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    Clinical Trial Results:
    Long Term Administration of Inhaled Dry Powder Mannitol In Cystic Fibrosis – A Safety and Efficacy Study

    Summary
    EudraCT number
    		 2007-001412-23
    Trial protocol
    		 IE   GB   DE  
    Global end of trial date
    24 Apr 2009

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Apr 2021
    First version publication date
    07 Apr 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    DPM-CF-301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00446680
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pharmaxis Pty Ltd
    Sponsor organisation address
    20 Rodborough Road, Frenchs Forest, Australia, 2086
    Public contact
    Brett Charlton, Pharmaxis Pty Ltd., Brett.Charlton@pharmaxis.com.au
    Scientific contact
    Brett Charlton, Pharmaxis Pty Ltd., Brett.Charlton@pharmaxis.com.au
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000436-PIP01-08
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Sep 2009
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Apr 2009
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Apr 2009
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the effect of IDPM compared to control on FEV1 in patients with CF.
    Protection of trial subjects
    DMC, use of Mannitol Tolerance test at screening to identify hyper-responsiveness to exclude susceptible patients.
    Background therapy
    		 Usual standard of care
    Evidence for comparator
    		 Comparator was low dose mannitol (50mg) - chosen to ensure blinding.
    Actual start date of recruitment
    05 Apr 2007
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 193
    Country: Number of subjects enrolled
    Ireland: 19
    Country: Number of subjects enrolled
    Australia: 97
    Country: Number of subjects enrolled
    New Zealand: 15
    Worldwide total number of subjects
    324
    EEA total number of subjects
    212
    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)
    52
    Adolescents (12-17 years)
    63
    Adults (18-64 years)
    209
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Following enrolment and prior to randomisation, subjects were administered an abbreviated version of the Aridol bronchial provocation test (MTT) to exclude those with bronchial hyper-responsiveness.

    Period 1
    Period 1 title
    Double Blind Phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Subject, Data analyst, Carer, Assessor
    Blinding implementation details
    Use of low dose inhaled mannitol as control (ie identical in appearance and taste). Both active and control treatments consisted of ten identical opaque capsules with indistinguishable taste.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bronchitol
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mannitol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    400mg Twice daily. Administered via a RS01 dry-powder inhaler device, after pre-medication but before physiotherapy or exercise. Capsules were loaded into the inhaler device, punctured, then inhaled in a deep, controlled manner; followed by a 5-second breath hold. Each consecutive capsule followed the previous immediately. The process was repeated until the contents of ten capsules had been inhaled.

    Arm title
    		 Control
    Arm description
    		 -
    Arm type
    		 Low dose control

    Investigational medicinal product name
    Mannitol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    50mg Twice daily. Administered via a RS01 dry-powder inhaler device, after pre-medication but before physiotherapy or exercise. Capsules were loaded into the inhaler device, punctured, then inhaled in a deep, controlled manner; followed by a 5-second breath hold. Each consecutive capsule followed the previous immediately. The process was repeated until the contents of ten capsules had been inhaled.

    Number of subjects in period 1
    		Bronchitol Control
    Started
    192
    132
    Completed
    112
    86
    Not completed
    80
    46
         Physician decision
    7
    -
         Consent withdrawn by subject
    28
    22
         Discountinued study prior to commencing trtment
    15
    -
         Adverse event, non-fatal
    29
    10
         Discontinued prior to commencing trt
    -
    14
         Unspecified reasons
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bronchitol
    Reporting group description
    		 -

    Reporting group title
    Control
    Reporting group description
    		 -

    Reporting group values
    		 Bronchitol Control Total
    Number of subjects
    		 192 132 324
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 33 19 52
        Adolescents (12-17 years)
    		 35 28 63
        Adults (18-64 years)
    		 124 85 209
    Gender categorical
    Units: Subjects
        Female
    		 81 70 151
        Male
    		 111 62 173
    FEV1 % predicted at baseline
    Forced Expiratory Volume in 1 second (FEV1) percentage of predicted value at week 0, start of treatment.
    Units: precentage
        arithmetic mean (standard deviation)
    		 62.33 ( 16.37 ) 62.06 ( 16.04 ) -
    Subject analysis sets

