IMP.

    Reporting group title
    Placebo
    Reporting group description
    in this arm, patients received Placebo treatment without active substance

    Subject analysis set title
    AP-301
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Here, all patients received the IMP, AP-301

    Subject analysis set title
    Placebo
    Subject analysis set type
    Full analysis
    Subject analysis set description
    In this arm, patients received Placebo treatment

    Primary: EVLWI

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    End point title
    EVLWI
    End point description
    EVLW stands for extravascular lung water, and upon damage of the alveolar capillary barrier the infiltration of water into the lung can happen (Hypermeability Oedema).
    End point type
    Primary
    End point timeframe
    Within the treatment period of seven days
    End point values
    Treatment Placebo AP-301 Placebo
    Number of subjects analysed
    20
    20
    19
    20
    Units: ml/PBW
        number (not applicable)
    1.94
    0.65
    1.94
    0.65
    Statistical analysis title
    Statistical Analysis of AP-301-II
    Comparison groups
    AP-301 v Placebo
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    > 0.05
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [1] - This has been a pilot study to evaluate the effect of AP-301 on the reduction of EVLW in ICU patients

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Twenty eight days after inclusion of study subjects
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Treatment
    Reporting group description
    In this arm, patients received the IMP.

    Reporting group title
    Placebo
    Reporting group description
    in this arm, patients received Placebo treatment without active substance

    Serious adverse events
    Treatment Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 20 (30.00%)
    5 / 20 (25.00%)
         number of deaths (all causes)
    6
    4
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    5 / 20 (25.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 5
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory insufficiency
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypoxaemia/hypoxia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Intracranial bleeding
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal disorders
    Acute abdomen
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Treatment Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 20 (60.00%)
    12 / 20 (60.00%)
    Surgical and medical procedures
    Tracheostomy
         subjects affected / exposed
    4 / 20 (20.00%)
    6 / 20 (30.00%)
         occurrences all number
    5
    8
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    4
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    6 / 20 (30.00%)
    7 / 20 (35.00%)
         occurrences all number
    11
    9
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    0 / 20 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    0
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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
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