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    Clinical Trial Results:
    Open-Label Phase 3 Trial to Evaluate the Safety of Aztreonam 75 mg Powder and Solvent for Nebuliser Solution/Aztreonam for Inhalation Solution (AZLI) in Children With Cystic Fibrosis (CF) and Chronic Pseudomonas Aeruginosa (PA) in the Lower Airways

    Summary
    EudraCT number
    2011-001362-18
    Trial protocol
    DE   ES   FR   IT   Outside EU/EEA  
    Global end of trial date
    03 Apr 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Mar 2016
    First version publication date
    05 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-205-0160
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01404234
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Clinical Trial Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.com
    Scientific contact
    Clinical Trial Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000827-PIP01-09
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Apr 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Apr 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This was an open-label, multicenter study in children ≤ 12 years of age with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa (PA) infection in the lower airways using three 28-day courses of Aztreonam for Inhalation Solution (AZLI) 75 mg three times daily, each followed by 28 days off AZLI. The total treatment duration was to be 6 months.
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    29 Dec 2011
    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
    Poland: 11
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    United States: 29
    Worldwide total number of subjects
    61
    EEA total number of subjects
    32
    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)
    2
    Children (2-11 years)
    45
    Adolescents (12-17 years)
    14
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects were enrolled at a total of 25 study sites in the United States and Europe. The first participant was screened on 29 December 2011. The last participant observation was on 03 April 2013.

    Pre-assignment
    Screening details
    74 participants were screened; 61 participants were enrolled and treated, and comprise the Safety Analysis Set and the Full Analysis Set.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    AZLI
    Arm description
    Participants received three 28-day courses of AZLI, each followed by 28 days off-treatment. AZLI 75 mg was administered 3 times daily via the investigational nebulizer.
    Arm type
    Experimental

    Investigational medicinal product name
    AZLI
    Investigational medicinal product code
    Other name
    Cayston®
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Aztreonam for Inhalation solution (AZLI) 75 mg powder and solvent for nebuliser solution administered via the investigational nebulizer at a minimum of 4 hours between doses.

    Number of subjects in period 1
    AZLI
    Started
    61
    Completed
    59
    Not completed
    2
         Withdrawal by Subject
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AZLI
    Reporting group description
    Participants received three 28-day courses of AZLI, each followed by 28 days off-treatment. AZLI 75 mg was administered 3 times daily via the investigational nebulizer.

    Reporting group values
    AZLI Total
    Number of subjects
    61 61
    Age categorical
    Units: Subjects
        < 2 years
    2 2
        ≥ 2 years to < 6 years
    7 7
        ≥ 6 years to ≤ 12 years
    52 52
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    9 ± 2.94 -
    Gender categorical
    Units: Subjects
        Female
    31 31
        Male
    30 30
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    5 5
        Not Hispanic or Latino
    55 55
        Unknown or not reported
    1 1
    Race
    Units: Subjects
        Black or African heritage
    2 2
        White
    55 55
        Other
    3 3
        Not permitted
    1 1
    Presence of Pseudomonas aeruginosa (PA)
    Units: Subjects
        Present
    58 58
        Absent
    3 3
    Body mass index
    Units: kg/m^2
        arithmetic mean (standard deviation)
    16.3 ± 1.66 -
    Forced expiratory volume in 1 second (FEV1) % predicted
    FEV1 % predicted is defined as FEV1 of the patient divided by the average FEV1 in the population for any person of similar age, sex, race, and body composition. Participants ≥ 6 years of age were analyzed at baseline for FEV1 % predicted (n = 52).
    Units: percentage of FEV1 % predicted
        arithmetic mean (standard deviation)
    80.31 ± 19.494 -
    FEV1
    FEV1 is defined as the maximal volume of air that can be exhaled in 1 second. Participants ≥ 6 years of age were analyzed at baseline for FEV1 (n = 52).
    Units: litre(s)
        arithmetic mean (standard deviation)
    1.67 ± 0.627 -
    Forced vital capacity (FVC)
    FVC is defined as the volume of air that can forcibly be blown out after taking a full breath. Participants ≥ 6 years of age were analyzed at baseline for FVC (n = 52).
    Units: litre(s)
        arithmetic mean (standard deviation)
    2.11 ± 0.687 -
    FEV25-75
    FEV25-75 is defined as the forced expiratory flow from 25% to 75% of the FVC. Participants ≥ 6 years of age were analyzed at baseline for FEV25-75 (n = 52).
    Units: litres per second
        arithmetic mean (standard deviation)
    1.82 ± 1.169 -
    CFQ-R RSS Score
    Respiratory symptoms (eg, coughing, congestion, wheezing) were assessed with the Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS). The range of scores (units) was 0 to 100 with higher scores indicating fewer symptoms. Participants ≥ 6 years of age were analyzed at baseline for CFQ-R RSS (n = 51; data was missing for one participant).
    Units: units on a scale
        arithmetic mean (standard deviation)
    71.73 ± 17.327 -

