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    Clinical Trial Results:
    Phase 3b Randomized, Double-Blind, Placebo-Controlled Two-Part Trial to Assess the Safety and Efficacy of Continuous Aztreonam for Inhalation Solution (AZLI) in Subjects With Cystic Fibrosis (CF) and Chronic Burkholderia Species Infection

    Summary
    EudraCT number
    		 2009-011740-19
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    12 Sep 2011

    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

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GS-US-205-0127
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01059565
    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)
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Sep 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Sep 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this research study was to determine if an experimental drug called Aztreonam for Inhalation Solution (AZLI) was safe and effective to treat Burkholderia lung infections in patients with cystic fibrosis (CF). Spirometry was used to assess pulmonary function, and the revised Cystic Fibrosis Questionnaire (CFQ-R) was used to assess quality of life. The CFQ-R is a validated, patient-reported outcome tool used to measure health-related quality of life for children and adults with CF. The study consisted of a 24-week randomized phase, and a 24-week open-label phase. Primary and secondary efficacy analyses were conducted for the 24-week randomized phase only. Safety data were collected for both the randomized and open-label phases.
    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
    22 Feb 2010
    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
    United States: 94
    Country: Number of subjects enrolled
    Canada: 7
    Worldwide total number of subjects
    101
    EEA total number of subjects
    0
    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)
    4
    Adolescents (12-17 years)
    13
    Adults (18-64 years)
    84
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at 34 sites in the United States and 1 site in Canada. The first participant was screened on 22 February 2010. The last participant observation was on 12 September 2011.

    Pre-assignment
    Screening details
    		 102 participants were screened and 101 were randomized. Of those participants randomized, 100 received at least one dose of study drug, and comprise the Safety Analysis Set and the Full Analysis Set.

    Period 1
    Period 1 title
    24-Week Randomized Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AZLI
    Arm description
    		 Participants received Aztreonam for inhalation solution (AZLI) for 24 weeks during the randomized phase and continued to receive AZLI during the open-label phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZLI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Aztreonam for inhalation solution (AZLI; 75 mg aztreonam/52.5 mg lysine monohydrate) was administered three times a day, with at least 4 hours between doses, using the eFlow investigational nebulizer.

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo to match AZLI for 24 weeks during the randomized phase and switched to AZLI during the open-label phase.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo to match AZLI (lactose and sodium chloride) was administered three times a day, with at least 4 hours between doses, using the eFlow investigational nebulizer.

    Number of subjects in period 1 [1]
    		AZLI Placebo
    Started
    48
    52
    Randomized and treated
    48
    52
    Completed
    39
    45
    Not completed
    9
    7
         Consent withdrawn by subject
    3
    1
         Adverse event, non-fatal
    5
    -
         Noncompliance with Study Drug Regimen
    1
    5
         Lost to follow-up
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: One participant who was randomized but not treated in the study was not included in the subject disposition table.
    Period 2
    Period 2 title
    24-Week Open-Label Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AZLI/AZLI
    Arm description
    		 Participants received Aztreonam for inhalation solution (AZLI) for 24 weeks during the randomized phase and continued to receive AZLI during the open-label phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZLI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Aztreonam for inhalation solution (AZLI; 75 mg aztreonam/52.5 mg lysine monohydrate) was administered three times a day, with at least 4 hours between doses, using the eFlow investigational nebulizer.

    Arm title
    		 Placebo/AZLI
    Arm description
    		 Participants received placebo to match AZLI for 24 weeks during the randomized phase and switched to AZLI during the open-label phase.
    Arm type
    		 Placebo

    Investigational medicinal product name
    AZLI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Aztreonam for inhalation solution (AZLI; 75 mg aztreonam/52.5 mg lysine monohydrate) was administered three times a day, with at least 4 hours between doses, using the eFlow investigational nebulizer.

    Number of subjects in period 2
    		AZLI/AZLI Placebo/AZLI
    Started
    39
    45
    Completed
    34
    42
    Not completed
    5
    3
         Subject noncompliance
    1
    -
         Consent withdrawn by subject
    1
    -
         Pulmonologist/participant decision
    -
    1
         Adverse event, non-fatal
    2
    -
         Worsening health (physician decision)
    1
    1
         Unable to clean device (hospitalization)
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AZLI
    Reporting group description
    		 Participants received Aztreonam for inhalation solution (AZLI) for 24 weeks during the randomized phase and continued to receive AZLI during the open-label phase.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo to match AZLI for 24 weeks during the randomized phase and switched to AZLI during the open-label phase.