    Subject analysis set title
    FAS randomised and treated
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects randomised and receiving at least one dose of study medication

    Subject analysis set title
    FAS - Bronchitol
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects who were randomised and received at least one dose

    Subject analysis set title
    FAS - Control
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All randomised subjects who received at least one dose of trial treatment

    Subject analysis set title
    Completers - Bronchitol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Completers are those who remained on trt to the 26 week time point

    Subject analysis set title
    Completers - Control
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects completing 6 months of trial treatment

    Subject analysis sets values
    		 FAS randomised and treated FAS - Bronchitol FAS - Control Completers - Bronchitol Completers - Control
    Number of subjects
    295
    177
    118
    116
    89
    Age categorical
    Units: Subjects
        Children (2-11 years)
    48
    31
    17
        Adolescents (12-17 years)
    57
    32
    25
        Adults (18-64 years)
    190
    114
    76
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    132
    71
    61
        Male
    163
    106
    57
    FEV1 % predicted at baseline
    Forced Expiratory Volume in 1 second (FEV1) percentage of predicted value at week 0, start of treatment.
    Units: precentage
        arithmetic mean (standard deviation)
    ( )
    62.4 ( 16.45 )
    61.4 ( 16.13 )
    ( )
    ( )

    End points

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    End points reporting groups
    Reporting group title
    Bronchitol
    Reporting group description
    		 -

    Reporting group title
    Control
    Reporting group description
    		 -

    Subject analysis set title
    FAS randomised and treated
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects randomised and receiving at least one dose of study medication

    Subject analysis set title
    FAS - Bronchitol
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects who were randomised and received at least one dose

    Subject analysis set title
    FAS - Control
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All randomised subjects who received at least one dose of trial treatment

    Subject analysis set title
    Completers - Bronchitol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Completers are those who remained on trt to the 26 week time point

    Subject analysis set title
    Completers - Control
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects completing 6 months of trial treatment

    Primary: Change in FEV1

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    End point title
    		 Change in FEV1
    End point description
    Mean Change in FEV1 (mL) From Baseline (Visit 1) Over the 26-week Treatment Period (to Visit 4). The mean absolute change from baseline FEV1 (mL) over 26 weeks (measured at week 6, 14 and 26) was compared between the two treatment groups with a REML (restricted maximum likelihood) based repeated measures approach. Least square means presented are for the average change over the 6, 14, and 26 week visits.
    End point type
    Primary
    End point timeframe
    Over 26 weeks
    End point values
    		 FAS - Bronchitol FAS - Control
    Number of subjects analysed
    160 [1]
    112 [2]
    Units: mL
        least squares mean (confidence interval 95%)
    118.01 (87.94 to 148.07)
    34.87 (0.59 to 69.15)
    Notes
    [1] - Only those with post-baseline FEV1 measures included
    [2] - Only those with post-baseline FEV1 measures included
    Statistical analysis title
    		 Primary analysis : MMRM
    Comparison groups
    FAS - Bronchitol v FAS - Control
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    83.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 39.49
         upper limit
    		 126.79

    Secondary: Change in FEV1 in rhDNase users

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    End point title
    		 Change in FEV1 in rhDNase users
    End point description
    For the subset of rhDNase users, the mean change in FEV1 (mL) From Baseline (Visit 1) Over the 26-week Treatment Period (to Visit 4). The mean absolute change from baseline FEV1 (mL) over 26 weeks (measured at week 6, 14 and 26) will be compared between the two treatment groups with a REML (restricted maximum likelihood) based repeated measures approach. Least square means presented are for the average change over the 6, 14, and 26 week visits.
    End point type
    Secondary
    End point timeframe
    Over 26 weeks
    End point values
    		 FAS - Bronchitol FAS - Control
    Number of subjects analysed
    160 [3]
    112 [4]
    Units: mL
        least squares mean (confidence interval 95%)
    86.01 (45.47 to 126.54)
    8.39 (-38.30 to 55.07)
    Notes
    [3] - Effect in rhDNase users estimated in model with all 272 patients (users were 147)
    [4] - Effect in rhDNase users estimated in model with all 272 patients (users were 147)
    Statistical analysis title
    		 MMRM with trt by rhDNase interaction
    Comparison groups
    FAS - Bronchitol v FAS - Control
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.011
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    77.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 18.16
         upper limit
    		 137.08