    End points

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    End points reporting groups
    Reporting group title
    AZLI
    Reporting group description
    Participants received three 28-day courses of AZLI, each followed by 28 days off-treatment. AZLI 75 mg was administered 3 times daily via the investigational nebulizer.

    Primary: Percentage of Participants Who Discontinued Study Drug Due to Safety or Tolerability Reasons

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    End point title
    Percentage of Participants Who Discontinued Study Drug Due to Safety or Tolerability Reasons [1]
    End point description
    Participants who discontinued study drug due to safety or tolerability reasons were defined as those with "Adverse Event (AE)/Safety or Tolerability" on the Study Drug Completion electronic case report form as the reason for early discontinuation. The 95% confidence interval (CI) was calculated using the exact binomial method. Two participants voluntarily withdrew from the study prior to completion (not due to AEs/safety or tolerability reasons) and were not included in the analysis.
    End point type
    Primary
    End point timeframe
    Baseline to Day 168
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No intergroup analysis was performed because the study was single-arm, and no analysis against a historic rate was performed because the study was not designed to demonstrate superiority or noninferiority.
    End point values
    AZLI
    Number of subjects analysed
    59
    Units: percentage of participants
        number (confidence interval 95%)
    0 (0 to 6.1)
    No statistical analyses for this end point

    Secondary: Change From Baseline in FEV1 % Predicted in Subjects Aged ≥ 6 Years

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    End point title
    Change From Baseline in FEV1 % Predicted in Subjects Aged ≥ 6 Years
    End point description
    The change in FEV1 % predicted was assessed at the end of each 28-day AZLI treatment course. FEV1 % predicted is defined as FEV1 of the patient divided by the average FEV1 in the population for any person of similar age, sex, race, and body composition. Participants ≥ 6 years of age were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline to Day 28, 84, and 140
    End point values
    AZLI
    Number of subjects analysed
    52
    Units: percentage of FEV1 % predicted
    arithmetic mean (standard deviation)
        Change at Day 28 (on-treatment, n = 52)
    4.73 ± 11.703
        Change at Day 84 (on-treatment, n = 51)
    1.72 ± 12.516
        Change at Day 140 (on-treatment, n = 50)
    1.65 ± 10.34
    No statistical analyses for this end point

    Secondary: Change From Baseline in CFQ-R Respiratory Symptoms Scale (RSS) Score in Subjects Aged ≥ 6 Years

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    End point title
    Change From Baseline in CFQ-R Respiratory Symptoms Scale (RSS) Score in Subjects Aged ≥ 6 Years
    End point description
    The change in CFQ-R RSS score was assessed at the end of each 28-day AZLI treatment course. The range of scores (units) was 0 to 100 with higher scores indicating fewer symptoms. Participants ≥ 6 years of age were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline to Day 28, 84, and 140
    End point values
    AZLI
    Number of subjects analysed
    52
    Units: units on a scale
    arithmetic mean (standard deviation)
        Change at Day 28 (on-treatment, n = 51)
    8.66 ± 14.903
        Change at Day 84 (on-treatment, n = 48)
    9.38 ± 18.243
        Change at Day 140 (on-treatment, n = 48)
    5.9 ± 15.372
    No statistical analyses for this end point