    Reporting group values
    		 AZLI Placebo Total
    Number of subjects
    		 48 52 100
    Age categorical
    Units: Subjects
        ≥ 6 to ≤ 12 years
    		 3 3 6
        > 12 to < 18 years
    		 3 8 11
        ≥ 18 years
    		 42 41 83
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 28 ( 10.3 ) 24.7 ( 10 ) -
    Gender, Male/Female
    Units: participants
        Female
    		 22 17 39
        Male
    		 26 35 61
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 1 1
        Not Hispanic or Latino
    		 48 51 99
        Unknown or Not Reported
    		 0 0 0
    Race
    Units: Subjects
        Black or African Heritage
    		 1 2 3
        White
    		 46 50 96
        Other
    		 1 0 1
    Forced expiratory volume in 1 second (FEV1) percent 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 and body composition.
    Units: percentage of FEV1 % predicted
        arithmetic mean (standard deviation)
    		 60.67 ( 21.71 ) 52.59 ( 23.71 ) -
    FEV1
    FEV1 is defined as the maximal volume of air that can be exhaled in 1 second.
    Units: liters
        arithmetic mean (standard deviation)
    		 2.13 ( 0.93 ) 1.93 ( 0.96 ) -
    Forced vital capacity (FVC)
    FVC is defined as the volume of air that can forcibly be blown out after taking a full breath.
    Units: liters
        arithmetic mean (standard deviation)
    		 3.23 ( 1.18 ) 2.99 ( 1.14 ) -
    Forced expiratory flow 25% to 75% (FEF25-75)
    FEF25-75 is defined as the forced expiratory flow from 25% to 75% of the FVC.
    Units: liters per second
        arithmetic mean (standard deviation)
    		 1.33 ( 0.95 ) 1.31 ( 1.22 ) -
    Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS) Score
    Respiratory symptoms (e.g., coughing, congestion, wheezing) were assessed with the CFQ-R Respiratory Symptoms Scale (RSS). The range of scores (units) is 0 to 100 with higher scores indicating fewer symptoms.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 58.3 ( 21.4 ) 59 ( 17.6 ) -
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 21.9 ( 4.5 ) 20.7 ( 3.2 ) -
    Burkholderia spp colony-forming units (CFU) in sputum
    Participants in the Full Analysis Set with evaluable assessments for Burkholderia spp. CFU in sputum at baseline were analyzed, which included 30 in the AZLI group, 32 in the placebo group, and 62 total.
    Units: log_10 CFU per gram
        arithmetic mean (standard deviation)
    		 6.39 ( 2.47 ) 6.41 ( 2.52 ) -

    End points

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    End points reporting groups
    Reporting group title
    AZLI
    Reporting group description
    		 Participants received Aztreonam for inhalation solution (AZLI) for 24 weeks during the randomized phase and continued to receive AZLI during the open-label phase.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo to match AZLI for 24 weeks during the randomized phase and switched to AZLI during the open-label phase.
    Reporting group title
    AZLI/AZLI
    Reporting group description
    		 Participants received Aztreonam for inhalation solution (AZLI) for 24 weeks during the randomized phase and continued to receive AZLI during the open-label phase.

    Reporting group title
    Placebo/AZLI
    Reporting group description
    		 Participants received placebo to match AZLI for 24 weeks during the randomized phase and switched to AZLI during the open-label phase.

    Primary: AUCave of relative change in FEV1 % predicted from baseline to Week 24

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    End point title
    		 AUCave of relative change in FEV1 % predicted from baseline to Week 24
    End point description
    The relative change (AUCave) in FEV1 % predicted from baseline to Week 24 was analyzed. FEV1 % predicted is defined as FEV1 % of the patient divided by the average FEV1 % in the population for any person of similar age, sex and body composition. AUCave is the calculated area under the curve corrected for baseline and adjusted by the number of days on study through Week 24.
    End point type
    Primary
    End point timeframe
    Baseline to Week 24
    End point values
    		 AZLI Placebo
    Number of subjects analysed
    48
    52
    Units: percent change in FEV1% predicted
        least squares mean (standard error)
    0.16 ( 1.5 )
    -0.75 ( 1.43 )
    Statistical analysis title
    		 AZLI vs placebo: Relative Change in FEV1 %
    Statistical analysis description
    The primary analysis was a test for superiority. Null hypothesis was no difference between the AZLI and placebo treatment groups versus the alternative hypothesis that there was a difference. A sample size of 50 participants per group provided at least 80% power to detect an 8.5% difference in mean AUCave of relative change from baseline in FEV1 % predicted through Week 24 using a two-sided 0.05-level test, assuming a common standard deviation of 15.
    Comparison groups
    AZLI v Placebo
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.663 [1]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in least squares mean (LSM)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.24
         upper limit
    		 5.06
    Notes
    [1] - To correct for multiplicity, a family alpha spending rule was used to control the type 1 error rate of alpha = 0.05. A gate-keeping procedure to control family-wise Type 1 error was established a priori for primary and key secondary endpoints.

