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    Clinical Trial Results:
    Efficacy and safety of Salmeterol/Fluticasone MDI HEXAL versus SeretideTM EvohalerTM in adolescent and adult patients with moderate-to-severe persistent asthma: A 12-week, multicenter, randomized, double-blind, double-dummy, parallel group study

    Summary
    EudraCT number
    		 2007-005235-29
    Trial protocol
    		 HU   CZ   PL  
    Global end of trial date
    27 Apr 2009

    Results information
    Results version number
    		 v3(current)
    This version publication date
    14 Apr 2016
    First version publication date
    06 Feb 2016
    Other versions
    		 v1 , v2
    Version creation reason
    • Correction of full data set
    Article 46 was not correct.

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    2007-41-DOS-3
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    HEXAL AG
    Sponsor organisation address
    Industriestraße 25, Holzkirchen, Germany, 83607
    Public contact
    Head of Clinical Research Department, Hexal AG, 0049 80249080,
    Scientific contact
    Head of Clinical Research Department, Hexal AG, 0049 80249080,
    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
    07 Aug 2009
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Apr 2009
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Apr 2009
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this study was to evaluate the long-term efficacy and safety of Salmeterol/Fluticasone MDI HEXAL compared to Seretide Evohaler in adolescent and adult patients suffering from moderate-to-severe persistent asthma.
    Protection of trial subjects
    Safety assessments included adverse events (AEs), physical examination, ECG, vital signs and clinical laboratory data. This study was conducted in accordance with International Conference on Harmonisation of Good Clinical Practice, the principles of the Declaration of Helsinki, as well as other applicable local ethical and legal requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Oct 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
    Czech Republic: 29
    Country: Number of subjects enrolled
    Hungary: 49
    Country: Number of subjects enrolled
    Poland: 175
    Country: Number of subjects enrolled
    Romania: 40
    Country: Number of subjects enrolled
    Ukraine: 279
    Worldwide total number of subjects
    572
    EEA total number of subjects
    293
    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)
    94
    Adults (18-64 years)
    477
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Double-blind, double-dummy, multicenter, multinational, randomized parallel group study in adolescent and adult patients suffering from moderate-to-severe asthma

    Pre-assignment
    Screening details
    		 A total number of 610 patients where screened and 572 patients were randomized. A 2-week run-in period followed by a 12-week blinded treatment period. The screening visit (Visit -1) was followed by a 2-week run-in period during which all asthma treatments except reliever medication were to be stopped.

    Pre-assignment period milestones
    Number of subjects started
    		 610 [1]
    Number of subjects completed
    		 572

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Adverse event, serious non-fatal: 1
    Reason: Number of subjects
    		 Consent withdrawn by subject: 4
    Reason: Number of subjects
    		 Adverse event, non-fatal: 1
    Reason: Number of subjects
    		 Physician decision: 1
    Reason: Number of subjects
    		 Pregnancy: 1
    Reason: Number of subjects
    		 Lost to follow-up: 3
    Reason: Number of subjects
    		 Ineligibility: 24
    Reason: Number of subjects
    		 Sponsor decision: 3
    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 didn't complete the study due to various reasons.
    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Salmeterol/Fluticasone MDI HEXAL (25 µg/50 µg)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Salmeterol/Fluticasone MDI HEXAL
    Investigational medicinal product code
    Other name
    NA
    Pharmaceutical forms
    Pressurised inhalation
    Routes of administration
    Inhalation use
    Dosage and administration details
    Salmeterol/Fluticasone MDI HEXAL (25 µg/50 µg of salmeterol/fluticasone per actuation), 2x2 actuations per day

    Arm title
    		 Seretide 50 Evohaler
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Seretide 50
    Investigational medicinal product code
    Other name
    NA
    Pharmaceutical forms
    Pressurised inhalation
    Routes of administration
    Inhalation use
    Dosage and administration details
    Seretide 50 Evohaler (25 µg/50 µg per actuation), 2x2 actuations per day

    Arm title
    		 Salmeterol/Fluticasone MDI HEXAL (25 µg/250 µg)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Salmeterol/Fluticasone MDI HEXAL
    Investigational medicinal product code
    Other name
    NA
    Pharmaceutical forms
    Pressurised inhalation
    Routes of administration
    Inhalation use
    Dosage and administration details
    Salmeterol/Fluticasone MDI HEXAL (25 µg/250 µg of salmeterol/fluticasone per actuation), 2x2 actuations per day

    Arm title
    		 Seretide 250 Evohaler
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Seretide 250
    Investigational medicinal product code
    Other name
    NA
    Pharmaceutical forms
    Pressurised inhalation
    Routes of administration
    Inhalation use
    Dosage and administration details
    Seretide 250 Evohaler (25 µg/250 µg per actuation), 2x2 actuations per day

    Number of subjects in period 1
    		Salmeterol/Fluticasone MDI HEXAL (25 µg/50 µg) Seretide 50 Evohaler Salmeterol/Fluticasone MDI HEXAL (25 µg/250 µg) Seretide 250 Evohaler
    Started
    195
    192
    96
    89
    Completed
    185
    180
    91
    81
    Not completed
    10
    12
    5
    8
         Consent withdrawn by subject
    4
    8
    4
    5
         Envelope opened
    -
    1
    -
    -
         Adverse event, non-fatal
    1
    1
    -
    2
         Lost to follow-up
    3
    -
    1
    1
         Sponsor decision
    1
    1
    -
    -
         Protocol deviation
    1
    -
    -
    -
         Lack of efficacy
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Salmeterol/Fluticasone MDI HEXAL (25 µg/50 µg)
    Reporting group description
    		 -

