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    Clinical Trial Results:
    A 24-week, multicenter, multinational, randomized, double-blind, triple-dummy, 3-arm parallel group study comparing the efficacy and safety of CHF 1535 200/6 (beclomethasone dipropionate 200 μg plus formoterol 6 μg/actuation), 2 puffs b.i.d., versus beclomethasone diproprionate HFA (250 μg/actuation), 4 puffs b.i.d., versus Seretide® 500/50 (fluticasone 500 μg plus salmeterol 50 μg/actuation), 1 inhalation b.i.d., in patients with severe asthma.

    Summary
    EudraCT number
    		 2007-002587-99
    Trial protocol
    		 LT   SI   CZ   EE   DE   LV   FR   ES   IT   BG  
    Global end of trial date
    10 Sep 2009

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Oct 2017
    First version publication date
    14 Oct 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CCD-0605-PR-0021
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Chiesi Farmaceutici SpA
    Sponsor organisation address
    Via Palermo 26/A, Parma, Italy, 43122
    Public contact
    Clinical Trial Transparency, Chiesi Farmaceutici SpA, Chiesi Farmaceutici SpA, 0521 2791, ClinicalTrial_info@chiesi.com
    Scientific contact
    Clinical Trial Transparency, Chiesi Farmaceutici SpA, Chiesi Farmaceutici SpA, 0521 2791, ClinicalTrial_info@chiesi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Nov 2010
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Sep 2009
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Sep 2009
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    In severe asthma patients, with forced expiratory volume in the first second (FEV1) <80% of predicted normal value and symptomatic on high-doses of inhaled corticosteroid (ICS) as monotherapy or medium doses of ICS + long-acting β2-agonist (LABA),, to demonstrate: - the superiority of CHF 1535 200/6 (two puffs b.i.d.) versus a high dose of BDP (beclomethasone diproprionate 2000 μg/day) given as monotherapy, in terms of: - pulmonary function (change from baseline in pre-dose morning FEV1 measured at clinic) and - asthma control (change from baseline in percentage of complete days without asthma symptoms), and - the non-inferiority versus Seretide® 500/50 (one inhalation b.i.d.), in terms of pulmonary function (change from baseline in pre-dose morning FEV1 measured at clinic) during a 24-week treatment period.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (GCP) guidelines and local law requirements. Other than routine care, no specific measures for protection of trial subjects were implemented.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Feb 2008
    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
    Poland: 112
    Country: Number of subjects enrolled
    Slovenia: 3
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Bulgaria: 64
    Country: Number of subjects enrolled
    Czech Republic: 19
    Country: Number of subjects enrolled
    Estonia: 25
    Country: Number of subjects enrolled
    France: 20
    Country: Number of subjects enrolled
    Germany: 49
    Country: Number of subjects enrolled
    Hungary: 38
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Latvia: 22
    Country: Number of subjects enrolled
    Lithuania: 14
    Country: Number of subjects enrolled
    Belarus: 8
    Country: Number of subjects enrolled
    Croatia: 37
    Country: Number of subjects enrolled
    Romania: 47
    Country: Number of subjects enrolled
    Russian Federation: 145
    Country: Number of subjects enrolled
    Ukraine: 113
    Worldwide total number of subjects
    721
    EEA total number of subjects
    455
    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)
    12
    Adults (18-64 years)
    649
    From 65 to 84 years
    60
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Male and female outpatients aged 12 to 70 inclusive (except for sites in Russia, Belarus, Estonia, Lithuania, France, Czech Republic, Hungary and Slovenia, where only patients aged ≥18 and ≤70 were enrolled) with severe persistent symptomatic (verified at screening and at randomisation) asthma diagnosed according to GINA guidance (revised 2006).

    Pre-assignment
    Screening details
    		 845 patients were screened, 818 were included in the run-in period and received at least one dose of single-blind treatment; 721 were randomised (237 in the CHF 1535 group, 242 in the BDP monotherapy group and 242 in the Seretide® group) and received at least one dose of randomised study drug.