    Secondary: Change in Pseudomonas Aeruginosa (PA) Sputum Density

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    End point title
    Change in Pseudomonas Aeruginosa (PA) Sputum Density
    End point description
    The change in PA sputum density (log10 colony-forming units per gram [cfu/g]) was assessed at the end of each 28-day AZLI treatment course.
    End point type
    Secondary
    End point timeframe
    Baseline to Day 28, 84, and 140
    End point values
    AZLI
    Number of subjects analysed
    61
    Units: log10 CFU/g
    arithmetic mean (standard deviation)
        Change at Day 28 (on-treatment, n = 24)
    -2.6 ± 2.5
        Change at Day 84 (on-treatment, n = 25)
    -2 ± 2.14
        Change at Day 140 (on-treatment, n = 23)
    -1.2 ± 2.13
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Used Additional (Non-study) Antipseudomonal Antibiotics

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    End point title
    Percentage of Participants Who Used Additional (Non-study) Antipseudomonal Antibiotics
    End point description
    The percentage of participants who used additional (non-study) antipseudomonal antibiotics (IV, inhaled, oral, IV/inhaled, IV/inhaled/oral) was summarized (number and percent) for all subjects.
    End point type
    Secondary
    End point timeframe
    Baseline to Day 168
    End point values
    AZLI
    Number of subjects analysed
    61
    Units: percentage of participants
    number (not applicable)
        Never used non-study antipseudomonal antibiotics
    42.6
        Used non-study antipseudomonal antibiotics
    57.4
    No statistical analyses for this end point

    Secondary: Percentage of Participants Hospitalized at Least Once Due to a Respiratory Event

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    End point title
    Percentage of Participants Hospitalized at Least Once Due to a Respiratory Event
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Day 168
    End point values
    AZLI
    Number of subjects analysed
    61
    Units: percentage of participants
    number (not applicable)
        Never hospitalized
    82
        Hospitalized at least once
    18
    No statistical analyses for this end point

    Secondary: Number of Days Participants Were Hospitalized Due to a Respiratory Event

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    End point title
    Number of Days Participants Were Hospitalized Due to a Respiratory Event
    End point description
    The average number of days hospitalized due to a respiratory event, among the 11 participants who were hospitalized for respiratory event, was reported.
    End point type
    Secondary
    End point timeframe
    Baseline to Day 168
    End point values
    AZLI
    Number of subjects analysed
    11
    Units: days
        arithmetic mean (standard deviation)
    12.6 ± 8.9
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Pulmonary Exacerbations

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    End point title
    Percentage of Participants With Pulmonary Exacerbations
    End point description
    Pulmonary exacerbations were defined as respiratory hospitalizations or discrete courses of non-study IV/inhaled antipseudomonal antibiotics. Use of oral antibiotics alone for respiratory signs or symptoms was considered to be representative of milder clinical events and, therefore, was not included in the definition of pulmonary exacerbations.
    End point type
    Secondary
    End point timeframe
    Baseline to Day 168
    End point values
    AZLI
    Number of subjects analysed
    61
    Units: percentage of participants
    number (not applicable)
        No pulmonary exacerbation
    62.3
        At least one pulmonary exacerbation
    37.7
    No statistical analyses for this end point

    Secondary: Time to Pulmonary Exacerbation

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    End point title
    Time to Pulmonary Exacerbation
    End point description
    The median days to first pulmonary exacerbation was summarized using Kaplan-Meier (KM) summary statistics.
    End point type
    Secondary
    End point timeframe
    Baseline to Day 168
    End point values
    AZLI
    Number of subjects analysed
    61
    Units: median days
    176
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Study-drug Induced Bronchospasm

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    End point title
    Percentage of Participants With Study-drug Induced Bronchospasm
    End point description
    Study-drug induced bronchospasm (airway reactivity) was assessed at the baseline visit as the percent change in FEV1 from the pretreatment measurement to 30 minutes following treatment for subjects ≥ 6 years or as from the Investigator's assessment for subjects < 6 years.
    End point type
    Secondary
    End point timeframe
    Pretreatment at Baseline to 30 minutes following treatment
    End point values
    AZLI
    Number of subjects analysed
    61
    Units: percentage of participants
        number (not applicable)
    3.3
    No statistical analyses for this end point