    Secondary: Change in FEV1 in rhDNase non-users

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    End point title
    		 Change in FEV1 in rhDNase non-users
    End point description
    In the subset of rhDNase non-users, the mean change in FEV1 (mL) From Baseline (Visit 1) Over the 26-week Treatment Period (to Visit 4). The mean absolute change from baseline FEV1 (mL) over 26 weeks (measured at week 6, 14 and 26) will be compared between the two treatment groups with a REML (restricted maximum likelihood) based repeated measures approach. Least square means presented are for the average change over the 6, 14, and 26 week visits.
    End point type
    Secondary
    End point timeframe
    Over 26 weeks
    End point values
    		 FAS - Bronchitol FAS - Control
    Number of subjects analysed
    160 [5]
    112 [6]
    Units: mL
        least squares mean (confidence interval 95%)
    150.29 (107.45 to 193.14)
    60.74 (10.78 to 110.71)
    Notes
    [5] - Effect in rhDNase users estimated in model with all 272 patients (non-users were 125)
    [6] - Effect in rhDNase users estimated in model with all 272 patients (non-users were 125)
    Statistical analysis title
    		 MMRM with trt by rhDNase interaction
    Comparison groups
    FAS - Control v FAS - Bronchitol
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    89.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 25.35
         upper limit
    		 153.75

    Secondary: FEV1 Responder

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    End point title
    		 FEV1 Responder
    End point description
    Responders were classified as those who had an absolute increase in FEV1 from baseline to Week 26 of at least 100mL
    End point type
    Secondary
    End point timeframe
    at 26 weeks
    End point values
    		 Completers - Bronchitol Completers - Control
    Number of subjects analysed
    116
    89
    Units: Number of Patients
    62
    33
    Statistical analysis title
    		 Logistic regression
    Comparison groups
    Completers - Bronchitol v Completers - Control
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.026
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.08
         upper limit
    		 3.58

    Secondary: FEV1 Responder - rhDNase users

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    End point title
    		 FEV1 Responder - rhDNase users
    End point description
    Response is increase of more than 100mL from baseline in FEV1
    End point type
    Secondary
    End point timeframe
    At week 26
    End point values
    		 Completers - Bronchitol Completers - Control
    Number of subjects analysed
    61
    50
    Units: Number of Patients
    30
    12
    Statistical analysis title
    		 Logistic regression
    Comparison groups
    Completers - Bronchitol v Completers - Control
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.017
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.21
         upper limit
    		 6.94

    Secondary: FEV1 Responder - rhDNase non-users

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    End point title
    		 FEV1 Responder - rhDNase non-users
    End point description
    Response is increase >=100mL from baseline in FEV1
    End point type
    Secondary
    End point timeframe
    At week 26
    End point values
    		 Completers - Bronchitol Completers - Control
    Number of subjects analysed
    55
    39
    Units: Number of Patients
    32
    21
    Statistical analysis title
    		 Logistic regression
    Comparison groups
    Completers - Bronchitol v Completers - Control
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.422
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 3.47

    Secondary: QoL responder

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    End point title
    		 QoL responder
    End point description
    Responders have 5 point or higher improvement from baseline in SGRQ respiratory score
    End point type
    Secondary
    End point timeframe
    At 26 weeks
    End point values
    		 Completers - Bronchitol Completers - Control
    Number of subjects analysed
    114
    87
    Units: Number of Patients
    45
    34
    Statistical analysis title
    		 Logistic regression
    Comparison groups
    Completers - Bronchitol v Completers - Control
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.385
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 1.46