    Period 1
    Period 1 title
    Overall Trial by 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
    Blinding implementation details
    This was a double-blind study except for the 2-week single-blind run-in period before randomisation. Each test and reference treatment was identical in appearance with its corresponding placebo in order to maintain the blind.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CHF 1535
    Arm description
    		 CHF 1535 hydroflouroalkane (HFA)-134a pressurised metered dose (pMDI) inhaler (fixed combination of beclomethasone dipropionate 200 μg plus formoterol 6 μg/unit dose).
    Arm type
    		 Experimental

    Investigational medicinal product name
    CHF 1535
    Investigational medicinal product code
    Other name
    fixed combination of beclomethasone dipropionate and formoterol
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    CHF 1535 hydroflouroalkane (HFA)-134a pressurised metered dose (pMDI) inhaler (fixed combination of beclomethasone dipropionate 200 μg plus formoterol 6 μg/unit dose), 2 inhalations of CHF 1535 HFA pMDI b.i.d. Administration scheme: - 2 inhalations of CHF 1535 HFA pMDI b.i.d. - 4 inhalations of BDP HFA pMDI placebo b.i.d. - 1 inhalation of Seretide Accuhaler placebo b.i.d.

    Investigational medicinal product name
    BDP HFA pMDI placebo
    Investigational medicinal product code
    Other name
    beclomethasone dipropionate
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    BDP HFA pMDI placebo, 4 inhalations b.i.d. Administration scheme: - 2 inhalations of CHF 1535 HFA pMDI b.i.d. - 4 inhalations of BDP HFA pMDI placebo b.i.d. - 1 inhalation of Seretide Accuhaler placebo b.i.d.

    Investigational medicinal product name
    Seretide® Accuhaler® placebo
    Investigational medicinal product code
    Other name
    Fluticasone plus salmeterol
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Seretide® Accuhaler® placebo, 1 inhalation b.i.d. Administration scheme: - 2 inhalations of CHF 1535 HFA pMDI b.i.d. - 4 inhalations of BDP HFA pMDI placebo b.i.d. - 1 inhalation of Seretide Accuhaler placebo b.i.d.

    Arm title
    		 BDP monotherapy
    Arm description
    		 BDP HFA-134a pMDI (beclomethasone dipropionate 250 μg/unit dose: Clenil®Modulite® 250).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    BDP HFA
    Investigational medicinal product code
    Other name
    beclomethasone dipropionate
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Beclomethasone dipropionate HFA pMDI 250 μg/unit dose (Clenil® 250) (daily dose of BDP “non extrafine” 2000 μg BDP); 4 inhalations b.i.d. Administration scheme: - 2 inhalations of CHF 1535 HFA pMDI placebo b.i.d. - 4 inhalations of BDP HFA pMDI b.i.d. - 1 inhalation of Seretide Accuhaler placebo b.i.d.

    Investigational medicinal product name
    CHF 1535 HFA pMDI placebo
    Investigational medicinal product code
    Other name
    fixed combination of beclomethasone dipropionate plus formoterol
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 inhalations of CHF 1535 HFA pMDI placebo b.i.d. Administration scheme: - 2 inhalations of CHF 1535 HFA pMDI placebo b.i.d. - 4 inhalations of BDP HFA pMDI b.i.d. - 1 inhalation of Seretide Accuhaler placebo b.i.d.

    Investigational medicinal product name
    Seretide® Accuhaler® placebo
    Investigational medicinal product code
    Other name
    Fluticasone plus salmeterol
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    1 inhalation of Seretide Accuhaler placebo b.i.d. Administration scheme: - 2 inhalations of CHF 1535 HFA pMDI placebo b.i.d. - 4 inhalations of BDP HFA pMDI b.i.d. - 1 inhalation of Seretide Accuhaler placebo b.i.d.

