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    Clinical Trial Results:
    A randomised, multicentre, double-blind, placebo-controlled, crossover trial determining the efficacy of dry powder mannitol in improving lung function in subjects with Cystic Fibrosis aged six to seventeen years

    Summary
    EudraCT number
    		 2012-002699-14
    Trial protocol
    		 GB   FR   BE   NL   IT  
    Global end of trial date
    15 Oct 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Dec 2019
    First version publication date
    20 Dec 2019
    Other versions
    Summary report(s)
    		 DPM-CF-204 CSR Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    DPM-CF-204
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01883531
    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
    23 May 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Oct 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Oct 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the effect of eight weeks of twice-daily treatment with inhaled dry powder mannitol on lung function (FEV1) in subjects with CF who are aged six to seventeen years
    Protection of trial subjects
    This study was conducted utilising practices that ensured adherence to GCP and protection of the patients, as required by the following Guidelines, Regulations and Directives in operation at the time: • Declaration of Helsinki, concerning medical research in humans ('Recommendations Guiding Physicians in Biomedical Research Involving Human Patients', Helsinki 1964, amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996, Edinburgh 2000). • US 21 Code of Federal Regulations dealing with clinical studies, parts 50 and 56, concerning Informed Patient Consent and IRB approval. • European Directive 75/318/EEC (as amended) on the approximation of laws of Member States relating to analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products. • ICH Guideline for Good Clinical Practice, May 9, 1997
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Jun 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 8
    Country: Number of subjects enrolled
    United Kingdom: 16
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    Switzerland: 8
    Worldwide total number of subjects
    92
    EEA total number of subjects
    73
    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)
    39
    Adolescents (12-17 years)
    53
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients recruited at 39 Sites in 8 countries (Belgium 4; Canada 6; France 5; Germany 7; Italy 3; Switzerland 3; the Netherlands 2; United Kingdom 9).

    Pre-assignment
    Screening details
    		 Diagnosis and main criteria for inclusion: Confirmed diagnosis of cystic fibrosis; aged ≥ 6 years and < 18 years; who have a screening percentage of predicted FEV1 of ≥ 30% and ≤ 90% based upon Wang criteria (if less than 8 years old) or NHanes III criteria. Eligible subjects had to pass mannitol tolerance test (MTT). 117 subjects underwent MTT.

    Period 1
    Period 1 title
    Run-in/Screening/Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Run-in - MTT screening
    Arm description
    		 Screening and MTT testing (117 patients) and then subjects randomised (95 patients). 92 patients went on to receive at least one dose of medication FAS)
    Arm type
    		 Tolerance test - single dose

    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
    Up to 400mg (tolerance test)

    Number of subjects in period 1
    		Run-in - MTT screening
    Started
    92
    Completed
    92
    Period 2
    Period 2 title
    Treatment Phase A
    Is this the baseline period?
    		 No
    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 - Placebo
    Arm description
    		 Mannitol 400mg bid (Phase A) followed by Non-respirable Mannitol (Phase B)
    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 for 8 weeks in Phase A

    Arm title
    		 Placebo - Mannitol
    Arm description
    		 Non-respirable mannitol bid for 8 weeks (phase A) followed by mannitol for 8 weeks in phase B
    Arm type
    		 Experimental

    Investigational medicinal product name
    Non-respirable mannitol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Non-respirable, 10 capsules, bid

    Number of subjects in period 2
    		Mannitol - Placebo Placebo - Mannitol
    Started
    48
    44
    Completed
    47
    43
    Not completed
    1
    1
         Consent withdrawn by subject
    1
    -
         Adverse event, non-fatal
    -
    1
    Period 3
    Period 3 title
    Washout
    Is this the baseline period?
    		 No
    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 - Placebo
    Arm description
    		 -
    Arm type
    		 Washout - no treatment

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Placebo - Mannitol
    Arm description
    		 -
    Arm type
    		 Washout - no treatment