    Secondary: Total number of systemic and/or inhaled antibiotic courses for respiratory events

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    End point title
    		 Total number of systemic and/or inhaled antibiotic courses for respiratory events
    End point description
    The total number of systemic and/or inhaled antibiotic courses for respiratory events from baseline to Week 24 was analyzed. A single antibiotic course may represent the use of multiple antibiotics.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 AZLI Placebo
    Number of subjects analysed
    48
    52
    Units: antibiotic treatment courses
        number (not applicable)
    54
    73
    Statistical analysis title
    		 AZLI vs placebo: # of Inhaled Antibiotic Courses
    Statistical analysis description
    The primary analysis was a test for superiority. Null hypothesis was no difference between the AZLI and placebo treatment groups versus the alternative hypothesis that there was a difference.
    Comparison groups
    AZLI v Placebo
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4158 [2]
    Method
    		 Negative binomial regression
    Confidence interval
    Notes
    [2] - To correct for multiplicity, a family alpha spending rule was used to control the type 1 error rate of alpha = 0.05. The negative binomial regression model included an offset parameter to account for potential differing study durations.

    Secondary: AUCave of change in CFQ-R RSS Scores from baseline to Week 24

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    End point title
    		 AUCave of change in CFQ-R RSS Scores from baseline to Week 24
    End point description
    The change (AUCave) in CFQ-R RSS scores from baseline to Week 24 was analyzed. The range of scores (units) within the RSS domain is 0 to 100 with higher scores indicating fewer symptoms.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 AZLI Placebo
    Number of subjects analysed
    45
    52
    Units: units on a scale
        least squares mean (standard error)
    2.97 ( 1.7 )
    2.79 ( 1.58 )
    Statistical analysis title
    		 AZLI vs placebo: Change in CFQ-R RSS Scores
    Statistical analysis description
    Null hypothesis was that there was no difference between the AZLI and placebo treatment groups versus the alternative hypothesis that there was a difference.
    Comparison groups
    AZLI v Placebo
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.939 [3]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in least squares mean (LSM)
    Point estimate
    0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.43
         upper limit
    		 1.78
    Notes
    [3] - To correct for multiplicity, a family alpha spending rule was used to control the type 1 error rate of alpha = 0.05. The AUCs of changes from baseline were compared between treatment groups using ANCOVA methods with baseline value as a covariate.

    Secondary: AUCave of relative change from baseline to Week 24 in FEV1

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    End point title
    		 AUCave of relative change from baseline to Week 24 in FEV1
    End point description
    The relative change (AUCave) from baseline to Week 24 in mean (SE) FEV1 was analyzed. FEV1 is defined as the maximal volume of air that can be exhaled in 1 second.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 AZLI Placebo
    Number of subjects analysed
    47
    52
    Units: percent change in FEV1 (liters)
        least squares mean (standard error)
    0.36 ( 1.49 )
    -0.41 ( 1.42 )
    Statistical analysis title
    		 AZLI vs placebo: Relative change in FEV1
    Statistical analysis description
    Null hypothesis was that there was no difference between the AZLI and placebo treatment groups versus the alternative hypothesis that there was a difference.
    Comparison groups
    AZLI v Placebo
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.711 [4]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in least squares mean (LSM)
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.33
         upper limit
    		 4.86
    Notes
    [4] - The AUCs of changes from baseline were compared between treatment groups using ANCOVA methods with baseline value as a covariate.

