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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Aztreonam for Inhalation Solution (AZLI) in a Continuous Alternating Therapy (CAT) Regimen of Inhaled Antibiotics for the Treatment of Chronic Pulmonary Pseudomonas aeruginosa Infection in Subjects with Cystic Fibrosis

    Summary
    EudraCT number
    		 2015-000398-11
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    15 Jan 2015

    Results information
    Results version number
    		 v2(current)
    This version publication date
    22 Apr 2016
    First version publication date
    31 Jul 2015
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    • Correction of full data set
    Correction of data entry errors and descriptive text, and addition of "Age, categorical" to baseline characteristics.

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-205-0170
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01641822
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND No: 064402, Clinical Trials.gov: NCT01641822
    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
    15 Jan 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Jan 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the safety and efficacy of a CAT regimen with aztreonam for inhalation solution (AZLI) and tobramycin inhalation solution (TIS) in adult and pediatric subjects with cystic fibrosis (CF) and pulmonary Pseudomonas aeruginosa (PA) infection. Participants were enrolled in a 28 day TIS run-in phase, and were eligible for randomization in the comparative phase if they had not received non-study oral antibiotics for a respiratory event or IV or inhaled antibiotics for any indication between Visits 2 and 3, had not developed a condition requiring hospitalization or other change in clinical status which, in the opinion of the investigator would preclude their ability to continue in the study, and had demonstrated at least 50% TIS compliance. Participants enrolled in the comparative phase were randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: AZLI or placebo for 28 days followed by TIS for 28 days.
    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
    13 Dec 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 107
    Worldwide total number of subjects
    107
    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)
    6
    Adolescents (12-17 years)
    13
    Adults (18-64 years)
    87
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in the United States. The first participant was screened on 13 December 2012. The last study visit occurred on 15 January 2015.

    Pre-assignment
    Screening details
    		 Following enrollment, participants received tobramycin inhalation solution (TIS) in the TIS Run-In Phase, and if still eligible were randomized 1 to 1 to receive aztreonam for inhalation solution (AZLI) or placebo to match AZLI alternating with TIS in the Comparative Phase.

    Period 1
    Period 1 title
    TIS Run-In Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 TIS Run-In Treatment Group
    Arm description
    		 Enrolled participants received 28 days of TIS during the run-in phase.
    Arm type
    		 Standard of care

    Investigational medicinal product name
    Tobramycin inhalation solution
    Investigational medicinal product code
    Other name
    TIS, TOBI®
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    TIS 300 mg 2 times daily using a PARI® LC Plus nebulizer and DeVilbiss Pulmo-Aide® air compressor

    Number of subjects in period 1
    		TIS Run-In Treatment Group
    Started
    107
    Completed
    93
    Not completed
    14
         Adverse event, non-fatal
    3
         Protocol-specified criteria for withdrawal
    9
         Noncompliance with study drug
    1
         Withdrew consent
    1
    Period 2
    Period 2 title
    Comparative Phase
    Is this the baseline period?
    		 Yes [1]
    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 were randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: AZLI for 28 days followed by TIS for 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aztreonam for inhalation solution
    Investigational medicinal product code
    Other name
    AZLI, Cayston®
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    AZLI 75 mg 3 times daily combined with diluent administered using an eFlow nebulizer

    Investigational medicinal product name
    Tobramycin inhalation solution
    Investigational medicinal product code
    Other name
    TIS, TOBI®
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    TIS 300 mg 2 times daily using a PARI® LC Plus nebulizer and DeVilbiss Pulmo-Aide® air compressor

    Arm title
    		 Placebo
    Arm description
    		 Participants were randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: placebo to match AZLI for 28 days followed by TIS for 28 days.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo to match AZLI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo to match AZLI 3 times daily combined with diluent administered using an eFlow nebulizer

    Investigational medicinal product name
    Tobramycin inhalation solution
    Investigational medicinal product code
    Other name
    TIS, TOBI®
    Pharmaceutical forms
    Nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    TIS 300 mg 2 times daily using a PARI® LC Plus nebulizer and DeVilbiss Pulmo-Aide® air compressor

