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    Clinical Trial Results:
    An Open-Label, Randomized, Phase 3 Trial to Evaluate the Efficacy and Safety of Aztreonam 75 mg Powder and Diluent for Nebuliser Solution (AZLI) versus Tobramycin Nebuliser Solution (TNS) in an Intermittent Aerosolized Antibiotic Regimen, in Subjects with Cystic Fibrosis Followed by an Open-Label, Single Arm Extension

    Summary
    EudraCT number
    		 2007-004277-26
    Trial protocol
    		 BE   FR   ES   GB   IE   DK   DE   NL   IT   PT   AT   Outside EU/EEA  
    Global end of trial date
    22 Nov 2010

    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-205-0110
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00757237
    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
    17 May 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Nov 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study was to assess the comparative safety and effectiveness of aztreonam 75 mg powder and diluent for nebuliser solution (AZLI) versus tobramycin nebuliser solution (TNS) in adult and pediatric participants with cystic fibrosis (CF) and pulmonary Pseudomonas aeruginosa (PA) infection.
    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
    07 Aug 2008
    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
    Netherlands: 3
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Belgium: 21
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    France: 20
    Country: Number of subjects enrolled
    Germany: 36
    Country: Number of subjects enrolled
    Ireland: 13
    Country: Number of subjects enrolled
    Italy: 47
    Country: Number of subjects enrolled
    United States: 95
    Country: Number of subjects enrolled
    Switzerland: 5
    Worldwide total number of subjects
    274
    EEA total number of subjects
    174
    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)
    11
    Adolescents (12-17 years)
    49
    Adults (18-64 years)
    213
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Seventy-three sites in the United States (US) and European Union (EU) enrolled a total of 274 participants in the study.

    Pre-assignment
    Screening details
    		 274 participants enrolled in the study; 1 experienced a serious adverse event (SAE) and was not randomized; 273 were randomized; 268 were treated (136 AZLI; 132 TNS)

    Period 1
    Period 1 title
    Randomized Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AZLI (75 mg TID)
    Arm description
    		 Aztreonam 75 mg powder and diluent for nebuliser solution (AZLI) self-administered for 28 days for each treatment cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aztreonam 75 mg powder and diluent for nebuliser solution (AZLI)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    AZLI (75 mg/1 mL aztreonam lysine when reconstituted in diluent [0.17% saline]; sterile, pH 4.2 to 7.0, and osmolality 300 to 550 mOsmol/kg) self-administered by inhalation three times a day (TID) using the PARI eFlow electronic investigational nebulizer

    Arm title
    		 TNS (300 mg BID)
    Arm description
    		 Tobramycin nebulizer solution (TNS) self-administered for 28 days for each treatment cycle
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tobramycin nebulizer solution (TNS)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    TNS (300 mg/5 mL) was self-administered by inhalation two times a day (BID) using the PARI LC PLUS(TM) Nebulizer with Compressor

    Number of subjects in period 1 [1]
    		AZLI (75 mg TID) TNS (300 mg BID)
    Started
    136
    132
    Completed
    124
    111
    Not completed
    12
    21
         Physician decision
    2
    3
         Unknown
    -
    1
         Withdrawal by Subject
    7
    9
         Safety or Tolerability
    3
    5
         Lost to follow-up
    -
    1
         Protocol deviation
    -
    2
    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: Six participants who were enrolled but not treated are not included in the subject disposition table.
    Period 2
    Period 2 title
    Extension Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Open-label Extension
    Arm description
    		 Eligible participants had the option to enter the Open-label Extension Phase to receive 3 additional courses of AZLI over a period of 48 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aztreonam 75 mg powder and diluent for nebuliser solution (AZLI)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    AZLI (75 mg/1 mL aztreonam lysine when reconstituted in diluent [0.17% saline]; sterile, pH 4.2 to 7.0, and osmolality 300 to 550 mOsmol/kg) self-administered by inhalation three times a day (TID) using the PARI eFlow electronic investigational nebulizer

    Number of subjects in period 2 [2]
    		Open-label Extension
    Started
    133
    Completed
    118
    Not completed
    15
         Protocol violation
    1
         Safety or tolerability reasons
    6
         Subject relocated
    1
         Investigator's discretion
    4
         Withdrew consent
    3
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: All eligible participants, including participants who discontinued early from the Randomized Phase, had the option to enter the Open-label Extension Phase (in the EU) to receive expanded access AZLI prior to its commercial availability.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AZLI (75 mg TID)
    Reporting group description
    		 Aztreonam 75 mg powder and diluent for nebuliser solution (AZLI) self-administered for 28 days for each treatment cycle