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    		Mannitol - Placebo Placebo - Mannitol
    Started
    47
    43
    Completed
    45
    41
    Not completed
    2
    2
         Consent withdrawn by subject
    1
    1
         Adverse event, non-fatal
    1
    -
         Sponsor decision
    -
    1
    Period 4
    Period 4 title
    Treatment Phase B
    Is this the baseline period?
    		 No
    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 - Placebo
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Non-respirable mannitol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Non-respirable, 10 capsules, bid for 8 weeks in Phase B

    Arm title
    		 Placebo - Mannitol
    Arm description
    		 -
    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 for 8 weeks in Phase B

    Number of subjects in period 4
    		Mannitol - Placebo Placebo - Mannitol
    Started
    45
    41
    Completed
    43
    41
    Not completed
    2
    0
         Consent withdrawn by subject
    1
    -
         Adverse event, non-fatal
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Run-in/Screening/Baseline
    Reporting group description
    		 -

    Reporting group values
    		 Run-in/Screening/Baseline Total
    Number of subjects
    		 92 92
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 39 39
        Adolescents (12-17 years)
    		 53 53
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 12.0 ± 3.0 -
    Gender categorical
    Units: Subjects
        Female
    		 55 55
        Male
    		 37 37
    Screening % Predicted FEV1
    Units: Subjects
        mild >70%
    		 59 59
        moderate >40% to <=70%
    		 32 32
        severe <=40%
    		 1 1
    Subject analysis sets

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Randomised and received at least one dose of trial treatment

    Subject analysis set title
    Mannitol treated
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    These patients were those who received at least one dose of mannitol in either Period A (if randomised to Mannitol - Placebo arm) or Period B (if randomised to Placebo-Mannitol arm).

    Subject analysis set title
    Placebo treated
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    These patients were those who received at least one dose of placebo in either Period A (if randomised to Placebo - Mannitol arm) or Period B (if randomised to Mannitol - Placebo arm).

    Subject analysis sets values
    		 FAS Mannitol treated Placebo treated
    Number of subjects
    92
    87
    87
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
    53
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    55
        Male
    37
    Screening % Predicted FEV1
    Units: Subjects
        mild >70%
    59
        moderate >40% to <=70%
    32
        severe <=40%
    1

    End points

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    End points reporting groups
    Reporting group title
    Run-in - MTT screening
    Reporting group description
    		 Screening and MTT testing (117 patients) and then subjects randomised (95 patients). 92 patients went on to receive at least one dose of medication FAS)
    Reporting group title
    Mannitol - Placebo
    Reporting group description
    		 Mannitol 400mg bid (Phase A) followed by Non-respirable Mannitol (Phase B)

    Reporting group title
    Placebo - Mannitol
    Reporting group description
    		 Non-respirable mannitol bid for 8 weeks (phase A) followed by mannitol for 8 weeks in phase B
    Reporting group title
    Mannitol - Placebo
    Reporting group description
    		 -

    Reporting group title
    Placebo - Mannitol
    Reporting group description
    		 -
    Reporting group title
    Mannitol - Placebo
    Reporting group description
    		 -

    Reporting group title
    Placebo - Mannitol
    Reporting group description
    		 -

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Randomised and received at least one dose of trial treatment

    Subject analysis set title
    Mannitol treated
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    These patients were those who received at least one dose of mannitol in either Period A (if randomised to Mannitol - Placebo arm) or Period B (if randomised to Placebo-Mannitol arm).

    Subject analysis set title
    Placebo treated
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    These patients were those who received at least one dose of placebo in either Period A (if randomised to Placebo - Mannitol arm) or Period B (if randomised to Mannitol - Placebo arm).