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: The TIS Run-In Phase (Period 1) was a period to determine eligibility in the randomized comparative phase (Period 2). The comparative phase was the primary phase of the study and the baseline period.
    Number of subjects in period 2 [2] [3]
    		AZLI Placebo
    Started
    43
    47
    Completed
    37
    37
    Not completed
    6
    10
         Adverse event, serious fatal
    1
    -
         Protocol-specified criteria for withdrawal
    1
    1
         Pregnancy
    -
    1
         Noncompliance with study drug
    1
    -
         Withdrew consent
    3
    7
         Investigator's discretion
    -
    1
    Notes
    [2] - 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: 107 participants were enrolled (worldwide) and entered the TIS Run-In Phase. 17 participants were not eligible to enter the comparative phase (baseline period).
    [3] - 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: 17 participants enrolled in the TIS Run-In Phase were not eligible to enter the comparative phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AZLI
    Reporting group description
    		 Participants were randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: AZLI for 28 days followed by TIS for 28 days.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants were randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: placebo to match AZLI for 28 days followed by TIS for 28 days.

    Reporting group values
    		 AZLI Placebo Total
    Number of subjects
    		 43 47 90
    Age categorical
    Units: Subjects
        6 - 12 years
    		 3 1 4
        13 - 17 years
    		 5 6 11
        ≥ 18 years
    		 35 40 75
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 28.8 ( 12.1 ) 28 ( 10.88 ) -
    Gender categorical
    Units: Subjects
        Female
    		 24 28 52
        Male
    		 19 19 38
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1
        White
    		 41 45 86
        Other
    		 2 1 3
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 5 4 9
        Not Hispanic or Latino
    		 38 43 81
    FEV1 % predicted at Day 1
    FEV1 is defined as the maximal volume of air that can be exhaled in 1 second. FEV1 % predicted is defined as FEV1 of the participant divided by the average FEV1 in the population for any person of similar age, sex, race, and body composition.
    Units: percentage of FEV1 % predicted
        arithmetic mean (standard deviation)
    		 49.95 ( 17.5 ) 50.25 ( 15.131 ) -
    CFQ-R Respiratory Score at Day 1
    Respiratory symptoms (eg, coughing, congestion, wheezing) were assessed with the Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS). The range of scores (units) was 0 to 100 with higher scores indicating fewer symptoms.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 59.72 ( 18.408 ) 64.24 ( 15.044 ) -

    End points

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    End points reporting groups
    Reporting group title
    TIS Run-In Treatment Group
    Reporting group description
    		 Enrolled participants received 28 days of TIS during the run-in phase.
    Reporting group title
    AZLI
    Reporting group description
    		 Participants were randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: AZLI for 28 days followed by TIS for 28 days.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants were randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: placebo to match AZLI for 28 days followed by TIS for 28 days.

    Primary: Rate of protocol-defined exacerbations (PDE) from baseline through Week 24

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    End point title
    		 Rate of protocol-defined exacerbations (PDE) from baseline through Week 24
    End point description
    PDEs were characterized by a change or worsening from baseline of 1 or more documented signs or symptoms (decreased exercise tolerance, increased cough, increased sputum or chest congestion, decreased appetite, or other signs or symptoms) associated with the use of non-study IV or inhaled antibiotics and be verified by a blinded independent adjudication committee.
    End point type
    Primary
    End point timeframe
    Baseline in the comparative phase to the end of study (average time on study during the Comparative Phase: 155.4 days)
    End point values
    		 AZLI Placebo
    Number of subjects analysed
    43
    47
    Units: PDEs per participant year
        number (not applicable)
    1.309
    1.762
    Statistical analysis title
    		 Ratio between rates
    Comparison groups
    Placebo v AZLI
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.25
    Method
    		 Negative binomial regression
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.743
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.446
         upper limit
    		 1.238

    Secondary: Average actual change from baseline in FEV1 % predicted across all courses of AZLI/placebo treatment (Weeks 4, 12 and 20)

