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    Clinical Trial Results:
    Long Term Administration of Inhaled Mannitol in Cystic Fibrosis – A Safety and Efficacy Trial in Adult Cystic Fibrosis Subjects

    Summary
    EudraCT number
    		 2013-005357-79
    Trial protocol
    		 CZ   HU   IT   BE   SK   GR   BG   SE  
    Global end of trial date
    21 Feb 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Dec 2019
    First version publication date
    19 Dec 2019
    Other versions
    Summary report(s)
    		 DPM-CF-303 Abbreviated Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    DPM-CF-303
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    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 Limited, +61 2 9454 7210 , Brett.Charlton@pharmaxis.com.au
    Scientific contact
    Brett Charlton, Pharmaxis Limited, +61 2 9454 7210 , 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
    07 Nov 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Feb 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine whether inhaled mannitol (400 mg b.i.d.) is superior to control (50mg b.i.d.) for improving lung function as measured by mean change from baseline FEV1 (mL) over the 26-week treatment period in adult subjects with cystic fibrosis (CF).
    Protection of trial subjects
    DMC monitoring of Safety profile
    Background therapy
    		 Standard CF therapy (excluding maintenance hypertonic saline
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Jul 2014
    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
    Poland: 44
    Country: Number of subjects enrolled
    Romania: 10
    Country: Number of subjects enrolled
    Slovakia: 17
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Bulgaria: 13
    Country: Number of subjects enrolled
    Czech Republic: 1
    Country: Number of subjects enrolled
    Greece: 7
    Country: Number of subjects enrolled
    Hungary: 17
    Country: Number of subjects enrolled
    Italy: 15
    Country: Number of subjects enrolled
    Argentina: 6
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Canada: 13
    Country: Number of subjects enrolled
    Israel: 11
    Country: Number of subjects enrolled
    Mexico: 5
    Country: Number of subjects enrolled
    New Zealand: 5
    Country: Number of subjects enrolled
    Russian Federation: 41
    Country: Number of subjects enrolled
    South Africa: 10
    Country: Number of subjects enrolled
    United States: 116
    Country: Number of subjects enrolled
    Ukraine: 63
    Country: Number of subjects enrolled
    Turkey: 8
    Worldwide total number of subjects
    423
    EEA total number of subjects
    141
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    420
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 486 [1]
    Number of subjects completed
    		 423

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Other inclusion/exclusion criteria not met: 31
    Reason: Number of subjects
    		 Failed or incomplete mannitol tolerance test: 32
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Patients were required to undergo a mannitol tolerance test (MTT) prior to entry and randomisation into the trial itself. As the MTT was a trial procedure have included this period in the reporting. However patients who failed or had incomplete MTT were not enrolled into the study itself.
    Period 1
    Period 1 title
    Treatment (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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Mannitol
    Arm description
    		 Mannitol 400mg bid
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mannitol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    400mg bid

    Arm title
    		 Control
    Arm description
    		 Control - mannitol 50mg bid
    Arm type
    		 Low dose control

    Investigational medicinal product name
    Mannitol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    50mg bid

    Number of subjects in period 1
    		Mannitol Control
    Started
    209
    214
    Completed
    183
    190
    Not completed
    26
    24
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    12
    13
         Adverse event, non-fatal
    10
    6
         Pregnancy
    -
    1
         Patient's choice - prefer to be on alternative trt
    -
    1
         relocation
    1
    -
         Lost to follow-up
    1
    1
         Lack of efficacy
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Mannitol
    Reporting group description
    		 Mannitol 400mg bid

    Reporting group title
    Control
    Reporting group description
    		 Control - mannitol 50mg bid

    Reporting group values
    		 Mannitol Control Total
    Number of subjects
    		 209 214 423
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 209 211 420
        From 65-84 years
    		 0 3 3
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 26.8 ± 7.63 28.6 ± 10.75 -
    Gender categorical
    Units: Subjects
        Female
    		 92 107 199
        Male
    		 117 107 224
    PE hospitalisations in 12 months before screening
    Units: Subjects
        00
    		 121 135 256
        01
    		 57 43 100
        02
    		 20 23 43
        03
    		 11 9 20
        04
    		 0 3 3
        >4
    		 0 1 1
    rhDNase use at screening
    Units: Subjects
        yes
    		 144 142 286
        no
    		 65 72 137
    Lung function at Screening
    Units: % of predicted
        arithmetic mean (standard deviation)
    		 63.72 ± 14.161 64.01 ± 12.933 -

    End points

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    End points reporting groups
    Reporting group title
    Mannitol
    Reporting group description
    		 Mannitol 400mg bid

    Reporting group title
    Control
    Reporting group description
    		 Control - mannitol 50mg bid