    Arm title
    		 Seretide
    Arm description
    		 Seretide® Accuhaler® (fluticasone propionate 500 μg plus salmeterol xinafoate 50 μg/actuation).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Seretide
    Investigational medicinal product code
    Other name
    Fluticasone plus salmeterol
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Seretide® Accuhaler® 500/50 μg/actuation (daily dose of fluticasone 1000 μg plus salmeterol 100 μg): 1 inhalation b.i.d. Administration scheme: - 2 inhalations of CHF 1535 HFA pMDI placebo b.i.d. - 4 inhalations of BDP HFA pMDI placebo b.i.d. - 1 inhalation of Seretide Accuhaler b.i.d.

    Investigational medicinal product name
    CHF 1535 HFA pMDI placebo
    Investigational medicinal product code
    Other name
    fixed combination of beclomethasone dipropionate plus formoterol
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 inhalations of CHF 1535 HFA pMDI placebo b.i.d. Administration scheme: - 2 inhalations of CHF 1535 HFA pMDI placebo b.i.d. - 4 inhalations of BDP HFA pMDI placebo b.i.d. - 1 inhalation of Seretide Accuhaler b.i.d.

    Investigational medicinal product name
    BDP HFA pMDI placebo
    Investigational medicinal product code
    Other name
    beclomethasone dipropionate
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    4 inhalations of BDP HFA pMDI placebo b.i.d. Administration scheme: - 2 inhalations of CHF 1535 HFA pMDI placebo b.i.d. - 4 inhalations of BDP HFA pMDI placebo b.i.d. - 1 inhalation of Seretide Accuhaler b.i.d.

    Number of subjects in period 1
    		CHF 1535 BDP monotherapy Seretide
    Started
    237
    242
    242
    Completed
    197
    204
    202
    Not completed
    40
    38
    40
         Consent withdrawn by subject
    10
    11
    13
         Adverse event, non-fatal
    3
    6
    2
         inclusion/exclusion criteria not met
    20
    15
    20
         Lost to follow-up
    1
    2
    -
         Protocol deviation
    3
    4
    2
         not specified
    3
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CHF 1535
    Reporting group description
    		 CHF 1535 hydroflouroalkane (HFA)-134a pressurised metered dose (pMDI) inhaler (fixed combination of beclomethasone dipropionate 200 μg plus formoterol 6 μg/unit dose).

    Reporting group title
    BDP monotherapy
    Reporting group description
    		 BDP HFA-134a pMDI (beclomethasone dipropionate 250 μg/unit dose: Clenil®Modulite® 250).

    Reporting group title
    Seretide
    Reporting group description
    		 Seretide® Accuhaler® (fluticasone propionate 500 μg plus salmeterol xinafoate 50 μg/actuation).

    Reporting group values
    		 CHF 1535 BDP monotherapy Seretide Total
    Number of subjects
    		 237 242 242 721
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 2 5 5 12
        Adults (18-64 years)
    		 215 216 218 649
        From 65-84 years
    		 20 21 19 60
    Gender categorical
    Units: Subjects
        Female
    		 129 140 141 410
        Male
    		 108 102 101 311
    Subject analysis sets

    Subject analysis set title
    CHF1535 ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised patients who received at least one administration of randomised study treatment and with at least one available efficacy evaluation after baseline. According to the ITT principle, the treatment groups for the ITT population were determined by the treatments to which the patients were randomised.

    Subject analysis set title
    BDP monotherapy ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised patients who received at least one administration of randomised study treatment and with at least one available efficacy evaluation after baseline. According to the ITT principle, the treatment groups for the ITT population were determined by the treatments to which the patients were randomised.

    Subject analysis set title
    Seretide ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised patients who received at least one administration of randomised study treatment and with at least one available efficacy evaluation after baseline. According to the ITT principle, the treatment groups for the ITT population were determined by the treatments to which the patients were randomised.

    Subject analysis sets values
    		 CHF1535 ITT BDP monotherapy ITT Seretide ITT
    Number of subjects
    234
    241
    241
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    2
    5
    5
        Adults (18-64 years)
    213
    215
    217
        From 65-84 years
    19
    21
    19
    Age continuous
    Units: years
        
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    128
    139
    141
        Male
    106
    102
    100

    End points

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    End points reporting groups
    Reporting group title
    CHF 1535
    Reporting group description
    		 CHF 1535 hydroflouroalkane (HFA)-134a pressurised metered dose (pMDI) inhaler (fixed combination of beclomethasone dipropionate 200 μg plus formoterol 6 μg/unit dose).