    Reporting group title
    TNS (300 mg BID)
    Reporting group description
    		 Tobramycin nebulizer solution (TNS) self-administered for 28 days for each treatment cycle

    Reporting group values
    		 AZLI (75 mg TID) TNS (300 mg BID) Total
    Number of subjects
    		 136 132 268
    Age Categorical
    Units: participants
        ≥ 6 years to ≤ 12 years
    		 8 5 13
        > 12 years to < 18 years
    		 20 26 46
        ≥ 18 years
    		 108 101 209
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 25.8 ± 9.1 25.1 ± 9 -
    Gender, Male/Female
    Units: participants
        Female
    		 68 66 134
        Male
    		 68 66 134
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 1 0 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 1 1
        White
    		 130 131 261
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 5 0 5
    Inhaled Tobramycin Use in the Previous 12 Months
    Units: Subjects
        < 84 days
    		 21 19 40
        ≥ 84 days
    		 115 113 228
    Disease Severity
    Forced Expiratory Volume (FEV1) percent predicted is a normalized value of FEV1 calculated using the Knudson equation and based upon participant age, gender, and height. This baseline measure indicates the number of participants with FEV1 greater than 50% and less than or equal to 50% of the predicted value based on age, gender, and height at screening.
    Units: Subjects
        ≤ 50% predicted
    		 60 57 117
        > 50% predicted
    		 76 75 151
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 20.22 ± 2.95 20.49 ± 2.82 -
    Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS) Score
    The CFQ-R is a validated, patient-reported outcome tool measuring health-related quality of life for children and adults with CF. The CFQ-R contains both general and CF-specific scales. Respiratory symptoms (e.g., coughing, congestion, wheezing) are 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)
    		 62.87 ± 20.42 58.02 ± 20.76 -
    Forced Expiratory Volume (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)
    		 52.3 ± 15.56 52.24 ± 14.57 -

    End points

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    End points reporting groups
    Reporting group title
    AZLI (75 mg TID)
    Reporting group description
    		 Aztreonam 75 mg powder and diluent for nebuliser solution (AZLI) self-administered for 28 days for each treatment cycle

    Reporting group title
    TNS (300 mg BID)
    Reporting group description
    		 Tobramycin nebulizer solution (TNS) self-administered for 28 days for each treatment cycle
    Reporting group title
    Open-label Extension
    Reporting group description
    		 Eligible participants had the option to enter the Open-label Extension Phase to receive 3 additional courses of AZLI over a period of 48 weeks.

    Primary: Relative Change from Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted at Day 28

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    End point title
    		 Relative Change from Baseline in Forced Expiratory Volume in 1 Second (FEV1) Percent Predicted at Day 28
    End point description
    Spirometry was performed according to American Thoracic Society (ATS) guidelines at each visit. FEV1 percent predicted is a normalized value of FEV1 calculated using the Knudson equation and based upon participant age, gender, and height. Treatment effect on the relative change from baseline in FEV1 percent predicted at Day 28 (Visit 4) was tested using an analysis of covariance (ANCOVA) model-based method. Analysis was based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug). The last observation carried forward (LOCF) method was used to impute missing data.
    End point type
    Primary
    End point timeframe
    Baseline and end of treatment Course 1 (Day 28)
    End point values
    		 AZLI (75 mg TID) TNS (300 mg BID)
    Number of subjects analysed
    136
    132
    Units: percent change in FEV1 percent predicted
        least squares mean (standard error)
    8.35 ± 1.7
    0.55 ± 1.77
    Statistical analysis title
    		 AZLI vs TNS: Mean relative change of FEV1 percent
    Statistical analysis description
    Null hypothesis: AZLI was inferior to TNS by more than 4% in the mean relative change of FEV1 percent predicted at Day 28. With 120 subjects per treatment group there was at least 85% power to declare noninferiority based on relative change from baseline at Day 28 in FEV1 percent predicted using the upper bound of a 2-tailed 95% CI for the difference in means with a noninferiority margin of 4, assuming a common standard deviation of 18% and true difference in means [TNS-AZLI] of -3.2%.
    Comparison groups
    AZLI (75 mg TID) v TNS (300 mg BID)
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -7.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.73
         upper limit
    		 -3.86
    Notes
    [1] - The treatment difference (TNS-AZLI) and standard error from the ANCOVA model were used to compute the two-sided 95% confidence interval. If the 95% upper boundary was less than the pre-specified non-inferiority margin of 4%, then the null hypothesis was rejected. The non-inferiority statistical analysis type was requested by the EMA.

