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    Clinical Trial Results:
    Long Term Administration of Inahled Mannitol in Cystic Fibrosis - A Safety and Efficacy Study

    Summary
    EudraCT number
    		 2008-002740-42
    Trial protocol
    		 DE   BE   FR   NL  
    Global end of trial date
    25 Oct 2010

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Jun 2021
    First version publication date
    03 Jun 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DPM-CF-302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00630812
    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)
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Oct 2010
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Apr 2010
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Oct 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine whether inhaled mannitol compared to control improves FEV1 in patients with Cystic Fibrosis.
    Protection of trial subjects
    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
    03 Sep 2008
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    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
    Canada: 20
    Country: Number of subjects enrolled
    Argentina: 82
    Country: Number of subjects enrolled
    United States: 146
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Belgium: 16
    Country: Number of subjects enrolled
    France: 25
    Country: Number of subjects enrolled
    Germany: 24
    Worldwide total number of subjects
    318
    EEA total number of subjects
    70
    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)
    62
    Adolescents (12-17 years)
    99
    Adults (18-64 years)
    157
    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, A screening test with inhaled mannitol (MTT) was administered at Visit 0 to identify subjects with hyperresponsive airways.

    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
    		 Subject, Investigator, Monitor, 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
    The 400 mg treatment dose was contained in 10 x 40 mg capsules and was administered via the RS01 dry-powder inhaler device after pre-medication but before physiotherapy or exercise. Inhaled Bronchitol was encapsulated prior to blister packing in aluminum foil. Blisters were packaged in 2 week supply cartons with 2 RS01 inhaler devices and instructions for use, Appendix 16.1.10.8. Capsules were loaded into the inhaler device, punctured, then inhaled in a deep, controlled manner; followed by a five second breath hold. Each consecutive capsule followed the previous immediately. The process was repeated until the contents of ten capsules had been inhaled. The standard premedication was four puffs of albuterol five to fifteen minutes pre treatment, though an alternative with subject contact bronchodilator could be substituted if preferred.

    Arm title
    		 Control
    Arm description
    		 Low dose mannitol (50mg)
    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
    The treatment dose was 50 mg B.I.D. for 26 weeks. The 50 mg treatment dose was contained in 10 x 5 mg capsules and was administered via the RS01 dry-powder inhaler after pre-medication but before physiotherapy or exercise. As with the active study drug, control capsules were blister packaged. Capsules were loaded into the inhaler device, punctured, and then inhaled in a deep, controlled manner, each followed by a five second breath hold. Each consecutive capsule followed the previous immediately. The process was repeated until the contents of ten capsules had been inhaled. The standard premedication was the same as described for the active study drug. The control product (10 x 5mg capsules) inhaled mannitol was administered using the same methodology as the active treatment.

    Number of subjects in period 1
    		Bronchitol Control
    Started
    192
    126
    Treated
    184
    121
    Completed
    153
    107
    Not completed
    39
    19
         Consent withdrawn by subject
    15
    10
         Physician decision
    2
    1
         Adverse event, non-fatal
    14
    6
         wanted to take drug as she wished not as protocol
    1
    -
         Non-compliance
    -
    1
         Lost to follow-up
    2
    -
         Protocol deviation
    5
    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
    		 Low dose mannitol (50mg)

    Reporting group values
    		 Bronchitol Control Total
    Number of subjects
    		 192 126 318
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 37 25 62
        Adolescents (12-17 years)
    		 58 41 99
        Adults (18-64 years)
    		 97 60 157
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 19.7 ± 9.50 20.3 ± 10.23 -
    Gender categorical
    Units: Subjects
        Female
    		 93 60 153
        Male
    		 99 66 165
    Subject analysis sets

    Subject analysis set title
    FAS Bronchitol
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Randomised and treated

    Subject analysis set title
    FAS Control
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Randomised and treated

    Subject analysis sets values
    		 FAS Bronchitol FAS Control
    Number of subjects
    184
    121
    Age categorical
    Units: Subjects
        Children (2-11 years)
    35
    24
        Adolescents (12-17 years)
    56
    39
        Adults (18-64 years)
    93
    58
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    19.6 ± 9.29
    20.4 ± 10.23
    Gender categorical
    Units: Subjects
        Female
    90
    58
        Male
    94
    63

    End points

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

    Reporting group title
    Control
    Reporting group description
    		 Low dose mannitol (50mg)

    Subject analysis set title
    FAS Bronchitol
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Randomised and treated

    Subject analysis set title
    FAS Control
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Randomised and treated