    Reporting group title
    BDP monotherapy
    Reporting group description
    		 BDP HFA-134a pMDI (beclomethasone dipropionate 250 μg/unit dose: Clenil®Modulite® 250).

    Reporting group title
    Seretide
    Reporting group description
    		 Seretide® Accuhaler® (fluticasone propionate 500 μg plus salmeterol xinafoate 50 μg/actuation).

    Subject analysis set title
    CHF1535 ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised patients who received at least one administration of randomised study treatment and with at least one available efficacy evaluation after baseline. According to the ITT principle, the treatment groups for the ITT population were determined by the treatments to which the patients were randomised.

    Subject analysis set title
    BDP monotherapy ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised patients who received at least one administration of randomised study treatment and with at least one available efficacy evaluation after baseline. According to the ITT principle, the treatment groups for the ITT population were determined by the treatments to which the patients were randomised.

    Subject analysis set title
    Seretide ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised patients who received at least one administration of randomised study treatment and with at least one available efficacy evaluation after baseline. According to the ITT principle, the treatment groups for the ITT population were determined by the treatments to which the patients were randomised.

    Primary: Change from baseline to end of treatment in pre-dose morning FEV1

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    End point title
    		 Change from baseline to end of treatment in pre-dose morning FEV1
    End point description
    Pre-dose morning FEV1 was measured at clinic visit.
    End point type
    Primary
    End point timeframe
    At each single visit, from Visit 1 (run-in), through Visit 2 (baseline), to Visit 7 (end of treatment)
    End point values
    		 CHF1535 ITT BDP monotherapy ITT Seretide ITT
    Number of subjects analysed
    234
    241
    241
    Units: Liters
        least squares mean (confidence interval 95%)
    0.2 (0.14 to 0.25)
    0.16 (0.11 to 0.21)
    0.22 (0.17 to 0.28)
    Statistical analysis title
    		 CHF1535 ITT vs BDP monotherapy ITT
    Comparison groups
    CHF1535 ITT v BDP monotherapy ITT
    Number of subjects included in analysis
    475
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    Method
    Parameter type
    		 least square mean difference
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.11
    Notes
    [1] - The two co-primary efficacy variables were analysed using a repeated measurements analysis of covariance (ANCOVA) model including baseline as covariate and terms for treatment and country
    Statistical analysis title
    		 CHF1535 ITT vs Seretide ITT
    Comparison groups
    CHF1535 ITT v Seretide ITT
    Number of subjects included in analysis
    475
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 least square mean difference
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.05

    Primary: Change from baseline to end of treatment in % of complete days without asthma symptoms

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    End point title
    		 Change from baseline to end of treatment in % of complete days without asthma symptoms
    End point description
    A complete day without asthma symptoms is considered a day with all 4 asthma symptom scores (cough, wheeze, chest tightness, breathlessness) recorded as 0 (“No Symptoms”), both in the evening and in the following morning.
    End point type
    Primary
    End point timeframe
    Asthma symptom scores were recorded daily at home with electronic peak-flow meter which allows symptoms and use of “rescue” medication to be recorded
    End point values
    		 CHF1535 ITT BDP monotherapy ITT Seretide ITT
    Number of subjects analysed
    234
    241
    241
    Units: Percentage
        least squares mean (confidence interval 95%)
    24.64 (19.05 to 30.24)
    21.95 (16.39 to 27.52)
    26.57 (21.13 to 32.01)
    Statistical analysis title
    		 CHF1535 ITT vs BDP ITT
    Comparison groups
    CHF1535 ITT v BDP monotherapy ITT
    Number of subjects included in analysis
    475
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.505
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    2.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.22
         upper limit
    		 10.6
    Notes
    [2] - The two co-primary efficacy variables were analysed using a repeated measurements analysis of covariance (ANCOVA) model including baseline as covariate and terms for treatment and country.
    Statistical analysis title
    		 CHF1535 ITT vs Seretide ITT
    Comparison groups
    CHF1535 ITT v Seretide ITT
    Number of subjects included in analysis
    475
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 = 0.628
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    -1.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.74
         upper limit
    		 5.89
    Notes
    [3] - The two co-primary efficacy variables were analysed using a repeated measurements analysis of covariance (ANCOVA) model including baseline as covariate and terms for treatment and country.