    Secondary: AUCave of relative change from baseline to Week 24 in FVC

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    End point title
    		 AUCave of relative change from baseline to Week 24 in FVC
    End point description
    The relative change (AUCave) from baseline to Week 24 in mean (SE) FVC was analyzed. FVC is defined as the volume of air that can forcibly be blown out after taking a full breath.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 AZLI Placebo
    Number of subjects analysed
    47
    52
    Units: percent change in FVC (liters)
        least squares mean (standard error)
    0.77 ( 1.42 )
    0.17 ( 1.35 )
    Statistical analysis title
    		 AZLI vs placebo: Relative Change in FVC
    Statistical analysis description
    Null hypothesis was that there was no difference between the AZLI and placebo treatment groups versus the alternative hypothesis that there was a difference.
    Comparison groups
    AZLI v Placebo
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.762 [5]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in least squares mean (LSM)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.3
         upper limit
    		 4.49
    Notes
    [5] - The AUCs of changes from baseline were compared between treatment groups using ANCOVA methods with baseline value as a covariate.

    Secondary: AUCave of relative change from baseline to Week 24 in FEF25-75

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    End point title
    		 AUCave of relative change from baseline to Week 24 in FEF25-75
    End point description
    The relative change (AUCave) from baseline to Week 24 in mean (SE) FEF25-75 was analyzed. FEF25-75 is defined as the forced expiratory flow from 25% to 75% of the FVC.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 AZLI Placebo
    Number of subjects analysed
    47
    52
    Units: percent change in FEF25-75 (liters/sec)
        least squares mean (standard error)
    1.4 ( 2.37 )
    -0.55 ( 2.25 )
    Statistical analysis title
    		 AZLI vs placebo: Relative Change in FEF25-75
    Statistical analysis description
    Null hypothesis was that there was no difference between the AZLI and placebo treatment groups versus the alternative hypothesis that there was a difference.
    Comparison groups
    Placebo v AZLI
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.553 [6]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in least squares mean (LSM)
    Point estimate
    1.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.54
         upper limit
    		 8.44
    Notes
    [6] - The AUCs of changes from baseline were compared between treatment groups using ANCOVA methods with baseline value as a covariate.

    Secondary: AUCave of the change from baseline to Week 24 in physical functioning score as assessed by the CFQ-R

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    End point title
    		 AUCave of the change from baseline to Week 24 in physical functioning score as assessed by the CFQ-R
    End point description
    The change (AUCave) from baseline to Week 24 in the physical functioning score as assessed by the CFQ-R was analyzed. The range of scores (units) in the CFQ-R physical functioning domain is 0 to 100 with higher scores indicating better QOL.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 AZLI Placebo
    Number of subjects analysed
    46
    52
    Units: units on a scale
        least squares mean (standard error)
    1.06 ( 1.57 )
    -1.93 ( 1.48 )
    Statistical analysis title
    		 AZLI vs placebo: Physical Functioning Score
    Statistical analysis description
    Null hypothesis was that there was no difference between the AZLI and placebo treatment groups versus the alternative hypothesis that there was a difference.
    Comparison groups
    AZLI v Placebo
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.17 [7]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in least squares mean (LSM)
    Point estimate
    2.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 7.28
    Notes
    [7] - Baseline was included as a covariate in this model.

    Secondary: AUCave of the change from baseline to Week 24 in weight score as assessed by the CFQ-R

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    End point title
    		 AUCave of the change from baseline to Week 24 in weight score as assessed by the CFQ-R
    End point description
    The change (AUCave) from baseline to Week 24 in the weight score as assessed by the CFQ-R was analyzed. The range of scores (units) in the CFQ-R weight domain is 0 to 100 with higher scores indicating better QOL.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 AZLI Placebo
    Number of subjects analysed
    44
    47
    Units: units on a scale
        least squares mean (standard error)
    0.54 ( 2.9 )
    3.11 ( 2.8 )
    Statistical analysis title
    		 AZLI vs placebo: Change in Weight Score
    Statistical analysis description
    Null hypothesis was that there was no difference between the AZLI and placebo treatment groups versus the alternative hypothesis that there was a difference.
    Comparison groups
    AZLI v Placebo
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.528 [8]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in least squares mean (LSM)
    Point estimate
    -2.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.62
         upper limit
    		 5.49
    Notes
    [8] - Baseline was included as a covariate in this model.