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    End point title
    		 Average actual change from baseline in FEV1 % predicted across all courses of AZLI/placebo treatment (Weeks 4, 12 and 20)
    End point description
    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. The adjusted mean is from a mixed-effect model repeated measures (MMRM) analysis. The model includes terms for baseline value, previous exacerbations (1, 2, ≥ 3), treatment, visit (categorical), and treatment by visit interaction.
    End point type
    Secondary
    End point timeframe
    Comparative Phase: Baseline and Weeks 4, 12, and 20
    End point values
    		 AZLI Placebo
    Number of subjects analysed
    42
    45
    Units: percentage of FEV1 % predicted
        least squares mean (standard error)
    1.37 ( 0.674 )
    0.04 ( 0.658 )
    Statistical analysis title
    		 Difference in change in FEV1 % predicted
    Comparison groups
    AZLI v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.16 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.55
         upper limit
    		 3.2
    Notes
    [1] - Intergroup analysis
    [2] - The p-value is from an MMRM analysis. The model includes terms for baseline value, previous exacerbations (1, 2, ≥ 3), treatment, visit (categorical), and treatment by visit interaction.

    Secondary: Percentage of participants who used non-study IV or inhaled antibiotics for protocol-defined pulmonary exacerbations

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    End point title
    		 Percentage of participants who used non-study IV or inhaled antibiotics for protocol-defined pulmonary exacerbations
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline in the comparative phase to the end of study (average time on study during the Comparative Phase: 155.4 days)
    End point values
    		 AZLI Placebo
    Number of subjects analysed
    43
    47
    Units: percentage of participants
        number (not applicable)
    48.8
    55.3
    Statistical analysis title
    		 Comparison of percentages
    Comparison groups
    AZLI v Placebo
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.67
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [3] - Intergroup analysis

    Secondary: Time to first protocol-defined pulmonary exacerbation

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    End point title
    		 Time to first protocol-defined pulmonary exacerbation
    End point description
    The time to first protocol-defined pulmonary exacerbation was calculated using the Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    Baseline in the comparative phase to the end of study (average time on study during the Comparative Phase: 155.4 days)
    End point values
    		 AZLI Placebo
    Number of subjects analysed
    43
    47
    Units: median days
    175
    140
    Statistical analysis title
    		 Comparison of time to exacerbation
    Comparison groups
    AZLI v Placebo
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    P-value
    		 = 0.71
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.59
    Notes
    [4] - Intergroup analysis

    Secondary: Rate of Hospitalization for a Respiratory Event

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    End point title
    		 Rate of Hospitalization for a Respiratory Event
    End point description
    The rate of hospitalizations for a respiratory event per participant year was calculated using negative binomial regression analysis.
    End point type
    Secondary
    End point timeframe
    Baseline in the comparative phase to the end of study (average time on study during the Comparative Phase: 155.4 days)
    End point values
    		 AZLI Placebo
    Number of subjects analysed
    43
    47
    Units: hospitalizations per participant year
        number (not applicable)
    1.043
    1.624
    Statistical analysis title
    		 Comparison of hospitalization rate
    Comparison groups
    AZLI v Placebo
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.14
    Method
    		 Negative binomial regression
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.642
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.355
         upper limit
    		 1.164
    Notes
    [5] - Intergroup analysis

    Secondary: Average change from baseline in the CFQ-R Respiratory Symptom Scale (RSS) score across all courses of AZLI/placebo treatment (Weeks 4, 12 and 20)