    Secondary: Morning PEF

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    End point title
    		 Morning PEF
    End point description
    Pre-dose morning PEF was measured daily at home by a portable electronic peak flow meter.
    End point type
    Secondary
    End point timeframe
    Pre-dose morning PEF was measured daily. Data are available for the run-in period and for 2-week periods from week 1 to week 22 and also last 2 weeks bef V7. Only data from last 2 weeks bef. V7 are reported here.
    End point values
    		 CHF1535 ITT BDP monotherapy ITT Seretide ITT
    Number of subjects analysed
    128 [4]
    123 [5]
    133 [6]
    Units: L/min
        arithmetic mean (standard deviation)
    330.83 ± 104.01
    315.54 ± 98.06
    334.5 ± 108.57
    Notes
    [4] - This is the actual number of patients analysed.
    [5] - This is the actual number of patients analysed.
    [6] - This is the actual number of patients analysed.
    No statistical analyses for this end point

    Secondary: Change from baseline in morning PEF

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    End point title
    		 Change from baseline in morning PEF
    End point description
    Pre-dose morning PEF was measured daily at home by a portable electronic peak flow meter.
    End point type
    Secondary
    End point timeframe
    Pre-dose morning PEF was measured daily. Data are available for the run-in period and for 2-week periods from week 1 to week 22 and also last 2 weeks bef V7. Only data on change from baseline to last 2 weeks bef. V7 are reported here.
    End point values
    		 CHF1535 ITT BDP monotherapy ITT Seretide ITT
    Number of subjects analysed
    99 [7]
    100 [8]
    105 [9]
    Units: L/min
        least squares mean (confidence interval 95%)
    12.28 (2.96 to 21.61)
    -9.06 (-17.96 to -0.15)
    13.72 (4.95 to 22.48)
    Notes
    [7] - This is the actual number of patients analysed.
    [8] - This is the actual number of patients analysed.
    [9] - This is the actual number of patients analysed.
    Statistical analysis title
    		 CHF1535 vs BDP monotherapy
    Comparison groups
    CHF1535 ITT v BDP monotherapy ITT
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.001
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    21.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.43
         upper limit
    		 34.25
    Notes
    [10] - Changes from baseline in morning PEF, evening PEF and PEF variability were analysed using the same repeated measurements ANCOVA as for the change in % of days without asthma symptoms.
    Statistical analysis title
    		 CHF1535 vs Seretide
    Comparison groups
    CHF1535 ITT v Seretide ITT
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [11]
    P-value
    		 = 0.826
    Method
    		 ANCOVA
    Parameter type
    		 least square mean difference
    Point estimate
    -1.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.26
         upper limit
    		 11.39
    Notes
    [11] - Changes from baseline in morning PEF, evening PEF and PEF variability were analysed using the same repeated measurements ANCOVA as for the change in % of days without asthma symptoms.

    Secondary: Daily total number of rescue medication puffs

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    End point title
    		 Daily total number of rescue medication puffs
    End point description
    The daily use of rescue medication were recorded in the SpirotelTM as follows: the number of puffs taken during the day were recorded each evening before taking the study drug, while the number of puffs taken during the night will be recorded each morning on awakening.
    End point type
    Secondary
    End point timeframe
    Throughout the study. Data are available for the run-in period and for 2-week periods from week 1 to week 22 and also last 2 weeks bef V7. Only data from last 2 weeks bef. V7 are reported here.
    End point values
    		 CHF1535 ITT BDP monotherapy ITT Seretide ITT
    Number of subjects analysed
    166 [12]
    162 [13]
    178 [14]
    Units: Puffs
        arithmetic mean (standard deviation)
    -0.84 ± 2.63
    -0.72 ± 2.38
    -1.05 ± 2.03
    Notes
    [12] - This is the actual number of patients analysed
    [13] - This is the actual number of patients analysed
    [14] - This is the actual number of patients analysed
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were assessed at each visit, from Visit 1 (run-in) to Visit 7 (of the treatment period)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.1
    Reporting groups
    Reporting group title
    CHF1535 - Safety
    Reporting group description
    		 Safety population: all randomised patients who received at least one administration of randomised study treatment. Patients were included in the analysis according to the treatment actually received.