    Primary: Change in FEV1

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    End point title
    		 Change in FEV1
    End point description
    End point type
    Primary
    End point timeframe
    Over 26 weeks
    End point values
    		 Mannitol Control
    Number of subjects analysed
    205 [1]
    212 [2]
    Units: Litres
        least squares mean (confidence interval 95%)
    0.063 (0.025 to 0.100)
    0.008 (-0.027 to 0.044)
    Notes
    [1] - Trial withdrawals related to safety/eff of trt imputed using BOCF (others not imputed)
    [2] - Trial withdrawals related to safety/eff of trt imputed using BOCF (others not imputed)
    Statistical analysis title
    		 MMRM using BOCF
    Comparison groups
    Mannitol v Control
    Number of subjects included in analysis
    417
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.054
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.008
         upper limit
    		 0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.023

    Secondary: Change in FVC

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    End point title
    		 Change in FVC
    End point description
    End point type
    Secondary
    End point timeframe
    Over 26 weeks
    End point values
    		 Mannitol Control
    Number of subjects analysed
    205 [3]
    212 [4]
    Units: Litres
        least squares mean (confidence interval 95%)
    0.028 (-0.014 to 0.070)
    -0.012 (-0.053 to 0.029)
    Notes
    [3] - Trial withdrawals related to safety/eff of trt imputed using BOCF (others not imputed)
    [4] - Trial withdrawals related to safety/eff of trt imputed using BOCF (others not imputed)
    Statistical analysis title
    		 MMRM using BOCF
    Comparison groups
    Control v Mannitol
    Number of subjects included in analysis
    417
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.128
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.012
         upper limit
    		 0.092
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.026

    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
    Median not reached in either group - have reported number with an event in each group.
    End point type
    Secondary
    End point timeframe
    During treatment period (up to 36 weeks)
    End point values
    		 Mannitol Control
    Number of subjects analysed
    209
    214
    Units: Weeks
        number (not applicable)
    28
    29
    Statistical analysis title
    		 Cox PH model
    Comparison groups
    Mannitol v Control
    Number of subjects included in analysis
    423
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.877
    Method
    		 Cox proportional hazards
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.029
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.719
         upper limit
    		 1.472

    Secondary: Number of days on Antibiotics due to PDPE

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    End point title
    		 Number of days on Antibiotics due to PDPE
    End point description
    End point type
    Secondary
    End point timeframe
    Over 26 weeks
    End point values
    		 Mannitol Control
    Number of subjects analysed
    209
    214
    Units: Number of days
        00
    181
    185
        1-7
    1
    2
        8-14
    0
    2
        15-21
    1
    2
        22-28
    3
    3
        29-35
    7
    6
        36-42
    5
    2
        50-56
    2
    5
        57-63
    0
    2
        64-70
    2
    1
        >71
    7
    4
    Statistical analysis title
    		 Negative Binomial model
    Comparison groups
    Mannitol v Control
    Number of subjects included in analysis
    423
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.67
    Method
    		 Negative Binomial Model
    Parameter type
    		 Adjusted Rate Ratio
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.198
         upper limit
    		 2.846

    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
    		 Mannitol Control
    Number of subjects analysed
    209
    214
    Units: Number of days
        00
    192
    199
        1-7
    1
    4
        8-14
    4
    6
        15-21
    5
    3
        22-28
    3
    2
        29-35
    3
    0
        >35
    1
    0
    Statistical analysis title
    		 Negative Binomial model
    Comparison groups
    Mannitol v Control
    Number of subjects included in analysis
    423
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.737
    Method
    		 Negative Binomial Model
    Parameter type
    		 Adjusted Rate Ratio
    Point estimate
    1.273
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.315
         upper limit
    		 5.154

    Secondary: Rate of PDPE

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    End point title
    		 Rate of PDPE
    End point description
    End point type
    Secondary
    End point timeframe
    Over 26 weeks
    End point values
    		 Mannitol Control
    Number of subjects analysed
    209
    214
    Units: Number of PDPEs
        00
    181
    185
        01
    24
    29
        02
    3
    0
        >2
    1
    0
    Statistical analysis title
    		 Negative Binomial model - with imputation
    Comparison groups
    Mannitol v Control
    Number of subjects included in analysis
    423
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.057
    Method
    		 Negative Binomial Model
    Parameter type
    		 Adjusted Rate ratio
    Point estimate
    1.545
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.99
         upper limit
    		 2.411
    Notes
    [5] - Imputation of historical rate of exacerbations for those withdrawing from study
    Statistical analysis title
    		 Negative Binomial model - no imputation
    Statistical analysis description
    Pre-specified sensitivity.
    Comparison groups
    Mannitol v Control
    Number of subjects included in analysis
    423
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.246
    Method
    		 Negative Binomial Model
    Parameter type
    		 Adjusted Rate ratio
    Point estimate
    1.357
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 2.275

    Secondary: Incidence of PDPE

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    End point title
    		 Incidence of PDPE
    End point description
    End point type
    Secondary
    End point timeframe
    Over 26 weeks
    End point values
    		 Mannitol Control
    Number of subjects analysed
    209
    214
    Units: Number of Patients
    28
    29
    Statistical analysis title
    		 Logistic regression
    Comparison groups
    Mannitol v Control
    Number of subjects included in analysis
    423
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.976
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.009
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.555
         upper limit
    		 1.836