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    End point title
    		 Average change from baseline in the CFQ-R Respiratory Symptom Scale (RSS) score across all courses of AZLI/placebo treatment (Weeks 4, 12 and 20)
    End point description
    Respiratory symptoms (eg, coughing, congestion, wheezing) were assessed with the Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Symptoms Scale (RSS). The range of scores (units) was 0 to 100 with higher scores indicating fewer symptoms. The adjusted mean is from a mixed-effect model repeated measures (MMRM) analysis. The model includes terms for baseline value, previous exacerbations (1, 2, ≥ 3), treatment, visit (categorical), and treatment by visit interaction.
    End point type
    Secondary
    End point timeframe
    Comparative Phase: Baseline and Weeks 4, 12, and 20
    End point values
    		 AZLI Placebo
    Number of subjects analysed
    39
    45
    Units: units on a scale
        least squares mean (standard deviation)
    1 ( 1.736 )
    -2.06 ( 1.629 )
    Statistical analysis title
    		 Difference in change in CFQ-R RSS
    Comparison groups
    AZLI v Placebo
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.21 [7]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.71
         upper limit
    		 7.82
    Notes
    [6] - Intergroup analysis
    [7] - The p-value is from an MMRM analysis. The model includes terms for baseline value, previous exacerbations (1, 2, ≥ 3), treatment, visit (categorical), and treatment by visit interaction.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    TIS Run-In Treatment Group: up to 28 days (plus 30 days if not continuing to the comparative phase). Comparative phase: from first dose of AZLI or Placebo through 30 days after last dose (average 155.4 days).
    Adverse event reporting additional description
    Safety analysis set: participants who were enrolled and received at least 1 dose of study drug
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    TIS Run-In Treatment Group (in Run-In Phase)
    Reporting group description
    		 Adverse events reported in this group are those experienced by participants during in the 28-day run-in TIS treatment phase.

    Reporting group title
    Placebo (in Comparative Phase)
    Reporting group description
    		 Adverse events reported in this group are those experienced by participants who were randomized to placebo in the comparative phase (after having completed the 28-day run-in TIS treatment phase) and received at least 1 dose of study drug. Participants were randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: placebo to match AZLI for 28 days followed by TIS for 28 days.

    Reporting group title
    AZLI (in Comparative Phase)
    Reporting group description
    		 Adverse events reported in this group are those experienced by participants who were randomized to AZLI in the comparative phase (after having completed the 28-day run-in TIS treatment phase) and received at least 1 dose of study drug. Participants were randomized to receive 3 cycles of treatment, each cycle consisting alternating regimens: AZLI for 28 days followed by TIS for 28 days.