    Reporting group title
    BDP monotherapy - safety
    Reporting group description
    		 Safety population: all randomised patients who received at least one administration of randomised study treatment. Patients were included in the analysis according to the treatment actually received

    Reporting group title
    Seretide - safety
    Reporting group description
    		 Safety population: all randomised patients who received at least one administration of randomised study treatment. Patients were included in the analysis according to the treatment actually received

    Serious adverse events
    		 CHF1535 - Safety BDP monotherapy - safety Seretide - safety
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 239 (2.09%)
    9 / 244 (3.69%)
    4 / 242 (1.65%)
         number of deaths (all causes)
    0
    1
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bowen's disease
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dislocation of vertebra
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 239 (0.42%)
    3 / 244 (1.23%)
    1 / 242 (0.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urinary retention
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
    Additional description: SAE occurred during the run-in period
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.4%
    Non-serious adverse events
    		 CHF1535 - Safety BDP monotherapy - safety Seretide - safety
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    87 / 239 (36.40%)
    90 / 244 (36.89%)
    87 / 242 (35.95%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 239 (0.84%)
    3 / 244 (1.23%)
    1 / 242 (0.41%)
         occurrences all number
    2
    3
    1
    Hypertensive crisis
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Pallor
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 239 (0.00%)
    3 / 244 (1.23%)
    0 / 242 (0.00%)
         occurrences all number
    0
    3
    0
    Asthenia
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    1 / 242 (0.41%)
         occurrences all number
    0
    1
    1
    Pyrexia
         subjects affected / exposed
    1 / 239 (0.42%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences all number
    1
    1
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences all number
    0
    1
    0
    Reproductive system and breast disorders
    Breast mass
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Urogenital prolapse
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Uterine cervical erosion
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    20 / 239 (8.37%)
    22 / 244 (9.02%)
    20 / 242 (8.26%)
         occurrences all number
    21
    24
    29
    Cough
         subjects affected / exposed
    6 / 239 (2.51%)
    7 / 244 (2.87%)
    8 / 242 (3.31%)
         occurrences all number
    6
    8
    8
    Dysphonia
         subjects affected / exposed
    4 / 239 (1.67%)
    2 / 244 (0.82%)
    7 / 242 (2.89%)
         occurrences all number
    4
    2
    7
    Pharyngolaryngeal pain
         subjects affected / exposed
    3 / 239 (1.26%)
    1 / 244 (0.41%)
    1 / 242 (0.41%)
         occurrences all number
    3
    1
    1
    Throat irritation
         subjects affected / exposed
    2 / 239 (0.84%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    2
    0
    1
    Dyspnoea
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    1 / 242 (0.41%)
         occurrences all number
    0
    11
    1
    Rhinitis allergic
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    2 / 242 (0.83%)
         occurrences all number
    0
    0
    2
    Nasal polyps
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Pharyngeal erythema
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Postnasal drip
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory disorder
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences all number
    0
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Sneezing
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Wheezing
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    3 / 242 (1.24%)
         occurrences all number
    0
    0
    3
    Restlessness
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Investigations
    Blood cortisol decreased
         subjects affected / exposed
    0 / 239 (0.00%)
    2 / 244 (0.82%)
    1 / 242 (0.41%)
         occurrences all number
    0
    2
    1
    Blood pressure increased
         subjects affected / exposed
    2 / 239 (0.84%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    2
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    0 / 239 (0.00%)
    2 / 244 (0.82%)
    0 / 242 (0.00%)
         occurrences all number
    0
    2
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 239 (0.00%)
    2 / 244 (0.82%)
    0 / 242 (0.00%)
         occurrences all number
    0
    2
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences all number
    0
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences all number
    0
    1
    0
    Blood cholesterol increased
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Blood cortisol increased
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences all number
    0
    1
    0
    Blood glucose increased
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Blood potassium increased