    Secondary: AUCave of the change from baseline to Week 24 in treatment burden score as assessed by the CFQ-R

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    End point title
    		 AUCave of the change from baseline to Week 24 in treatment burden score as assessed by the CFQ-R
    End point description
    The change (AUCave) from baseline to Week 24 in the treatment burden score as assessed by the CFQ-R was analyzed. The range of scores (units) in the CFQ-R treatment burden domain is 0 to 100 with higher scores indicating better QOL.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 AZLI Placebo
    Number of subjects analysed
    46
    52
    Units: units on a scale
        least squares mean (standard error)
    -2.73 ( 1.73 )
    -6.35 ( 1.62 )
    Statistical analysis title
    		 AZLI vs placebo: Change in Treatment Burden Score
    Statistical analysis description
    Null hypothesis was that there was no difference between the AZLI and placebo treatment groups versus the alternative hypothesis that there was a difference.
    Comparison groups
    AZLI v Placebo
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.132 [9]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in least squares mean (LSM)
    Point estimate
    3.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.11
         upper limit
    		 8.34
    Notes
    [9] - Baseline was included as a covariate in this model.

    Secondary: Change in BMI from baseline to Week 24

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    End point title
    		 Change in BMI from baseline to Week 24
    End point description
    The change in BMI from baseline to Week 24 was analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 AZLI Placebo
    Number of subjects analysed
    39
    45
    Units: kg/m^2
        least squares mean (standard error)
    0.34 ( 0.16 )
    0.21 ( 0.15 )
    Statistical analysis title
    		 AZLI vs placebo: Change in BMI
    Statistical analysis description
    Null hypothesis was that there was no difference between the AZLI and placebo treatment groups versus the alternative hypothesis that there was a difference.
    Comparison groups
    AZLI v Placebo
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.531 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in least squares mean (LSM)
    Point estimate
    0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.29
         upper limit
    		 0.56
    Notes
    [10] - P-value was based on a Mixed-Effect Model Repeated Measure model that included terms for treatment, visit, baseline, and treatment/visit interaction.

    Secondary: Change in Burkholderia spp. CFU in sputum from baseline to Week 24

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    End point title
    		 Change in Burkholderia spp. CFU in sputum from baseline to Week 24
    End point description
    The change in Burkholderia spp. CFU in sputum from baseline to Week 24 was analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 AZLI Placebo
    Number of subjects analysed
    15
    20
    Units: log_10 CFU per gram of sputum
        least squares mean (standard error)
    1.41 ( 0.58 )
    0.48 ( 0.5 )
    Statistical analysis title
    		 AZLI vs placebo: Change in Burkholderia Spp. CFU
    Statistical analysis description
    Null hypothesis was that there was no difference between the AZLI and placebo treatment groups versus the alternative hypothesis that there was a difference.
    Comparison groups
    AZLI v Placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.232 [11]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in least squares mean (LSM)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.62
         upper limit
    		 2.48
    Notes
    [11] - Baseline was included as a covariate in this model.

    Secondary: Percentage of days participants used antibiotics

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    End point title
    		 Percentage of days participants used antibiotics
    End point description
    The percentage of days participants used antibiotics from baseline to Week 24 was analyzed. Antibiotics ongoing at baseline or started on or after first dose date were included in the analysis. A single antibiotic course could represent the use of multiple antibiotics. Days of antibiotic use included unique days.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 AZLI Placebo
    Number of subjects analysed
    47
    52
    Units: percentage of days
        arithmetic mean (standard deviation)
    44.4 ( 35.2 )
    56.3 ( 34.8 )
    Statistical analysis title
    		 AZLI vs placebo: Percent of Days Using Antibiotics
    Statistical analysis description
    Null hypothesis was that there was no difference between the AZLI and placebo treatment groups versus the alternative hypothesis that there was a difference.
    Comparison groups
    AZLI v Placebo
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.103
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Percent of days hospitalized

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    End point title
    		 Percent of days hospitalized
    End point description
    The percentage of days hospitalized from baseline to Week 24 was analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 AZLI Placebo
    Number of subjects analysed
    48
    52
    Units: percentage of days
        arithmetic mean (standard deviation)
    4.9 ( 10.3 )
    4.8 ( 8.7 )
    Statistical analysis title
    		 AZLI vs placebo: Percent of Days Hospitalized
    Statistical analysis description
    Null hypothesis was that there was no difference between the AZLI and placebo treatment groups versus the alternative hypothesis that there was a difference.
    Comparison groups
    AZLI v Placebo
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.646
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Percentage of missed school or work days

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    End point title
    		 Percentage of missed school or work days
    End point description
    The percentage of days participants missed school or work from baseline to Week 24 was analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 AZLI Placebo
    Number of subjects analysed
    32
    40
    Units: percentage of days
        arithmetic mean (standard deviation)
    1.9 ( 3.3 )
    4.7 ( 7.2 )
    Statistical analysis title
    		 AZLI vs placebo: Percent Missed School/Work Days
    Statistical analysis description
    Null hypothesis was that there was no difference between the AZLI and placebo treatment groups versus the alternative hypothesis that there was a difference.
    Comparison groups
    AZLI v Placebo
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.284
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to Week 24
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    AZLI
    Reporting group description
    		 For the reporting of Adverse Events, this group includes participants who were randomized to receive AZLI at baseline, and were analyzed from Baseline to Week 24.