    Primary: Mean Actual change from baseline in FEV1 percent predicted across 3 treatment courses

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    End point title
    		 Mean Actual change from baseline in FEV1 percent predicted across 3 treatment courses
    End point description
    Spirometry was performed according to ATS guidelines at each visit. FEV1 percent predicted is a normalized value of FEV1 calculated using the Knudson equation and based upon participant age, gender, and height. Analysis was based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug). Treatment effect on the average adjusted means for the actual change in FEV1 percent predicted at Visits 4, 6, and 8 (Weeks 4, 12, and 20) was tested by mixed-effect model repeated measures (MMRM) analysis using the ITT population analysis set.
    End point type
    Primary
    End point timeframe
    Baseline, and end of treatment Courses 1 (Week 4), 2 (Week 12), and 3 (Week 20)
    End point values
    		 AZLI (75 mg TID) TNS (300 mg BID)
    Number of subjects analysed
    136
    132
    Units: actual change in FEV1 percent predicted
        least squares mean (standard error)
    2.05 ± 0.69
    -0.66 ± 0.72
    Statistical analysis title
    		 AZLI vs TNS: Mean actual change of FEV1 percent
    Statistical analysis description
    Null hypothesis: there was no difference between AZLI and TNS treatment groups in the mean actual change of FEV1 percent predicted across 3 treatment courses among all participants. With 120 subjects per treatment group, there was at least 90% power at a 5% significance level to detect differences based upon actual change from baseline in FEV1 percent predicted (3.61%, 2.98%, 2.32%) between AZLI and TNS at Weeks 4, 12, and 20 with a common standard deviation of 9%.
    Comparison groups
    AZLI (75 mg TID) v TNS (300 mg BID)
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0023 [2]
    Method
    		 MMRM analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.43
         upper limit
    		 -0.98
    Notes
    [2] - Based on the Benjamini & Hochberg method, superiority at Weeks 4, 12, and 20 of actual change in FEV1 percent predicted was tested at the 0.05 level, given the significance of the coprimary endpoint (p < 0.05).

    Secondary: Relative change from baseline in FEV1 percent predicted at Day 28 in subjects who received inhaled tobramycin for ≥ 84 days in the 12 months prior to randomization

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    End point title
    		 Relative change from baseline in FEV1 percent predicted at Day 28 in subjects who received inhaled tobramycin for ≥ 84 days in the 12 months prior to randomization
    End point description
    Spirometry was performed according to ATS guidelines. FEV1 percent predicted is a normalized value of FEV1 calculated using the Knudson equation and based upon participant age, gender, and height. Treatment effect on the relative change from baseline in FEV1 percent predicted at Day 28 (Visit 4) was tested using an ANCOVA model-based method, using the population of participants with prior inhaled tobramycin use of ≥ 84 days in the previous 12 months. Analysis was based on participants with previous inhaled tobramycin use of ≥ 84 days within the previous 12 months using the ITT analysis set. The last observation carried forward (LOCF) method was used to impute missing data for statistical analyses.
    End point type
    Secondary
    End point timeframe
    Baseline and end of treatment Course 1 (Day 28)
    End point values
    		 AZLI (75 mg TID) TNS (300 mg BID)
    Number of subjects analysed
    115
    113
    Units: percent change in FEV1 percent predicted
        least squares mean (standard error)
    10.04 ± 1.56
    0.54 ± 1.57
    Statistical analysis title
    		 AZLI vs TNS: Mean relative change of FEV1 percent
    Statistical analysis description
    Null hypothesis: AZLI was inferior to TNS by more than 4% in terms of the participant means in relative change of FEV1 percent predicted at Day 28 among all participants having ≥ 84 days of inhaled tobramycin use in the previous 12 months.
    Comparison groups
    AZLI (75 mg TID) v TNS (300 mg BID)
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 < 0.0001 [4]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -9.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.86
         upper limit
    		 -5.14
    Notes
    [3] - The treatment difference (TNS-AZLI) and standard error from the ANCOVA model were used to compute the two-sided 95% confidence interval. If the 95% upper boundary was less than the pre-specified non-inferiority margin of 4%, then the null hypothesis was rejected.
    [4] - Secondary endpoints were tested sequentially by the closed testing procedure initiated by the significance of the primary endpoints. Given the coprimary endpoints were met at the 0.05 level, this non-inferiority endpoint was tested at the 0.05 level.