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Blood pressure diastolic increased
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences all number
    0
    1
    0
    Electrocardiogram ST segment abnormal
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    QRS axis abnormal
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    2 / 242 (0.83%)
         occurrences all number
    0
    0
    2
    Joint dislocation
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    1 / 242 (0.41%)
         occurrences all number
    0
    1
    1
    Joint sprain
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences all number
    0
    1
    0
    Muscle strain
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Rib fracture
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Skin laceration
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 239 (0.00%)
    2 / 244 (0.82%)
    1 / 242 (0.41%)
         occurrences all number
    0
    2
    1
    Palpitations
         subjects affected / exposed
    0 / 239 (0.00%)
    2 / 244 (0.82%)
    0 / 242 (0.00%)
         occurrences all number
    0
    3
    0
    Sinus arrhythmia
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    2 / 242 (0.83%)
         occurrences all number
    0
    0
    2
    Supraventricular extrasystoles
         subjects affected / exposed
    1 / 239 (0.42%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences all number
    1
    1
    0
    Tachycardia
         subjects affected / exposed
    2 / 239 (0.84%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    2
    0
    0
    Angina pectoris
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Aortic valve disease
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Bundle branch block left
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Bundle branch block
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Cardiac discomfort
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Cardiac failure chronic
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac failure
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Right ventricular hypertrophy
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Sinus bradycardia
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 239 (3.77%)
    8 / 244 (3.28%)
    6 / 242 (2.48%)
         occurrences all number
    17
    8
    14
    Dizziness
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    3 / 242 (1.24%)
         occurrences all number
    0
    1
    3
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Convulsions local
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Facial nerve disorder
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences all number
    0
    1
    0
    Hypotonia
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences all number
    0
    1
    0
    MIgrane
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences all number
    0
    1
    0
    Radiculitis
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Syncope
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Tremor
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    2 / 242 (0.83%)
         occurrences all number
    0
    0
    2
    Thrombocytopenia
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    2 / 242 (0.83%)
         occurrences all number
    0
    0
    2
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Leukocytosis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences all number
    0
    1
    0
    Leukopenia
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    2
    Conjunctivitis
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Eye irritation
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences all number
    0
    1
    0
    Scleral haemorrhage
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 239 (0.84%)
    1 / 244 (0.41%)
    3 / 242 (1.24%)
         occurrences all number
    2
    1
    3
    Diarrhoea
         subjects affected / exposed
    2 / 239 (0.84%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences all number
    2
    1
    0
    Food poisoning
         subjects affected / exposed
    3 / 239 (1.26%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    3
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 239 (0.42%)
    2 / 244 (0.82%)
    0 / 242 (0.00%)
         occurrences all number
    1
    2
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    1 / 242 (0.41%)
         occurrences all number
    0
    1
    1
    Glossodynia
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    1 / 242 (0.41%)
         occurrences all number
    0
    1
    1
    Abdominal distension
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Dry mouth
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Duodenal ulcer
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Dysphagia
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences all number
    0
    1
    0
    Gastric ulcer
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Gastritis atrophic
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Oesophageal disorder
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences all number
    0
    1
    0
    Pancreatitis
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Stomatitis
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Tongue coated