    Serious adverse events
    		 TIS Run-In Treatment Group (in Run-In Phase) Placebo (in Comparative Phase) AZLI (in Comparative Phase)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 107 (3.74%)
    24 / 46 (52.17%)
    21 / 42 (50.00%)
         number of deaths (all causes)
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 46 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 46 (2.17%)
    0 / 42 (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
    Joint dislocation
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 46 (2.17%)
    0 / 42 (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
    Postoperative respiratory failure
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 46 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 46 (2.17%)
    0 / 42 (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
    Upper limb fracture
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 46 (2.17%)
    0 / 42 (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
    Cardiac disorders
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 46 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Eye disorders
    Blindness unilateral
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 46 (0.00%)
    1 / 42 (2.38%)
         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 upper
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 46 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 46 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 46 (0.00%)
    1 / 42 (2.38%)
         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
    Cholelithiasis
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 46 (0.00%)
    1 / 42 (2.38%)
         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
    Lung disorder
         subjects affected / exposed
    1 / 107 (0.93%)
    13 / 46 (28.26%)
    9 / 42 (21.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 18
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 46 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 46 (2.17%)
    0 / 42 (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
    Respiratory disorder
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 46 (2.17%)
    0 / 42 (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
    Respiratory failure
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 46 (0.00%)
    1 / 42 (2.38%)
         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
    Nephrolithiasis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 46 (2.17%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    2 / 107 (1.87%)
    5 / 46 (10.87%)
    9 / 42 (21.43%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 8
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 107 (0.00%)
    3 / 46 (6.52%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 46 (2.17%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 46 (2.17%)
    0 / 42 (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
    Gastroenteritis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 46 (2.17%)
    0 / 42 (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 exacerbation of bronchiectasis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 46 (2.17%)
    0 / 42 (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
    Pseudomonal bacteraemia
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 46 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 46 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 46 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 46 (0.00%)
    1 / 42 (2.38%)
         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
    		 TIS Run-In Treatment Group (in Run-In Phase) Placebo (in Comparative Phase) AZLI (in Comparative Phase)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 107 (25.23%)
    44 / 46 (95.65%)
    38 / 42 (90.48%)
    Investigations
    Pulmonary function test decreased
         subjects affected / exposed
    0 / 107 (0.00%)
    10 / 46 (21.74%)
    11 / 42 (26.19%)
         occurrences all number
    0
    12
    13
    Weight decreased
         subjects affected / exposed
    0 / 107 (0.00%)
    5 / 46 (10.87%)
    4 / 42 (9.52%)
         occurrences all number
    0
    5
    7
    Forced expiratory volume decreased
         subjects affected / exposed
    0 / 107 (0.00%)
    2 / 46 (4.35%)
    4 / 42 (9.52%)
         occurrences all number
    0
    2
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 107 (0.00%)
    8 / 46 (17.39%)
    7 / 42 (16.67%)
         occurrences all number
    0
    10
    8
    Sinus headache
         subjects affected / exposed
    0 / 107 (0.00%)
    2 / 46 (4.35%)
    3 / 42 (7.14%)
         occurrences all number
    0
    2
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    6 / 107 (5.61%)
    17 / 46 (36.96%)
    11 / 42 (26.19%)
         occurrences all number
    6
    20
    17
    Chest discomfort
         subjects affected / exposed
    7 / 107 (6.54%)
    13 / 46 (28.26%)
    8 / 42 (19.05%)
         occurrences all number
    7
    15
    8
    Exercise tolerance decreased
         subjects affected / exposed
    0 / 107 (0.00%)
    12 / 46 (26.09%)
    3 / 42 (7.14%)
         occurrences all number
    0
    14
    3
    Chest pain
         subjects affected / exposed
    0 / 107 (0.00%)
    7 / 46 (15.22%)
    4 / 42 (9.52%)
         occurrences all number
    0
    9
    5
    Chills
         subjects affected / exposed
    0 / 107 (0.00%)
    5 / 46 (10.87%)
    3 / 42 (7.14%)
         occurrences all number
    0
    5
    5
    Pyrexia
         subjects affected / exposed
    0 / 107 (0.00%)
    13 / 46 (28.26%)
    8 / 42 (19.05%)
         occurrences all number
    0
    17
    12
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 107 (0.00%)
    10 / 46 (21.74%)
    6 / 42 (14.29%)
         occurrences all number
    0
    14
    9
    Vomiting