    Secondary: Mean Actual change from baseline in FEV1 percent predicted across 3 treatment courses in subjects who received inhaled tobramycin for ≥ 84 days in the 12 months prior to randomization

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    End point title
    		 Mean Actual change from baseline in FEV1 percent predicted across 3 treatment courses in subjects who received inhaled tobramycin for ≥ 84 days in the 12 months prior to randomization
    End point description
    Spirometry was performed according to ATS guidelines at each visit. FEV1 percent predicted is a normalized value of FEV1 calculated using the Knudson equation and based upon participant age, gender, and height. Analysis was based on participants with prior inhaled tobramycin use ≥ 84 days in the previous 12 months using the ITT analysis set. Treatment effect on the average adjusted means for the actual change in FEV1 percent predicted at Visits 4, 6, and 8 (Weeks 4, 12, and 20) was tested by MMRM analysis using the population of participants with prior inhaled tobramycin use of ≥ 84 days in the previous 12 months.
    End point type
    Secondary
    End point timeframe
    Baseline and end of treatment Courses 1 (Week 4), 2 (Week 12), and 3 (Week 20)
    End point values
    		 AZLI (75 mg TID) TNS (300 mg BID)
    Number of subjects analysed
    115
    113
    Units: actual change in FEV1 percent predicted
        least squares mean (standard error)
    3.26 ± 0.65
    -0.21 ± 0.66
    Statistical analysis title
    		 AZLI vs TNS: Mean actual change of FEV1 percent
    Statistical analysis description
    Null hypothesis: there was no difference between AZLI and TNS treatment groups in the mean actual change of FEV1 percent predicted across 3 treatment courses in the stratum of subjects having ≥ 84 days of inhaled tobramycin use in the previous 12 months.
    Comparison groups
    AZLI (75 mg TID) v TNS (300 mg BID)
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.0002 [6]
    Method
    		 MMRM analysis
    Confidence interval
    Notes
    [5] - Comparative analysis
    [6] - Secondary endpoints were tested sequentially to control the Type I error rate based on the closed testing procedure. Given the significance of the coprimary endpoints and previous secondary endpoint, this endpoint was also tested at the 0.05 level.

    Secondary: Time to need for intravenous (IV) antipseudomonal antibiotics for respiratory events

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    End point title
    		 Time to need for intravenous (IV) antipseudomonal antibiotics for respiratory events
    End point description
    IV antipseudomonal antibiotic use for a respiratory event was determined through the adjudication of events by a sponsor-independent, blinded review committee. Use was compiled from data recorded on the concomitant medications electronic case report form (eCRF) and compared to reported adverse events (AEs) to determine use for a respiratory event. The time to IV antipseudomonal antibiotic use was measured in days from baseline (Visit 2) to the date of first IV antipseudomonal antibiotic use or the date of study completion (last visit)/or early withdrawal if censored. Analysis was based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug). 9999 = Median not reached due to insufficient number of events. 99999 = Upper limit of the 95% CI not reached due to insufficient number of events.
    End point type
    Secondary
    End point timeframe
    Day 0 to Day 168 (end of study)
    End point values
    		 AZLI (75 mg TID) TNS (300 mg BID)
    Number of subjects analysed
    136
    132
    Units: days
        median (confidence interval 95%)
    9999 (177 to 99999)
    151 (113 to 99999)
    Statistical analysis title
    		 AZLI vs TNS: Time needed for IV antibiotics
    Statistical analysis description
    Null hypothesis: there was no difference between AZLI and TNS treatment groups with respect to time to need for IV antipseudomonal antibiotics for respiratory events.
    Comparison groups
    AZLI (75 mg TID) v TNS (300 mg BID)
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.0025 [8]
    Method
    		 Logrank
    Confidence interval
    Notes
    [7] - Comparative analysis
    [8] - Secondary endpoints were tested sequentially to control the Type I error rate based on the closed testing procedure. Given the significance of the coprimary endpoints and previous secondary endpoint, this endpoint was also tested at the 0.05 level.