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Tongue disorder
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Dermatitis atopic
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Rash
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Seborrhoeic dermatitis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences all number
    0
    1
    0
    Urticaria thermal
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Urticaria
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences all number
    0
    1
    0
    Renal colic
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 239 (0.84%)
    2 / 244 (0.82%)
    2 / 242 (0.83%)
         occurrences all number
    2
    2
    2
    Muscle spasms
         subjects affected / exposed
    4 / 239 (1.67%)
    1 / 244 (0.41%)
    1 / 242 (0.41%)
         occurrences all number
    4
    1
    1
    Arthralgia
         subjects affected / exposed
    1 / 239 (0.42%)
    1 / 244 (0.41%)
    2 / 242 (0.83%)
         occurrences all number
    1
    2
    7
    Arthritis
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Bone pain
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Osteochondrosis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences all number
    0
    1
    0
    Osteopenia
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 239 (3.77%)
    14 / 244 (5.74%)
    16 / 242 (6.61%)
         occurrences all number
    10
    15
    17
    Respiratory tract infection
         subjects affected / exposed
    2 / 239 (0.84%)
    5 / 244 (2.05%)
    5 / 242 (2.07%)
         occurrences all number
    2
    5
    6
    Bronchitis
         subjects affected / exposed
    4 / 239 (1.67%)
    6 / 244 (2.46%)
    1 / 242 (0.41%)
         occurrences all number
    4
    6
    1
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 239 (0.42%)
    5 / 244 (2.05%)
    5 / 242 (2.07%)
         occurrences all number
    1
    6
    7
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 239 (1.26%)
    3 / 244 (1.23%)
    4 / 242 (1.65%)
         occurrences all number
    3
    3
    6
    Influenza
         subjects affected / exposed
    2 / 239 (0.84%)
    4 / 244 (1.64%)
    3 / 242 (1.24%)
         occurrences all number
    2
    6
    3
    Pharyngitis
         subjects affected / exposed
    3 / 239 (1.26%)
    3 / 244 (1.23%)
    2 / 242 (0.83%)
         occurrences all number
    3
    3
    2
    Oral candidiasis
         subjects affected / exposed
    1 / 239 (0.42%)
    5 / 244 (2.05%)
    1 / 242 (0.41%)
         occurrences all number
    1
    7
    1
    Acute tonsillitis
         subjects affected / exposed
    1 / 239 (0.42%)
    3 / 244 (1.23%)
    2 / 242 (0.83%)
         occurrences all number
    1
    3
    2
    Viral infection
         subjects affected / exposed
    4 / 239 (1.67%)
    1 / 244 (0.41%)
    1 / 242 (0.41%)
         occurrences all number
    4
    1
    1
    Rhinitis
         subjects affected / exposed
    1 / 239 (0.42%)
    1 / 244 (0.41%)
    2 / 242 (0.83%)
         occurrences all number
    1
    1
    2
    Sinusitis
         subjects affected / exposed
    0 / 239 (0.00%)
    2 / 244 (0.82%)
    2 / 242 (0.83%)
         occurrences all number
    0
    2
    2
    Laryngitis
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    1
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    1 / 242 (0.41%)
         occurrences all number
    0
    1
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    1 / 242 (0.41%)
         occurrences all number
    0
    1
    1
    Bronchitis bacterial
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences all number
    0
    1
    0
    Cervicitis
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Cystitis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences all number
    0
    2
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Pyelonephritis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 244 (0.41%)
    0 / 242 (0.00%)
         occurrences all number
    0
    1
    0
    Tracheitis
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    0 / 239 (0.00%)
    0 / 244 (0.00%)
    1 / 242 (0.41%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    4 / 239 (1.67%)
    2 / 244 (0.82%)
    1 / 242 (0.41%)
         occurrences all number
    4
    2
    1
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 239 (0.42%)
    2 / 244 (0.82%)
    0 / 242 (0.00%)
         occurrences all number
    1
    2
    0
    Diabetes mellitus
         subjects affected / exposed
    2 / 239 (0.84%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    2
    0
    0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 239 (0.00%)
    2 / 244 (0.82%)
    0 / 242 (0.00%)
         occurrences all number
    0
    2
    0
    Dyslipidaemia
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Hypernatraemia
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 244 (0.00%)
    0 / 242 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jul 2007
    Changes were made to improve some safety measures of the protocol.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    There are no limitation or caveats applicable to this summary of results.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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