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    Clinical Trial Results:
    Lung Clearance Index as an OUTcome parameter to detect the efficacy f Aztreonam Lysine Inhalation in cystic fibrosis patients with near normal spirometry - an observational proof-of concept study

    Summary
    EudraCT number
    		 2013-004295-35
    Trial protocol
    		 AT  
    Global end of trial date
    11 Jul 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Jan 2023
    First version publication date
    27 Jan 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LCI-OUT
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Medical University Innsbruck
    Sponsor organisation address
    Christoph-Probst-Platz 1, Innrain 52, Innsbruck, Austria, 6020
    Public contact
    Clinical Trial Center, Medical University Innsbruck, Department of Child and Adolescent Health, Paediatrics III, +43 (0)512 9003 70086, KKS-Innsbruck@i-med.ac.at
    Scientific contact
    Clinical Trial Center, Medical University Innsbruck, Department of Child and Adolescent Health, Paediatrics III, +43 (0)512 9003 70086, KKS-Innsbruck@i-med.ac.at
    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
    31 Dec 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 May 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jul 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the changes in lung clearance index before and after each 4-week-on/4-week-off cycle of different inhaled antibiotics
    Protection of trial subjects
    The standard inhaled antibiotic was tobramycin in all subjects, with n = 5 subjects using TOBI Podhaler® 112 mg BID and n = 3 inhaling TOBI® 300 mg/5 ml nebuliser solution BID. Since previous authors had reported comparable safety and efficacy profiles of the two tobramycin treatments, we analysed the combined results from both treatments.
    Background therapy
    		 -
    Evidence for comparator
    		 This single-centre, observational, open-label, feasibility study compared two treatment phases, each consisting of 4-week on/off-cycles with inhaled antibiotics: Phase 1, weeks 0 to 8: standard inhaled antibiotic (tobramycin/TOBI® 300mg/5ml BID or TOBI Podhaler® 112mg BID), and Phase 2, weeks 8 to 16: AZLI 75 mg TID. ALZI was provided by Gilead Sciences, the manufacturer of AZLI.
    Actual start date of recruitment
    15 Nov 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 8
    Worldwide total number of subjects
    8
    EEA total number of subjects
    8
    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)
    1
    Adults (18-64 years)
    7
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The patient recruitment period was from June 2014 to January 2016.

    Pre-assignment
    Screening details
    		 The main inclusion criteria were: clinically stable patients aged ≥ 12 years with CF, FEV1 ≥ 75% of the predicted normal value, chronic P. aeruginosa lung infection, and at least two previous on/off cycles or > 8 weeks of continuous inhaled antibiotic treatment with tobramycin.

    Period 1
    Period 1 title
    Phase 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 TOBI
    Arm description
    		 Phase 1, weeks 0 to 8: standard inhaled antibiotic (tobramycin/TOBI1 300mg/5ml BID or TOBI Podhaler1 112mg. For each patient, the study started at the end of a 4-week off-period without standard inhaled antibiotic (“washout”).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tobramycin Sulfate
    Investigational medicinal product code
    Other name
    Tobi
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    300 mg/5 ml BID

    Investigational medicinal product name
    Tobramycin
    Investigational medicinal product code
    Other name
    TOBI Podhaler®
    Pharmaceutical forms
    Powder for nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    112mg/BID

    Number of subjects in period 1
    		TOBI
    Started
    8
    Completed
    8
    Period 2
    Period 2 title
    Phase 2
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 AZLI
    Arm description
    		 Phase 2, weeks 8 to 16: AZLI 75 mg TID. ALZI was provided by Gilead Sciences, the manufacturer of AZLI. For each patient, the study started at the end of a 4-week off-period without standard inhaled antibiotic (“washout”).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aztreonam
    Investigational medicinal product code
    Other name
    Cayston 75 mg
    Pharmaceutical forms
    Powder for nebuliser suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    75 mg TID

    Number of subjects in period 2
    		AZLI
    Started
    8
    Completed
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase 1
    Reporting group description
    		 -

    Reporting group values
    		 Phase 1 Total
    Number of subjects
    		 8 8
    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)
    		 1 1
        Adults (18-64 years)
    		 7 7
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 28 (15 to 49) -
    Gender categorical
    Units: Subjects
        Female
    		 4 4
        Male
    		 4 4

    End points

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    End points reporting groups
    Reporting group title
    TOBI
    Reporting group description
    		 Phase 1, weeks 0 to 8: standard inhaled antibiotic (tobramycin/TOBI1 300mg/5ml BID or TOBI Podhaler1 112mg. For each patient, the study started at the end of a 4-week off-period without standard inhaled antibiotic (“washout”).
    Reporting group title
    AZLI
    Reporting group description
    		 Phase 2, weeks 8 to 16: AZLI 75 mg TID. ALZI was provided by Gilead Sciences, the manufacturer of AZLI. For each patient, the study started at the end of a 4-week off-period without standard inhaled antibiotic (“washout”).

    Primary: Lung clearance index (LCI)

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    End point title
    		 Lung clearance index (LCI)
    End point description
    The primary endpoint was lung clearance index (LCI) measured by nitrogen multiple breath washout using 100% oxygen (EasyOne Pro® LAB MBW Module, ndd Medical Technologies, Zürich, Switzerland), with an upper limit of normal of 7.0
    End point type
    Primary
    End point timeframe
    After 4 weeks of AZLI treatment, the primary endpoint LCI improved (i.e. declined) in 7 of 8 patients.
    End point values
    		 TOBI AZLI
    Number of subjects analysed
    8
    8
    Units: LCI
        number (not applicable)
    1
    7
    Statistical analysis title
    		 LCI
    Statistical analysis description
    The treatment responses determined with LCI were more favourable after AZLI than after tobramycin (-0.365 vs. +0.120, p = 0.039).
    Comparison groups
    TOBI v AZLI
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.039
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    15.11.2013-31.05.2016
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    5.0
    Reporting groups
    Reporting group title
    Phase 1
    Reporting group description
    		 For each patient, the study started at the end of a 4-week off-period without standard inhaled antibiotic (“washout”).

    Serious adverse events
    		 Phase 1
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 8 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Phase 1
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 8 (0.00%)
    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: No AEs or SAEs were observed during this tral.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Jan 2016
    Extension of study duration

    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.
    The patients cohort of this single-centre study was small compared to the international, multi-centre pivotal studies. We were unable to recruit the desired number of 10 patients within a reasonable time. This limits the power of the study.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31498805
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