    Reporting group title
    Placebo
    Reporting group description
    		 For the reporting of Adverse Events, this group includes participants who were randomized to receive placebo at baseline, and were analyzed from Baseline to Week 24.

    Reporting group title
    Open-Label AZLI
    Reporting group description
    		 For the reporting of Adverse Events, this group includes participants who were randomized to receive either AZLI or placebo at baseline and switched to open-label AZLI for up to 24 weeks (analyzed from Week 24 to Week 48).

    Serious adverse events
    		 AZLI Placebo Open-Label AZLI
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 48 (35.42%)
    21 / 52 (40.38%)
    43 / 84 (51.19%)
         number of deaths (all causes)
    2
    0
    2
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Pulmonary function test decreased
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 52 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Procedural site reaction
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 52 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 52 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 52 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 52 (1.92%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 52 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 52 (1.92%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 52 (1.92%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 52 (1.92%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 52 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Haematospermia
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 52 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 52 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 52 (0.00%)
    4 / 84 (4.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 52 (1.92%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus disorder
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 52 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 52 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 52 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Lung disorder
         subjects affected / exposed
    7 / 48 (14.58%)
    14 / 52 (26.92%)
    18 / 84 (21.43%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 20
    0 / 24
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Respiratory arrest
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 52 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 52 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 52 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 52 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 52 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholethiasis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 52 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 52 (0.00%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis reactive
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 52 (1.92%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 52 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia bacterial
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 52 (1.92%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infective pulmonary exacerbation of cycstic fibrosis
         subjects affected / exposed
    10 / 48 (20.83%)
    6 / 52 (11.54%)
    19 / 84 (22.62%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 10
    0 / 26
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 52 (1.92%)
    2 / 84 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 52 (1.92%)
    0 / 84 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 52 (1.92%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 52 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 52 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 52 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 52 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 52 (0.00%)
    2 / 84 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 52 (0.00%)
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 AZLI Placebo Open-Label AZLI
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    47 / 48 (97.92%)
    46 / 52 (88.46%)
    83 / 84 (98.81%)
    Investigations
    Forced expiratory volume decreased
         subjects affected / exposed
    2 / 48 (4.17%)
    3 / 52 (5.77%)
    6 / 84 (7.14%)
         occurrences all number
    2
    4
    7
    Pulmonary function test decreased
         subjects affected / exposed
    5 / 48 (10.42%)
    8 / 52 (15.38%)
    12 / 84 (14.29%)
         occurrences all number
    5
    8
    17
    Weight decreased
         subjects affected / exposed
    3 / 48 (6.25%)
    3 / 52 (5.77%)
    11 / 84 (13.10%)
         occurrences all number
    3
    5