    Secondary: PDPE rate

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    End point title
    		 PDPE rate
    End point description
    PDPE is a protocol defined pulmonary exacerbation defined by Fuchs criteria
    End point type
    Secondary
    End point timeframe
    Over 26 weeks
    End point values
    		 FAS - Bronchitol FAS - Control
    Number of subjects analysed
    177
    118
    Units: rate per subject per year
        arithmetic mean (standard deviation)
    0.78 ( 1.976 )
    1.05 ( 2.148 )
    Statistical analysis title
    		 Negative Binomial model
    Comparison groups
    FAS - Control v FAS - Bronchitol
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.205
    Method
    		 Negative Binomial Model
    Parameter type
    		 Rate ratio
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 1.18

    Secondary: PDPE rate - rhDNase users

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    End point title
    		 PDPE rate - rhDNase users
    End point description
    PDPE is a protocol defined pulmonary exacerbation defined by Fuchs criteria
    End point type
    Secondary
    End point timeframe
    Over 26 weeks
    End point values
    		 FAS - Bronchitol FAS - Control
    Number of subjects analysed
    96
    67
    Units: rate per person per year
        arithmetic mean (standard deviation)
    0.52 ( 1.144 )
    0.6 ( 1.152 )
    Statistical analysis title
    		 Negative Binomial model
    Comparison groups
    FAS - Bronchitol v FAS - Control
    Number of subjects included in analysis
    163
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.29
    Method
    		 Negative Binomial Model
    Parameter type
    		 Rate ratio
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 1.27

    Secondary: PDPE rate - rhDNase non-users

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    End point title
    		 PDPE rate - rhDNase non-users
    End point description
    PDPE is a protocol defined pulmonary exacerbation defined by Fuchs criteria
    End point type
    Secondary
    End point timeframe
    Over 26 weeks
    End point values
    		 FAS - Bronchitol FAS - Control
    Number of subjects analysed
    81
    51
    Units: rate per person per year
        arithmetic mean (standard deviation)
    0.17 ( 0.495 )
    0.29 ( 0.576 )
    Statistical analysis title
    		 Negative Binomial model
    Comparison groups
    FAS - Bronchitol v FAS - Control
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.259
    Method
    		 Negative Binomial Model
    Parameter type
    		 Rate ratio
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.24
         upper limit
    		 1.47

    Secondary: Change in CFQ-R respiratory score

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    End point title
    		 Change in CFQ-R respiratory score
    End point description
    The CFQ-R respiratory domain score is a scale from 0 to 100. Higher scores are a more favourable response.
    End point type
    Secondary
    End point timeframe
    at week 26
    End point values
    		 Completers - Bronchitol Completers - Control
    Number of subjects analysed
    114
    87
    Units: score
        least squares mean (standard deviation)
    1.3 ( 15.95 )
    -2.5 ( 17.55 )
    No statistical analyses for this end point

    Secondary: Number of days of rescue antibiotic use

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    End point title
    		 Number of days of rescue antibiotic use
    End point description
    End point type
    Secondary
    End point timeframe
    Over 26 weeks
    End point values
    		 FAS - Bronchitol FAS - Control
    Number of subjects analysed
    177
    118
    Units: days
        arithmetic mean (standard deviation)
    5.72 ( 20.616 )
    12.3 ( 44.142 )
    Statistical analysis title
    		 Negative Binomial model
    Comparison groups
    FAS - Bronchitol v FAS - Control
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.407
    Method
    		 Negative Binomial Model
    Parameter type
    		 Rate ratio
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.25
         upper limit
    		 1.76

    Secondary: Number of days in Hospital due to PDPE

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    End point title
    		 Number of days in Hospital due to PDPE
    End point description
    End point type
    Secondary
    End point timeframe
    Over 26 weeks
    End point values
    		 FAS - Bronchitol FAS - Control
    Number of subjects analysed
    177
    118
    Units: days
        arithmetic mean (standard deviation)
    2.41 ( 6.962 )
    2.38 ( 5.791 )
    Statistical analysis title
    		 Negative Binomial model
    Comparison groups
    FAS - Bronchitol v FAS - Control
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.924
    Method
    		 Negative Binomial Model
    Parameter type
    		 Rate ratio
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.26
         upper limit
    		 3.42