    Secondary: Change in Ease of Expectoration VAS score

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    End point title
    		 Change in Ease of Expectoration VAS score
    End point description
    End point type
    Secondary
    End point timeframe
    Over 26 weeks
    End point values
    		 Mannitol Control
    Number of subjects analysed
    209
    214
    Units: cm
        least squares mean (confidence interval 95%)
    0.795 (0.556 to 1.034)
    0.537 (0.306 to 0.767)
    Statistical analysis title
    		 MMRM using BOCF
    Comparison groups
    Mannitol v Control
    Number of subjects included in analysis
    423
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.083
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.259
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.034
         upper limit
    		 0.551

    Secondary: Change in CFQ-R Respiratory Domain scaled score

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    End point title
    		 Change in CFQ-R Respiratory Domain scaled score
    End point description
    End point type
    Secondary
    End point timeframe
    Over 26 weeks
    End point values
    		 Mannitol Control
    Number of subjects analysed
    209
    214
    Units: Points on scale
        least squares mean (confidence interval 95%)
    0.308 (-1.554 to 2.169)
    -0.562 (-2.357 to 1.234)
    Statistical analysis title
    		 MMRM using BOCF
    Comparison groups
    Mannitol v Control
    Number of subjects included in analysis
    423
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.453
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.406
         upper limit
    		 3.145

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Over 26 weeks
    Adverse event reporting additional description
    Treatment emergent (after start of treatment and within 28 days of permanent discontinuation of study drug) are reported. Summaries were performed for all and serious adverse events - no separate summary for non-serious events - therefore the summaries for non-serious also include serious.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.1
    Reporting groups
    Reporting group title
    Mannitol treated
    Reporting group description
    		 -

    Reporting group title
    Control treated
    Reporting group description
    		 Received at least one dose of control treatment

    Serious adverse events
    		 Mannitol treated Control treated
    Total subjects affected by serious adverse events
         subjects affected / exposed
    31 / 207 (14.98%)
    29 / 213 (13.62%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Injury, poisoning and procedural complications
    Intentional overdose
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Guillan-Barre syndrome
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         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 this event term for consistency with other Phase 3 trials
         subjects affected / exposed
    20 / 207 (9.66%)
    15 / 213 (7.04%)
         occurrences causally related to treatment / all
    1 / 25
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    1 / 207 (0.48%)
    2 / 213 (0.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 207 (0.48%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 213 (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
    1 / 207 (0.48%)
    3 / 213 (1.41%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumomediastinum
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 213 (0.47%)
         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 / 207 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 207 (0.00%)
    2 / 213 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Subcutaneous emphysema
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug abuse
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 213 (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
    Lung Infection
         subjects affected / exposed
    1 / 207 (0.48%)
    2 / 213 (0.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 207 (0.48%)
    2 / 213 (0.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    bronchitis
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection viral
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 213 (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
    1 / 207 (0.48%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis bacterial
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 213 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 213 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 213 (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 treated Control treated
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    144 / 207 (69.57%)
    140 / 213 (65.73%)
    Nervous system disorders
    headache
         subjects affected / exposed
    12 / 207 (5.80%)
    22 / 213 (10.33%)
         occurrences all number
    41
    47
    General disorders and administration site conditions
    Condition aggravated
    Additional description: Includes serious events as well (summaries were done for all events only not just non-serious) Pulmonary exacerbations were coded to this term for consistency with previous Phase III trials
         subjects affected / exposed
    56 / 207 (27.05%)
    59 / 213 (27.70%)
         occurrences all number
    84
    75
    Pyrexia
         subjects affected / exposed
    13 / 207 (6.28%)
    8 / 213 (3.76%)
         occurrences all number
    18
    9
    Respiratory, thoracic and mediastinal disorders
    cough
         subjects affected / exposed
    23 / 207 (11.11%)
    21 / 213 (9.86%)
         occurrences all number
    25
    25
    Haemoptysis
    Additional description: Includes serious AEs also (summaries done for serious and all events - no separate summary for non-serious)
         subjects affected / exposed
    21 / 207 (10.14%)
    11 / 213 (5.16%)
         occurrences all number
    28
    36
    Upper respiratory tract infection
    Additional description: Includes serious AEs also (summaries done for all and serious adverse events - no separate summary for non-serious)
         subjects affected / exposed
    15 / 207 (7.25%)
    11 / 213 (5.16%)
         occurrences all number
    18
    12
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    12 / 207 (5.80%)
    10 / 213 (4.69%)
         occurrences all number
    17
    11

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Oct 2014
    Addition of IMP discontinuation visit for subjects who discontinue study treatment but continue their participation in the trial. Disclosing the identity of the control. Clarification on bronchodilator use.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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