    13
    Breath sounds abmormal
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 52 (0.00%)
    6 / 84 (7.14%)
         occurrences all number
    2
    0
    7
    Vitamin D decreased
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 52 (0.00%)
    6 / 84 (7.14%)
         occurrences all number
    0
    0
    6
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 52 (1.92%)
    5 / 84 (5.95%)
         occurrences all number
    0
    1
    6
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    0 / 48 (0.00%)
    2 / 52 (3.85%)
    6 / 84 (7.14%)
         occurrences all number
    0
    2
    6
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 48 (10.42%)
    3 / 52 (5.77%)
    1 / 84 (1.19%)
         occurrences all number
    6
    4
    1
    Headache
         subjects affected / exposed
    6 / 48 (12.50%)
    7 / 52 (13.46%)
    14 / 84 (16.67%)
         occurrences all number
    6
    9
    21
    Sinus headache
         subjects affected / exposed
    8 / 48 (16.67%)
    3 / 52 (5.77%)
    10 / 84 (11.90%)
         occurrences all number
    8
    4
    11
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    13 / 48 (27.08%)
    8 / 52 (15.38%)
    15 / 84 (17.86%)
         occurrences all number
    15
    9
    23
    Chest pain
         subjects affected / exposed
    7 / 48 (14.58%)
    1 / 52 (1.92%)
    23 / 84 (27.38%)
         occurrences all number
    7
    1
    28
    Chills
         subjects affected / exposed
    6 / 48 (12.50%)
    2 / 52 (3.85%)
    11 / 84 (13.10%)
         occurrences all number
    6
    2
    12
    Exercise tolerance decreased
         subjects affected / exposed
    5 / 48 (10.42%)
    1 / 52 (1.92%)
    4 / 84 (4.76%)
         occurrences all number
    5
    1
    4
    Fatigue
         subjects affected / exposed
    10 / 48 (20.83%)
    11 / 52 (21.15%)
    26 / 84 (30.95%)
         occurrences all number
    11
    14
    30
    Non-cardiac chest pain
         subjects affected / exposed
    3 / 48 (6.25%)
    3 / 52 (5.77%)
    5 / 84 (5.95%)
         occurrences all number
    3
    3
    6
    Pain
         subjects affected / exposed
    6 / 48 (12.50%)
    2 / 52 (3.85%)
    8 / 84 (9.52%)
         occurrences all number
    7
    2
    10
    Pyrexia
         subjects affected / exposed
    19 / 48 (39.58%)
    17 / 52 (32.69%)
    35 / 84 (41.67%)
         occurrences all number
    28
    24
    52
    Asthenia
         subjects affected / exposed
    4 / 48 (8.33%)
    3 / 52 (5.77%)
    6 / 84 (7.14%)
         occurrences all number
    5
    3
    6
    Malaise
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 52 (1.92%)
    5 / 84 (5.95%)
         occurrences all number
    1
    1
    5
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 48 (6.25%)
    3 / 52 (5.77%)
    10 / 84 (11.90%)
         occurrences all number
    5
    3
    12
    Abdominal pain upper
         subjects affected / exposed
    4 / 48 (8.33%)
    1 / 52 (1.92%)
    3 / 84 (3.57%)
         occurrences all number
    4
    1
    3
    Constipation
         subjects affected / exposed
    3 / 48 (6.25%)
    3 / 52 (5.77%)
    6 / 84 (7.14%)
         occurrences all number
    4
    3
    8
    Diarrhoea
         subjects affected / exposed
    6 / 48 (12.50%)
    6 / 52 (11.54%)
    10 / 84 (11.90%)
         occurrences all number
    6
    8
    11
    Nausea
         subjects affected / exposed
    11 / 48 (22.92%)
    10 / 52 (19.23%)
    14 / 84 (16.67%)
         occurrences all number
    13
    11
    15
    Vomiting
         subjects affected / exposed
    7 / 48 (14.58%)
    5 / 52 (9.62%)
    8 / 84 (9.52%)
         occurrences all number
    7
    5
    10
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    34 / 48 (70.83%)
    32 / 52 (61.54%)
    65 / 84 (77.38%)
         occurrences all number
    52
    59
    129
    Dyspnoea
         subjects affected / exposed
    14 / 48 (29.17%)
    15 / 52 (28.85%)
    38 / 84 (45.24%)
         occurrences all number
    20
    21
    57
    Haemoptysis
         subjects affected / exposed
    13 / 48 (27.08%)
    17 / 52 (32.69%)
    19 / 84 (22.62%)
         occurrences all number
    25
    22
    33
    Increased viscosity of bronchial secretion
         subjects affected / exposed
    4 / 48 (8.33%)
    2 / 52 (3.85%)
    3 / 84 (3.57%)
         occurrences all number
    5
    2
    3
    Nasal congestion
         subjects affected / exposed
    12 / 48 (25.00%)
    14 / 52 (26.92%)
    30 / 84 (35.71%)
         occurrences all number
    14
    15
    34
    Oropharyngeal pain
         subjects affected / exposed
    15 / 48 (31.25%)
    11 / 52 (21.15%)
    30 / 84 (35.71%)
         occurrences all number
    17
    13
    33
    Paranasal sinus hypersecretion