    Secondary: Time to first respiratory hospitalization

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    End point title
    		 Time to first respiratory hospitalization
    End point description
    This endpoint was determined through the adjudication of events by a sponsor-independent, blinded review committee. Committee members reviewed all hospitalizations and determined which were related to respiratory events. Analysis was based on ITT population (all participants randomized to treatment who received at least part of one dose of study drug). Details of all hospitalizations, including the dates of admission and discharge, were recorded on the serious adverse event (SAE) eCRF. Time to first respiratory hospitalization was the number of days from baseline (Visit 2) to the date of first respiratory hospitalization or the date of study completion (last visit) /or early withdrawal if censored. 999 = Lower limit of the 95% CI not reached due to insufficient number of events. 9999 = Median not reached due to insufficient number of events. 99999 = Upper limit of the 95% CI not reached due to insufficient number of events.
    End point type
    Secondary
    End point timeframe
    Day 0 to Day 168 (end of study)
    End point values
    		 AZLI (75 mg TID) TNS (300 mg BID)
    Number of subjects analysed
    136
    132
    Units: days
        median (confidence interval 95%)
    9999 (999 to 99999)
    9999 (999 to 99999)
    Statistical analysis title
    		 AZLI vs TNS: Time to first resp hospitalization
    Statistical analysis description
    Null hypothesis: there was no difference between AZLI and TNS treatment groups with respect to time to first respiratory hospitalization.
    Comparison groups
    AZLI (75 mg TID) v TNS (300 mg BID)
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1114 [9]
    Method
    		 Logrank
    Confidence interval
    Notes
    [9] - Secondary endpoints were tested sequentially to control the Type I error rate based on the closed testing procedure. Given the significance of the coprimary endpoints and previous secondary endpoint, this endpoint was also tested at the 0.05 level.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events (AEs) were collected continuously from Day 0 (first dose) through Day 168 (Week 24), and for an additional 48 weeks during the optional extension phase (open-label AZLI).
    Adverse event reporting additional description
    An AE was any physical/clinical worsening in symptoms/disease (including clinically significant change in lab values) experienced by a participant at any time during study, whether or not the AE was considered related to study participation or procedures. Participants were only counted once within a System Organ Class (SOC) and preferred term.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.1
    Reporting groups
    Reporting group title
    AZLI (75 mg TID)
    Reporting group description
    		 AZLI self-administered for 28 days for each treatment cycle

    Reporting group title
    TNS (300 mg BID)
    Reporting group description
    		 TNS self-administered for 28 days for each treatment cycle

    Reporting group title
    Open-Label AZLI
    Reporting group description
    		 -