    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 6, 14 and 26 weeks) was compared between the 2 treatment groups using 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
    177 [1]
    120 [2]
    Units: mL
        least squares mean (confidence interval 95%)
    106.53 (62.43 to 150.62)
    52.38 (2.09 to 102.68)
    Notes
    [1] - Only subjects with post-baseline FEV1 are included
    [2] - Only subjects with post-baseline FEV1 are included
    Statistical analysis title
    		 Primary analysis: MMRM
    Comparison groups
    FAS Bronchitol v FAS Control
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.059
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    54.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.97
         upper limit
    		 110.26

    Secondary: Change in FEV1 % predicted

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    End point title
    		 Change in FEV1 % predicted
    End point description
    change from baseline to 26 weeks. Those with missing data at 26 weeks are imputed using baseline observation carried forward (BOCF)
    End point type
    Secondary
    End point timeframe
    At 26 weeks
    End point values
    		 FAS Bronchitol FAS Control
    Number of subjects analysed
    184
    121
    Units: % of predicted
        least squares mean (confidence interval 95%)
    3.14 (1.49 to 4.78)
    0.72 (-1.18 to 2.62)
    Statistical analysis title
    		 ANCOVA with BOCF
    Comparison groups
    FAS Bronchitol v FAS Control
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.024
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 4.51

    Secondary: Change in FEV1 from baseline over 26 weeks - dornase users

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    End point title
    		 Change in FEV1 from baseline over 26 weeks - dornase users
    End point description
    In the subset of dornase users, the mean absolute change from baseline FEV1 (mL) averaged 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. Change from baseline over 26 weeks (measured at 6,14, 26 weeks) in subset of dornase users
    End point type
    Secondary
    End point timeframe
    Over 26 weeks
    End point values
    		 FAS Bronchitol FAS Control
    Number of subjects analysed
    137
    92
    Units: mL
        least squares mean (confidence interval 95%)
    78.60 (27.64 to 129.56)
    35.11 (-20.99 to 91.21)
    Statistical analysis title
    		 MMRM
    Comparison groups
    FAS Bronchitol v FAS Control
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.177
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    43.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.8
         upper limit
    		 106.78

    Secondary: Rate of Protocol Defined Pulmonary Exacerbations (PDPEs)

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    End point title
    		 Rate of Protocol Defined Pulmonary Exacerbations (PDPEs)
    End point description
    Exacerbations treated with IV antibiotics and with at least 4 signs and symptoms according to Fuchs criteria (1994). Summary table presents the number with 0, 1,2 and 3 PDPEs during the 26 week treatment period.
    End point type
    Secondary
    End point timeframe
    26 weeks
    End point values
    		 FAS Bronchitol FAS Control
    Number of subjects analysed
    184
    121
    Units: Participants
        0 PDPEs
    156
    98
        1 PDPE
    21
    18
        2 PDPEs
    6
    4
        3 PDPEs
    1
    1
    Statistical analysis title
    		 Poisson regression of count data
    Comparison groups
    FAS Bronchitol v FAS Control
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.52
    Method
    		 Poisson regression
    Parameter type
    		 Rate Ratio
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 1.41
    Notes
    [3] - Rate ratio for Mannitol/Control

    Secondary: Hospitalisation associated with PDPEs

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    End point title
    		 Hospitalisation associated with PDPEs
    End point description
    End point type
    Secondary
    End point timeframe
    26 weeks
    End point values
    		 FAS Bronchitol FAS Control
    Number of subjects analysed
    184
    121
    Units: Participants
        0 hospitalisations
    162
    102
        1 hospitalisation
    18
    14
        2 hospitalisations
    3
    5
        3 hospitalisations
    1
    0
    Statistical analysis title
    		 Poisson regression
    Comparison groups
    FAS Bronchitol v FAS Control
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.328
    Method
    		 Poisson Regression
    Parameter type
    		 Rate Ratio
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 1.33
    Notes
    [4] - Analysis of rate ratio Mannitol/Control

    Secondary: Antibiotic use associated with PDPEs

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    End point title
    		 Antibiotic use associated with PDPEs
    End point description
    End point type
    Secondary
    End point timeframe
    Over 26 weeks
    End point values
    		 FAS Bronchitol FAS Control
    Number of subjects analysed
    184
    121
    Units: participants
        0 Courses
    156
    98
        1 Course
    22
    19
        2 Courses
    5
    2
        3 Courses
    1
    2
    Statistical analysis title
    		 Poisson Regression
    Comparison groups
    FAS Bronchitol v FAS Control
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.368
    Method
    		 Poisson regression
    Parameter type
    		 Rate Ratio
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.15
    Notes
    [5] - Rate ratio Mannitol / Control