         subjects affected / exposed
    2 / 48 (4.17%)
    3 / 52 (5.77%)
    4 / 84 (4.76%)
         occurrences all number
    2
    4
    4
    Pleuritic pain
         subjects affected / exposed
    3 / 48 (6.25%)
    0 / 52 (0.00%)
    4 / 84 (4.76%)
         occurrences all number
    4
    0
    5
    Productive cough
         subjects affected / exposed
    4 / 48 (8.33%)
    1 / 52 (1.92%)
    8 / 84 (9.52%)
         occurrences all number
    8
    2
    12
    Rales
         subjects affected / exposed
    5 / 48 (10.42%)
    6 / 52 (11.54%)
    13 / 84 (15.48%)
         occurrences all number
    6
    8
    15
    Respiratory tract congestion
         subjects affected / exposed
    7 / 48 (14.58%)
    14 / 52 (26.92%)
    24 / 84 (28.57%)
         occurrences all number
    9
    17
    28
    Rhinorrheoa
         subjects affected / exposed
    8 / 48 (16.67%)
    6 / 52 (11.54%)
    19 / 84 (22.62%)
         occurrences all number
    9
    6
    22
    Sinus congestion
         subjects affected / exposed
    8 / 48 (16.67%)
    5 / 52 (9.62%)
    15 / 84 (17.86%)
         occurrences all number
    11
    5
    19
    Sputum discoloured
         subjects affected / exposed
    1 / 48 (2.08%)
    3 / 52 (5.77%)
    8 / 84 (9.52%)
         occurrences all number
    1
    3
    11
    Sputum increased
         subjects affected / exposed
    23 / 48 (47.92%)
    20 / 52 (38.46%)
    33 / 84 (39.29%)
         occurrences all number
    31
    28
    47
    Upper-airway cough syndrome
         subjects affected / exposed
    4 / 48 (8.33%)
    6 / 52 (11.54%)
    4 / 84 (4.76%)
         occurrences all number
    4
    6
    4
    Wheezing
         subjects affected / exposed
    10 / 48 (20.83%)
    3 / 52 (5.77%)
    14 / 84 (16.67%)
         occurrences all number
    11
    4
    20
    Epistaxis
         subjects affected / exposed
    2 / 48 (4.17%)
    2 / 52 (3.85%)
    5 / 84 (5.95%)
         occurrences all number
    2
    2
    6
    Pharyngeal erythema
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 52 (1.92%)
    5 / 84 (5.95%)
         occurrences all number
    0
    1
    5
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    3 / 48 (6.25%)
    0 / 52 (0.00%)
    2 / 84 (2.38%)
         occurrences all number
    3
    0
    2
    Pruritus
         subjects affected / exposed
    1 / 48 (2.08%)
    3 / 52 (5.77%)
    3 / 84 (3.57%)
         occurrences all number
    1
    3
    4
    Rash
         subjects affected / exposed
    2 / 48 (4.17%)
    1 / 52 (1.92%)
    8 / 84 (9.52%)
         occurrences all number
    2
    1
    9
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 48 (8.33%)
    1 / 52 (1.92%)
    9 / 84 (10.71%)
         occurrences all number
    4
    1
    10
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 48 (6.25%)
    6 / 52 (11.54%)
    8 / 84 (9.52%)
         occurrences all number
    4
    7
    8
    Back pain
         subjects affected / exposed
    4 / 48 (8.33%)
    6 / 52 (11.54%)
    6 / 84 (7.14%)
         occurrences all number
    5
    6
    6
    Pain in extremity
         subjects affected / exposed
    1 / 48 (2.08%)
    2 / 52 (3.85%)
    5 / 84 (5.95%)
         occurrences all number
    1
    3
    5
    Myalgia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 52 (1.92%)
    6 / 84 (7.14%)
         occurrences all number
    0
    1
    6
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    0 / 48 (0.00%)
    3 / 52 (5.77%)
    1 / 84 (1.19%)
         occurrences all number
    0
    3
    1
    Sinusitis
         subjects affected / exposed
    1 / 48 (2.08%)
    4 / 52 (7.69%)
    9 / 84 (10.71%)
         occurrences all number
    1
    4
    10
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    8 / 48 (16.67%)
    6 / 52 (11.54%)
    15 / 84 (17.86%)
         occurrences all number
    9
    7
    18
    Hyperglycaemia
         subjects affected / exposed
    3 / 48 (6.25%)
    0 / 52 (0.00%)
    2 / 84 (2.38%)
         occurrences all number
    3
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Nov 2009
    Added an optional screening period and references to "Visit 1" and "Visit 2" were changed to "Screening" or "Baseline" for clarity because some subjects might have a combination visit instead.
    18 May 2010
    Clarified the definition of chronic infection with Burkholderia spp. to include bronchoalveolar lavage and oropharyngeal swab cultures in addition to sputum cultures.
    12 Jul 2010
    To increase the sample size from 76 subjects to 100 subjects.

    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.
    There were no limitations affecting the analysis or results.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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