    Serious adverse events
    		 AZLI (75 mg TID) TNS (300 mg BID) Open-Label AZLI
    Total subjects affected by serious adverse events
         subjects affected / exposed
    42 / 136 (30.88%)
    44 / 132 (33.33%)
    35 / 133 (26.32%)
         number of deaths (all causes)
    2
    1
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Hyperaemia
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 132 (0.76%)
    0 / 133 (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
    Vein Disorder
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 132 (0.76%)
    0 / 133 (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
    General disorders and administration site conditions
    Chest Discomfort
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 132 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest Pain
         subjects affected / exposed
    3 / 136 (2.21%)
    2 / 132 (1.52%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 132 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Exercise Tolerance Decreased
         subjects affected / exposed
    6 / 136 (4.41%)
    3 / 132 (2.27%)
    9 / 133 (6.77%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 136 (0.74%)
    3 / 132 (2.27%)
    4 / 133 (3.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 132 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema Peripheral
         subjects affected / exposed
    0 / 136 (0.00%)
    2 / 132 (1.52%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    2 / 136 (1.47%)
    0 / 132 (0.00%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    11 / 136 (8.09%)
    8 / 132 (6.06%)
    9 / 133 (6.77%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 10
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 132 (0.00%)
    1 / 133 (0.75%)
         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
    Cough
         subjects affected / exposed
    27 / 136 (19.85%)
    26 / 132 (19.70%)
    22 / 133 (16.54%)
         occurrences causally related to treatment / all
    0 / 31
    0 / 30
    0 / 32
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    10 / 136 (7.35%)
    15 / 132 (11.36%)
    9 / 133 (6.77%)
         occurrences causally related to treatment / all
    1 / 13
    0 / 17
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea Exertional
         subjects affected / exposed
    1 / 136 (0.74%)
    1 / 132 (0.76%)
    0 / 133 (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
    Haemoptysis
         subjects affected / exposed
    5 / 136 (3.68%)
    3 / 132 (2.27%)
    6 / 133 (4.51%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 4
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 132 (0.00%)
    0 / 133 (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
    Lung Infiltration
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 132 (0.76%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasal Congestion
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 132 (0.00%)
    0 / 133 (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
    Nasal Mucosal Disorder
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 132 (0.00%)
    0 / 133 (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
    Oropharyngeal Pain
         subjects affected / exposed
    4 / 136 (2.94%)
    0 / 132 (0.00%)
    2 / 133 (1.50%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleuritic Pain
         subjects affected / exposed
    0 / 136 (0.00%)
    2 / 132 (1.52%)
    2 / 133 (1.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Productive Cough
         subjects affected / exposed
    16 / 136 (11.76%)
    23 / 132 (17.42%)
    20 / 133 (15.04%)
         occurrences causally related to treatment / all
    1 / 20
    0 / 29
    0 / 28
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rales
         subjects affected / exposed
    2 / 136 (1.47%)
    3 / 132 (2.27%)
    2 / 133 (1.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory Tract Congestion
         subjects affected / exposed
    1 / 136 (0.74%)
    3 / 132 (2.27%)
    4 / 133 (3.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhinorrhoea
         subjects affected / exposed
    3 / 136 (2.21%)
    0 / 132 (0.00%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhonchi
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 132 (0.00%)
    0 / 133 (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
    Sinus Congestion
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 132 (0.00%)
    0 / 133 (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
    Sputum Discoloured
         subjects affected / exposed
    2 / 136 (1.47%)
    1 / 132 (0.76%)
    3 / 133 (2.26%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachypnoea
         subjects affected / exposed
    1 / 136 (0.74%)
    2 / 132 (1.52%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wheezing
         subjects affected / exposed
    3 / 136 (2.21%)
    5 / 132 (3.79%)
    4 / 133 (3.01%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchial Secretion Retention
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 132 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Increased Bronchial Secretion
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 132 (0.00%)
    1 / 133 (0.75%)
         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
    Insomnia
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 132 (0.00%)
    0 / 133 (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
    Investigations
    Body Temperature Increased
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 132 (0.76%)
    2 / 133 (1.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breath Sounds Abnormal
         subjects affected / exposed
    1 / 136 (0.74%)
    1 / 132 (0.76%)
    0 / 133 (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
    C-Reactive Protein Increased
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 132 (0.00%)
    0 / 133 (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
    Forced Expiratory Volume Decreased