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During 26 week double blind treatment period. Subjects who withdrew prematurely were followed for AEs for a period of 7 days after the last dose
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    9.1
    Reporting groups
    Reporting group title
    Bronchitol
    Reporting group description
    		 -

    Reporting group title
    Control
    Reporting group description
    		 -

    Serious adverse events
    		 Bronchitol Control
    Total subjects affected by serious adverse events
         subjects affected / exposed
    46 / 177 (25.99%)
    35 / 118 (29.66%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Bacteria sputum identified
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Postoperative ileus
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Treatment noncompliance
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Catheterisation venous
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Antibiotic prophylaxis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hospitalisation
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Condition Aggravated
    Additional description: Pulmonary exacerbations were coded to condition aggravated
         subjects affected / exposed
    33 / 177 (18.64%)
    25 / 118 (21.19%)
         occurrences causally related to treatment / all
    1 / 40
    0 / 31
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 177 (0.00%)
    2 / 118 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth impacted
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    6 / 177 (3.39%)
    2 / 118 (1.69%)
         occurrences causally related to treatment / all
    4 / 6
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Polymyositis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    4 / 177 (2.26%)
    2 / 118 (1.69%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection pseudomonal
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Bronchitol Control
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    154 / 177 (87.01%)
    109 / 118 (92.37%)
    Investigations
    Bacteria sputum identified
         subjects affected / exposed
    33 / 177 (18.64%)
    21 / 118 (17.80%)
         occurrences all number
    40
    32
    Nervous system disorders
    Headache
         subjects affected / exposed
    38 / 177 (21.47%)
    28 / 118 (23.73%)
         occurrences all number
    102
    79
    General disorders and administration site conditions
    Condition Aggravated
         subjects affected / exposed
    27 / 177 (15.25%)
    21 / 118 (17.80%)
         occurrences all number
    38
    27
    Abdominal pain
         subjects affected / exposed
    6 / 177 (3.39%)
    7 / 118 (5.93%)
         occurrences all number
    6
    26
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    12 / 177 (6.78%)
    7 / 118 (5.93%)
         occurrences all number
    21
    10
    Vomiting
         subjects affected / exposed
    13 / 177 (7.34%)
    4 / 118 (3.39%)
         occurrences all number
    20
    4
    Toothache
         subjects affected / exposed
    9 / 177 (5.08%)
    3 / 118 (2.54%)
         occurrences all number
    12
    3
    Constipation
         subjects affected / exposed
    6 / 177 (3.39%)
    4 / 118 (3.39%)
         occurrences all number
    6
    6
    Diarrhoea
         subjects affected / exposed
    9 / 177 (5.08%)
    1 / 118 (0.85%)
         occurrences all number
    14
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    45 / 177 (25.42%)
    24 / 118 (20.34%)
         occurrences all number
    62
    37
    Haemoptysis
         subjects affected / exposed
    16 / 177 (9.04%)
    8 / 118 (6.78%)
         occurrences all number
    25
    9
    Pharyngolaryngeal pain
         subjects affected / exposed
    24 / 177 (13.56%)
    5 / 118 (4.24%)
         occurrences all number
    36
    6
    Upper respiratory tract infection
         subjects affected / exposed
    14 / 177 (7.91%)
    8 / 118 (6.78%)
         occurrences all number
    16
    11
    Productive cough
         subjects affected / exposed
    12 / 177 (6.78%)
    7 / 118 (5.93%)
         occurrences all number
    14
    11
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    12 / 177 (6.78%)
    7 / 118 (5.93%)
         occurrences all number
    12
    7
    Back pain
         subjects affected / exposed
    7 / 177 (3.95%)
    7 / 118 (5.93%)
         occurrences all number
    7
    9
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    25 / 177 (14.12%)
    17 / 118 (14.41%)
         occurrences all number
    35
    23
    Lower respiratory tract infection
         subjects affected / exposed
    12 / 177 (6.78%)
    18 / 118 (15.25%)
         occurrences all number
    14
    24

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Aug 2007
    No. of subjects increased to 340 (previously 250). Interim analysis added.
    16 Nov 2008
    Additional Open label extension period added (for a further 26 weeks)

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/21478216
    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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