    Secondary: Adverse Event Rates Adjusted for Study Duration

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    End point title
    Adverse Event Rates Adjusted for Study Duration
    End point description
    Adverse events occurring in ≥ 5% of participants adjusted for study duration were summarized. The adjustment was made by using a standardized rate calculated as the sum of study duration across patients divided by 28 for the total number of patient months. Rate calculations presented are the number of adverse events (AEs) per patient month.
    End point type
    Secondary
    End point timeframe
    Baseline to Day 168
    End point values
    AZLI
    Number of subjects analysed
    61
    Units: AEs (per patient month)
    number (not applicable)
        Cough
    0.163
        Nasal congestion
    0.05
        Rhinnorrhoea
    0.041
        Wheezing
    0.033
        Sputum increased
    0.033
        Productive cough
    0.03
        Lung disorder
    0.025
        Haemoptysis
    0.019
        Rhonchi
    0.019
        Oropharyngeal pain
    0.017
        Rales
    0.017
        Respiratory tract congestion
    0.014
        Abdominal pain
    0.03
        Diarrhoea
    0.019
        Vomiting
    0.019
        Abdominal pain upper
    0.017
        Pyrexia
    0.061
        Fatigue
    0.025
        Rhinitis
    0.03
        Pulmonary function test decreased
    0.014
        Forced expiratory volume decreased
    0.011
        Decreased appetite
    0.017
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to Day 168
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    AZLI
    Reporting group description
    Participants received three 28-day courses of AZLI, each followed by 28 days off-treatment. AZLI 75 mg was administered 3 times daily via the investigational nebulizer.

    Serious adverse events
    AZLI
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 61 (21.31%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Respiratory, thoracic and mediastinal disorders
    Lung disorder
         subjects affected / exposed
    5 / 61 (8.20%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Appendiceal mucocoele
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bronchopneumonia
         subjects affected / exposed
    2 / 61 (3.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    2 / 61 (3.28%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    AZLI
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    50 / 61 (81.97%)
    Investigations
    Forced expiratory volume decreased
         subjects affected / exposed
    4 / 61 (6.56%)
         occurrences all number
    4
    Pulmonary function test decreased
         subjects affected / exposed
    5 / 61 (8.20%)
         occurrences all number
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    36 / 61 (59.02%)
         occurrences all number
    58
    Haemoptysis
         subjects affected / exposed
    6 / 61 (9.84%)
         occurrences all number
    7
    Nasal congestion
         subjects affected / exposed
    12 / 61 (19.67%)
         occurrences all number
    16
    Oropharyngeal pain
         subjects affected / exposed
    6 / 61 (9.84%)
         occurrences all number
    6
    Productive cough
         subjects affected / exposed
    8 / 61 (13.11%)
         occurrences all number
    11
    Rales
         subjects affected / exposed
    5 / 61 (8.20%)
         occurrences all number
    6
    Respiratory tract congestion
         subjects affected / exposed
    5 / 61 (8.20%)
         occurrences all number
    5
    Rhinorrhoea
         subjects affected / exposed
    10 / 61 (16.39%)
         occurrences all number
    15
    Rhonchi
         subjects affected / exposed
    6 / 61 (9.84%)
         occurrences all number
    7
    Sputum increased
         subjects affected / exposed
    9 / 61 (14.75%)
         occurrences all number
    12
    Wheezing
         subjects affected / exposed
    9 / 61 (14.75%)
         occurrences all number
    12
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    8 / 61 (13.11%)
         occurrences all number
    9
    Pyrexia
         subjects affected / exposed
    16 / 61 (26.23%)
         occurrences all number
    22
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 61 (9.84%)
         occurrences all number
    9
    Abdominal pain upper
         subjects affected / exposed
    5 / 61 (8.20%)
         occurrences all number
    6
    Diarrhoea
         subjects affected / exposed
    7 / 61 (11.48%)
         occurrences all number
    7
    Vomiting
         subjects affected / exposed
    6 / 61 (9.84%)
         occurrences all number
    7
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 61 (8.20%)
         occurrences all number
    6
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    10 / 61 (16.39%)
         occurrences all number
    11

    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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