         subjects affected / exposed
    3 / 136 (2.21%)
    0 / 132 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Glycosylated Haemoglobin Increased
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 132 (0.76%)
    0 / 133 (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
    Oxygen Saturation Decreased
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 132 (0.76%)
    5 / 133 (3.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Function Test Decreased
         subjects affected / exposed
    5 / 136 (3.68%)
    4 / 132 (3.03%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight Decreased
         subjects affected / exposed
    1 / 136 (0.74%)
    2 / 132 (1.52%)
    2 / 133 (1.50%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol Poisoning
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 132 (0.00%)
    0 / 133 (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
    Feeding Tube Complication
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 132 (0.00%)
    0 / 133 (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
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 132 (0.76%)
    0 / 133 (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
    Cyanosis
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 132 (0.76%)
    0 / 133 (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
    Tachycardia
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 132 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Coma
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 132 (0.00%)
    0 / 133 (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
    Headache
         subjects affected / exposed
    1 / 136 (0.74%)
    1 / 132 (0.76%)
    2 / 133 (1.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 132 (0.00%)
    3 / 133 (2.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Poor Quality Sleep
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 132 (0.00%)
    0 / 133 (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
    Sinus Headache
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 132 (0.00%)
    0 / 133 (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
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 132 (0.76%)
    0 / 133 (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
    Gastrointestinal disorders
    Abdominal Distension
         subjects affected / exposed
    0 / 136 (0.00%)
    2 / 132 (1.52%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal Discomfort
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 132 (0.00%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    5 / 136 (3.68%)
    1 / 132 (0.76%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 132 (0.00%)
    0 / 133 (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
    Nausea
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 132 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    4 / 136 (2.94%)
    0 / 132 (0.00%)
    2 / 133 (1.50%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 132 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Anuria
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 132 (0.76%)
    0 / 133 (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
    Diabetic Nephropathy
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 132 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 132 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 132 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Joint Swelling
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 132 (0.76%)
    0 / 133 (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
    Muscle Spasms
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 132 (0.00%)
    0 / 133 (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
    Pain in Extremity
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 132 (0.76%)
    0 / 133 (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
    Back Pain
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 132 (0.00%)
    2 / 133 (1.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Catheter Related Infection
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 132 (0.00%)
    0 / 133 (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
    Systemic Candida
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 132 (0.00%)
    0 / 133 (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
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    3 / 136 (2.21%)
    2 / 132 (1.52%)
    5 / 133 (3.76%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes Mellitus Inadequate Control
         subjects affected / exposed
    2 / 136 (1.47%)
    0 / 132 (0.00%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anorexia
         subjects affected / exposed
    0 / 136 (0.00%)
    0 / 132 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         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 (75 mg TID) TNS (300 mg BID) Open-Label AZLI
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    123 / 136 (90.44%)
    125 / 132 (94.70%)
    118 / 133 (88.72%)
    Investigations
    Breath Sounds Abnormal
         subjects affected / exposed
    7 / 136 (5.15%)
    14 / 132 (10.61%)
    5 / 133 (3.76%)
         occurrences all number
    10
    18
    5
    Forced Expiratory Volume Decreased
         subjects affected / exposed
    7 / 136 (5.15%)
    5 / 132 (3.79%)
    4 / 133 (3.01%)
         occurrences all number
    10
    6
    5
    Pulmonary Function Test Decreased
         subjects affected / exposed
    6 / 136 (4.41%)
    15 / 132 (11.36%)
    9 / 133 (6.77%)
         occurrences all number
    8
    18
    10
    Nervous system disorders
    Headache
         subjects affected / exposed
    28 / 136 (20.59%)
    27 / 132 (20.45%)
    21 / 133 (15.79%)
         occurrences all number
    69
    42
    41
    General disorders and administration site conditions
    Chest Pain
         subjects affected / exposed
    6 / 136 (4.41%)
    8 / 132 (6.06%)
    4 / 133 (3.01%)
         occurrences all number
    6