    Secondary: Change in FVC

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    End point title
    		 Change in FVC
    End point description
    Change from baseline in forced vital capacity (FVC) across 26 weeks (measured at 6,14 and 26 weeks). Analysed using the same methodology as the primary endpoint
    End point type
    Secondary
    End point timeframe
    Over 26 weeks
    End point values
    		 FAS Bronchitol FAS Control
    Number of subjects analysed
    177
    120
    Units: mL
        least squares mean (confidence interval 95%)
    136.33 (88.54 to 184.11)
    64.98 (10.58 to 119.37)
    Statistical analysis title
    		 MMRM
    Comparison groups
    FAS Bronchitol v FAS Control
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.022
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    71.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 10.57
         upper limit
    		 132.13

    Secondary: Change from baseline FEF25-75

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    End point title
    		 Change from baseline FEF25-75
    End point description
    Change from baseline in forced expiratory flow at 25-75% of forced vital capacity (FEF25-75) (mL/s) averaged over 26 weeks (measured at 6,14 and 26 weeks) The mean absolute change from baseline 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
    Secondary
    End point timeframe
    Over 26 weeks
    End point values
    		 FAS Bronchitol FAS Control
    Number of subjects analysed
    177
    120
    Units: mL/s
        least squares mean (confidence interval 95%)
    84.65 (6.66 to 162.63)
    50.31 (-38.24 to 138.86)
    Statistical analysis title
    		 MMRM
    Comparison groups
    FAS Bronchitol v FAS Control
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.49
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    34.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -63.47
         upper limit
    		 132.14

    Secondary: Sputum weight after first dose

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    End point title
    		 Sputum weight after first dose
    End point description
    End point type
    Secondary
    End point timeframe
    After first dose of trial medication
    End point values
    		 FAS Bronchitol FAS Control
    Number of subjects analysed
    180 [6]
    114 [7]
    Units: gram
        arithmetic mean (standard deviation)
    4.9 ± 6.18
    3.5 ± 4.40
    Notes
    [6] - Randomised and treated with sputum weight data available
    [7] - Randomised and treated with sputum weight data available
    Statistical analysis title
    		 wilcoxon
    Comparison groups
    FAS Bronchitol v FAS Control
    Number of subjects included in analysis
    294
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.042
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    26 weeks
    Adverse event reporting additional description
    Double blind phase only
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11
    Reporting groups
    Reporting group title
    Mannitol - safety
    Reporting group description
    		 All treated

    Reporting group title
    Control - safety
    Reporting group description
    		 All treated

    Serious adverse events
    		 Mannitol - safety Control - safety
    Total subjects affected by serious adverse events
         subjects affected / exposed
    31 / 184 (16.85%)
    30 / 121 (24.79%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    27 / 184 (14.67%)
    20 / 121 (16.53%)
         occurrences causally related to treatment / all
    2 / 35
    1 / 25
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    2 / 184 (1.09%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthmatic crisis
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleuritic pain
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchopneumonia
         subjects affected / exposed
    1 / 184 (0.54%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 184 (0.00%)
    3 / 121 (2.48%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute tonsillitis
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 184 (0.00%)
    1 / 121 (0.83%)
         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 / 184 (0.54%)
    0 / 121 (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
    		 Mannitol - safety Control - safety
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    165 / 184 (89.67%)
    106 / 121 (87.60%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    26 / 184 (14.13%)
    22 / 121 (18.18%)
         occurrences all number
    54
    29
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    57 / 184 (30.98%)
    50 / 121 (41.32%)
         occurrences all number
    75
    55
    Pyrexia
         subjects affected / exposed
    17 / 184 (9.24%)
    13 / 121 (10.74%)
         occurrences all number
    22
    20
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    14 / 184 (7.61%)
    8 / 121 (6.61%)
         occurrences all number
    28
    8
    Abdominal pain upper
         subjects affected / exposed
    6 / 184 (3.26%)
    7 / 121 (5.79%)
         occurrences all number
    7
    10
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    28 / 184 (15.22%)
    16 / 121 (13.22%)
         occurrences all number
    32
    18
    Pharyngolaryngeal pain
         subjects affected / exposed
    19 / 184 (10.33%)
    13 / 121 (10.74%)
         occurrences all number
    26
    14
    Haemoptysis
         subjects affected / exposed
    11 / 184 (5.98%)
    3 / 121 (2.48%)
         occurrences all number
    17
    6
    Nasopharyngitis
         subjects affected / exposed
    11 / 184 (5.98%)
    6 / 121 (4.96%)
         occurrences all number
    13
    8
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 184 (5.43%)
    11 / 121 (9.09%)
         occurrences all number
    11
    16
    Sinusitis
         subjects affected / exposed
    8 / 184 (4.35%)
    7 / 121 (5.79%)
         occurrences all number
    9
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Apr 2008
    Planned subject numbers increased from 250 to 300, expected attrition changes from 20% to 30%, MTT protocol changed to closer resemble a test dose of Bronchitol

    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/22198974
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