    Primary: Change in FEV1 % predicted

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    End point title
    		 Change in FEV1 % predicted
    End point description
    End point type
    Primary
    End point timeframe
    8 weeks
    End point values
    		 Mannitol treated Placebo treated
    Number of subjects analysed
    87
    87
    Units: Percentage
        least squares mean (confidence interval 95%)
    3.59 (1.81 to 5.37)
    0.17 (-1.60 to 1.95)
    Statistical analysis title
    		 Crossover ANCOVA
    Statistical analysis description
    Repeated analysis of covariance (ANCOVA) model including terms for patient, period, baseline within each period and treatment. Missing values were imputed using BOCF
    Comparison groups
    Mannitol treated v Placebo treated
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.0041
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    3.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.12
         upper limit
    		 5.71
    Notes
    [1] - 92 distinct patients (crossover study) - 87 were treated with mannitol, 87 with placebo. BOCF for missing values

    Secondary: Change in FVC % predicted

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    End point title
    		 Change in FVC % predicted
    End point description
    End point type
    Secondary
    End point timeframe
    8 weeks
    End point values
    		 Mannitol treated Placebo treated
    Number of subjects analysed
    87
    87
    Units: Percentage
        least squares mean (confidence interval 95%)
    2.20 (0.32 to 4.08)
    0.40 (-1.48 to 2.28)
    Statistical analysis title
    		 Crossover ANCOVA
    Comparison groups
    Placebo treated v Mannitol treated
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1578
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.71
         upper limit
    		 4.32

    Secondary: Change in FEF % predicted

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    End point title
    		 Change in FEF % predicted
    End point description
    End point type
    Secondary
    End point timeframe
    8 weeks
    End point values
    		 Mannitol treated Placebo treated
    Number of subjects analysed
    87
    87
    Units: Percentage
        least squares mean (confidence interval 95%)
    5.85 (2.70 to 9.00)
    0.10 (-3.04 to 3.24)
    Statistical analysis title
    		 Crossover ANCOVA
    Comparison groups
    Mannitol treated v Placebo treated
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0047
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    5.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.82
         upper limit
    		 9.69

    Secondary: Sputum weight

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    End point title
    		 Sputum weight
    End point description
    End point type
    Secondary
    End point timeframe
    After first dose
    End point values
    		 Mannitol treated Placebo treated
    Number of subjects analysed
    87
    87
    Units: grams
        least squares mean (confidence interval 95%)
    2.63 (1.72 to 3.55)
    1.30 (0.39 to 2.21)
    Statistical analysis title
    		 Crossover ANCOVA
    Comparison groups
    Mannitol treated v Placebo treated
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0124
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 2.37

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study medication
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Mannitol treated
    Reporting group description
    		 -

    Reporting group title
    Placebo treated
    Reporting group description
    		 -

    Serious adverse events
    		 Mannitol treated Placebo treated
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 87 (11.49%)
    13 / 87 (14.94%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anal fistula
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 87 (2.30%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory tract infection
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Productive cough
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchopulmonary aspergillosis allergic
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    7 / 87 (8.05%)
    8 / 87 (9.20%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 87 (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
    0 / 87 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         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 Placebo treated
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    67 / 87 (77.01%)
    59 / 87 (67.82%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 87 (6.90%)
    7 / 87 (8.05%)
         occurrences all number
    8
    10
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    17 / 87 (19.54%)
    20 / 87 (22.99%)
         occurrences all number
    19
    21
    Nasopharyngitis
         subjects affected / exposed
    6 / 87 (6.90%)
    6 / 87 (6.90%)
         occurrences all number
    7
    7
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
    Additional description: Includes serious and non-serious numbers
         subjects affected / exposed
    8 / 87 (9.20%)
    13 / 87 (14.94%)
         occurrences all number
    9
    15
    Lung infection
         subjects affected / exposed
    2 / 87 (2.30%)
    5 / 87 (5.75%)
         occurrences all number
    2
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Sep 2013
    Changes to study design that included deletion of home spirometry, adding of visit windows and inclusion of 5 additional telephone contacts

    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/28258928
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