    11
    5
    Chest Discomfort
         subjects affected / exposed
    13 / 136 (9.56%)
    13 / 132 (9.85%)
    4 / 133 (3.01%)
         occurrences all number
    16
    16
    4
    Exercise Tolerance Decreased
         subjects affected / exposed
    20 / 136 (14.71%)
    24 / 132 (18.18%)
    8 / 133 (6.02%)
         occurrences all number
    24
    32
    8
    Fatigue
         subjects affected / exposed
    23 / 136 (16.91%)
    22 / 132 (16.67%)
    8 / 133 (6.02%)
         occurrences all number
    28
    30
    10
    Pain
         subjects affected / exposed
    9 / 136 (6.62%)
    4 / 132 (3.03%)
    1 / 133 (0.75%)
         occurrences all number
    10
    6
    1
    Pyrexia
         subjects affected / exposed
    34 / 136 (25.00%)
    36 / 132 (27.27%)
    41 / 133 (30.83%)
         occurrences all number
    55
    52
    62
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    15 / 136 (11.03%)
    8 / 132 (6.06%)
    9 / 133 (6.77%)
         occurrences all number
    17
    13
    13
    Diarrhoea
         subjects affected / exposed
    4 / 136 (2.94%)
    12 / 132 (9.09%)
    13 / 133 (9.77%)
         occurrences all number
    4
    16
    20
    Nausea
         subjects affected / exposed
    13 / 136 (9.56%)
    10 / 132 (7.58%)
    7 / 133 (5.26%)
         occurrences all number
    15
    14
    7
    Vomiting
         subjects affected / exposed
    12 / 136 (8.82%)
    14 / 132 (10.61%)
    4 / 133 (3.01%)
         occurrences all number
    15
    15
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    92 / 136 (67.65%)
    95 / 132 (71.97%)
    81 / 133 (60.90%)
         occurrences all number
    168
    174
    142
    Dysphonia
         subjects affected / exposed
    5 / 136 (3.68%)
    8 / 132 (6.06%)
    4 / 133 (3.01%)
         occurrences all number
    5
    10
    4
    Dyspnoea
         subjects affected / exposed
    26 / 136 (19.12%)
    28 / 132 (21.21%)
    21 / 133 (15.79%)
         occurrences all number
    32
    45
    25
    Haemoptysis
         subjects affected / exposed
    30 / 136 (22.06%)
    20 / 132 (15.15%)
    12 / 133 (9.02%)
         occurrences all number
    45
    32
    20
    Nasal Congestion
         subjects affected / exposed
    29 / 136 (21.32%)
    26 / 132 (19.70%)
    10 / 133 (7.52%)
         occurrences all number
    42
    33
    13
    Oropharyngeal Pain
         subjects affected / exposed
    34 / 136 (25.00%)
    37 / 132 (28.03%)
    20 / 133 (15.04%)
         occurrences all number
    39
    46
    27
    Productive Cough
         subjects affected / exposed
    63 / 136 (46.32%)
    67 / 132 (50.76%)
    52 / 133 (39.10%)
         occurrences all number
    94
    108
    71
    Rales
         subjects affected / exposed
    29 / 136 (21.32%)
    32 / 132 (24.24%)
    16 / 133 (12.03%)
         occurrences all number
    32
    43
    23
    Respiratory Tract Congestion
         subjects affected / exposed
    15 / 136 (11.03%)
    16 / 132 (12.12%)
    7 / 133 (5.26%)
         occurrences all number
    26
    23
    10
    Rhinitis
         subjects affected / exposed
    4 / 136 (2.94%)
    7 / 132 (5.30%)
    0 / 133 (0.00%)
         occurrences all number
    5
    7
    0
    Rhinorrhoea
         subjects affected / exposed
    24 / 136 (17.65%)
    33 / 132 (25.00%)
    21 / 133 (15.79%)
         occurrences all number
    31
    37
    27
    Sinus Congestion
         subjects affected / exposed
    3 / 136 (2.21%)
    8 / 132 (6.06%)
    1 / 133 (0.75%)
         occurrences all number
    5
    8
    1
    Wheezing
         subjects affected / exposed
    13 / 136 (9.56%)
    15 / 132 (11.36%)
    8 / 133 (6.02%)
         occurrences all number
    13
    19
    8
    Musculoskeletal and connective tissue disorders
    Arthalgia
         subjects affected / exposed
    10 / 136 (7.35%)
    2 / 132 (1.52%)
    9 / 133 (6.77%)
         occurrences all number
    15
    2
    9
    Back Pain
         subjects affected / exposed
    7 / 136 (5.15%)
    4 / 132 (3.03%)
    4 / 133 (3.01%)
         occurrences all number
    10
    4
    4
    Myalgia
         subjects affected / exposed
    9 / 136 (6.62%)
    6 / 132 (4.55%)
    2 / 133 (1.50%)
         occurrences all number
    10
    6
    3
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    17 / 136 (12.50%)
    17 / 132 (12.88%)
    5 / 133 (3.76%)
         occurrences all number
    21
    20
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Dec 2007
    Removed the requirement for previous inhaled tobramycin use in order to better reflect overall cystic fibrosis population and adjusted the sample size from 160 to 200 randomized to power the noninferiority analysis.
    10 Sep 2008
    Added an open label, single arm extension, to provide expanded access to AZLI prior to its commercial availability in the EU.
    31 Jul 2009
    Increased the study sample size from 200 subjects to 240 subjects to ensure adequate power for the primary superiority analysis and updated the statistical methods to reflect the change in primary analysis from noninferiority to superiority.
    01 Oct 2009
    To satisfy the requirements of the two health authorities, the analysis plan was revised to include coprimary endpoints: one for the EMA and one for the FDA. The noninferiority endpoint from the original protocol became a coprimary endpoint. Secondary endpoints were revised based on updated analysis plan. The sample size was increased to 240 subjects in order to adequately power these additional analyses.
    12 Feb 2010
    Revised one coprimary endpoint from relative change to actual change from baseline in FEV1 % predicted across 3 treatment courses among all subjects and added an over-enrollment threshold of 15% to the target enrollment of 240 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.
    None reported
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    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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