         subjects affected / exposed
    0 / 107 (0.00%)
    9 / 46 (19.57%)
    5 / 42 (11.90%)
         occurrences all number
    0
    11
    7
    Diarrhoea
         subjects affected / exposed
    0 / 107 (0.00%)
    5 / 46 (10.87%)
    6 / 42 (14.29%)
         occurrences all number
    0
    5
    7
    Abdominal pain
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 46 (2.17%)
    4 / 42 (9.52%)
         occurrences all number
    0
    1
    5
    Constipation
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 46 (0.00%)
    4 / 42 (9.52%)
         occurrences all number
    0
    0
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    21 / 107 (19.63%)
    33 / 46 (71.74%)
    32 / 42 (76.19%)
         occurrences all number
    21
    67
    52
    Sputum increased
         subjects affected / exposed
    12 / 107 (11.21%)
    31 / 46 (67.39%)
    20 / 42 (47.62%)
         occurrences all number
    12
    51
    32
    Dyspnoea
         subjects affected / exposed
    9 / 107 (8.41%)
    24 / 46 (52.17%)
    13 / 42 (30.95%)
         occurrences all number
    9
    38
    25
    Haemoptysis
         subjects affected / exposed
    0 / 107 (0.00%)
    11 / 46 (23.91%)
    11 / 42 (26.19%)
         occurrences all number
    0
    12
    15
    Respiratory tract congestion
         subjects affected / exposed
    0 / 107 (0.00%)
    11 / 46 (23.91%)
    11 / 42 (26.19%)
         occurrences all number
    0
    12
    14
    Wheezing
         subjects affected / exposed
    6 / 107 (5.61%)
    9 / 46 (19.57%)
    9 / 42 (21.43%)
         occurrences all number
    6
    10
    9
    Nasal congestion
         subjects affected / exposed
    0 / 107 (0.00%)
    4 / 46 (8.70%)
    11 / 42 (26.19%)
         occurrences all number
    0
    4
    12
    Rhinorrhoea
         subjects affected / exposed
    0 / 107 (0.00%)
    8 / 46 (17.39%)
    5 / 42 (11.90%)
         occurrences all number
    0
    8
    6
    Oropharyngeal pain
         subjects affected / exposed
    0 / 107 (0.00%)
    5 / 46 (10.87%)
    6 / 42 (14.29%)
         occurrences all number
    0
    5
    8
    Sinus congestion
         subjects affected / exposed
    0 / 107 (0.00%)
    7 / 46 (15.22%)
    3 / 42 (7.14%)
         occurrences all number
    0
    10
    4
    Sputum discoloured
         subjects affected / exposed
    0 / 107 (0.00%)
    3 / 46 (6.52%)
    5 / 42 (11.90%)
         occurrences all number
    0
    3
    7
    Dyspnoea exertional
         subjects affected / exposed
    0 / 107 (0.00%)
    2 / 46 (4.35%)
    5 / 42 (11.90%)
         occurrences all number
    0
    3
    8
    Dysphonia
         subjects affected / exposed
    0 / 107 (0.00%)
    2 / 46 (4.35%)
    4 / 42 (9.52%)
         occurrences all number
    0
    2
    4
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 107 (0.00%)
    4 / 46 (8.70%)
    2 / 42 (4.76%)
         occurrences all number
    0
    5
    3
    Increased viscosity of bronchial secretion
         subjects affected / exposed
    0 / 107 (0.00%)
    4 / 46 (8.70%)
    1 / 42 (2.38%)
         occurrences all number
    0
    5
    2
    Paranasal sinus hypersecretion
         subjects affected / exposed
    0 / 107 (0.00%)
    3 / 46 (6.52%)
    1 / 42 (2.38%)
         occurrences all number
    0
    3
    1
    Rales
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 46 (2.17%)
    3 / 42 (7.14%)
         occurrences all number
    0
    1
    4
    Pleuritic pain
         subjects affected / exposed
    0 / 107 (0.00%)
    3 / 46 (6.52%)
    0 / 42 (0.00%)
         occurrences all number
    0
    3
    0
    Productive cough
         subjects affected / exposed
    0 / 107 (0.00%)
    3 / 46 (6.52%)
    0 / 42 (0.00%)
         occurrences all number
    0
    6
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 46 (2.17%)
    4 / 42 (9.52%)
         occurrences all number
    0
    1
    4
    Pruritus
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 46 (2.17%)
    3 / 42 (7.14%)
         occurrences all number
    0
    1
    3
    Night sweats
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 46 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    0
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 107 (0.00%)
    3 / 46 (6.52%)
    3 / 42 (7.14%)
         occurrences all number
    0
    3
    3
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 107 (0.00%)
    4 / 46 (8.70%)
    3 / 42 (7.14%)
         occurrences all number
    0
    5
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 107 (0.00%)
    16 / 46 (34.78%)
    5 / 42 (11.90%)
         occurrences all number
    0
    21
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Jun 2012
    Use of the Cystic Fibrosis Respiratory Symptom Diary (CFRSD) was added; clarification that participants who experienced a protocol-defined exacerbation (PDE) after Visit 3 and took antibiotics were expected to remain on study; the definition of PDE was clarified as a change or worsening from baseline of 1 or more documented signs or symptoms (decreased exercise tolerance, increased cough, increased sputum or chest congestion, decreased appetite, or other signs or symptoms) associated with the use of nonstudy antibiotics, and had to be verified by a blinded independent adjudication committee; the study duration was increased from 24 weeks to 28 weeks to include the 4-week TIS run-in phase.
    08 Aug 2012
    The primary endpoint definition was clarified by adding ‘IV or inhaled’ to nonstudy antibiotic use throughout protocol document; Sample Cystic Fibrosis Questionnaire–Revised (CFQ-R) and European Questionnaire-5 Dimensions (EQ-5D) were added.
    21 Mar 2013
    Throat swab cultures were allowed to document history of PA infection.

    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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