    Reporting group title
    Seretide 50 Evohaler
    Reporting group description
    		 -

    Reporting group title
    Salmeterol/Fluticasone MDI HEXAL (25 µg/250 µg)
    Reporting group description
    		 -

    Reporting group title
    Seretide 250 Evohaler
    Reporting group description
    		 -

    Reporting group values
    		 Salmeterol/Fluticasone MDI HEXAL (25 µg/50 µg) Seretide 50 Evohaler Salmeterol/Fluticasone MDI HEXAL (25 µg/250 µg) Seretide 250 Evohaler Total
    Number of subjects
    		 195 192 96 89 572
    Age Categorical
    Age Categorical Characteristic
    Units: Subjects
        In Utero
    		 0 0 0 0 0
        Preterm newborn- gestational age < 37 wk
    		 0 0 0 0 0
        Newborns (0-27days)
    		 0 0 0 0 0
        Infants and toddlers (28days – 23months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 year)
    		 30 34 18 12 94
        From 18 - 64 years
    		 164 158 78 77 477
        From 65 – 84 years
    		 1 0 0 0 1
        Over 85 years
    		 0 0 0 0 0
    Age Continuous
    Age Continuous Characteristic
    Units: Years
        arithmetic mean (standard deviation)
    		 39.9 ( 15.8 ) 41 ( 17.2 ) 40 ( 17.3 ) 39.3 ( 16.3 ) -
    Gender Categorical
    Gender Categorical Characteristic
    Units: Subjects
        Female
    		 118 115 55 49 337
        Male
    		 77 77 41 40 235

    End points

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    End points reporting groups
    Reporting group title
    Salmeterol/Fluticasone MDI HEXAL (25 µg/50 µg)
    Reporting group description
    		 -

    Reporting group title
    Seretide 50 Evohaler
    Reporting group description
    		 -

    Reporting group title
    Salmeterol/Fluticasone MDI HEXAL (25 µg/250 µg)
    Reporting group description
    		 -

    Reporting group title
    Seretide 250 Evohaler
    Reporting group description
    		 -

    Subject analysis set title
    Salmeterol/Fluticasone MDI HEXAL (25 µg/50 µg) - Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The analysis consist of all patients who - were randomized - received at least one dose of IP

    Subject analysis set title
    Seretide 50 Evohaler - Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The analysis consist of all patients who - were randomized - received at least one dose of IP

    Subject analysis set title
    Salmeterol/Fluticasone MDI HEXAL (25 µg/250 µg) - Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The analysis consist of all patients who - were randomized - received at least one dose of IP

    Subject analysis set title
    Seretide 250 Evohaler - Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The analysis consist of all patients who - were randomized - received at least one dose of IP

    Subject analysis set title
    Salmeterol/Fluticasone MDI HEXAL (25 µg/50 µg) - FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The analysis consist of all patients who - are included in the Safety analysis set - had FEV1 data after the baseline visit

    Subject analysis set title
    Seretide 50 Evohaler - FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The analysis consist of all patients who - are included in the Safety analysis set - had FEV1 data after the baseline visit

    Subject analysis set title
    Salmeterol/Fluticasone MDI HEXAL (25 µg/250 µg) - FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The analysis consist of all patients who - are included in the Safety analysis set - had FEV1 data after the baseline visit

    Subject analysis set title
    Seretide 250 Evohaler - FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The analysis consist of all patients who - are included in the Safety analysis set - had FEV1 data after the baseline visit

    Subject analysis set title
    Salmeterol/Fluticasone MDI HEXAL (25 µg/50 µg) - PPS
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The analysis consist of all patients who - are included in the FA set - completed the study - had no major protocol violations

    Subject analysis set title
    Seretide 50 Evohaler - PPS
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The analysis consist of all patients who - are included in the FA set - completed the study - had no major protocol violations

    Subject analysis set title
    Salmeterol/Fluticasone MDI HEXAL (25 µg/250 µg) - PPS
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The analysis consist of all patients who - are included in the FA set - completed the study - had no major protocol violations

    Subject analysis set title
    Seretide 250 Evohaler - PPS
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The analysis consist of all patients who - are included in the FA set - completed the study - had no major protocol violations

    Primary: The mean change in FEV1 from baseline to the end of 12-week study period (Visit 6)

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    End point title
    		 The mean change in FEV1 from baseline to the end of 12-week study period (Visit 6)
    End point description
    The change from baseline at the end of the 12-week treatment period. Missing values of the primary endpoint ‘change in FEV1’ were replaced using the last-value-carried-forward strategy as follows: in case if both pre–dose FEV1 values were missing at Visit 6/ET, the last value observed under treatment before Visit 6/ET was imputed as Visit 6/ET value. If there is no such last value under treatment, no imputation was made. If there is only one assessment of FEV1 pre-dose values at Visit 0 or Visit 6/ET is done, the available value was used for analysis.
    End point type
    Primary
    End point timeframe
    From baseline (Visit 0) to end of 12 weeks study period (Visit 6)
    End point values
    		 Salmeterol/Fluticasone MDI HEXAL (25 µg/50 µg) - FAS Seretide 50 Evohaler - FAS Salmeterol/Fluticasone MDI HEXAL (25 µg/250 µg) - FAS Seretide 250 Evohaler - FAS Salmeterol/Fluticasone MDI HEXAL (25 µg/50 µg) - PPS Seretide 50 Evohaler - PPS Salmeterol/Fluticasone MDI HEXAL (25 µg/250 µg) - PPS Seretide 250 Evohaler - PPS
    Number of subjects analysed
    192
    190
    95
    88
    183
    177
    89
    81
    Units: Litre
    arithmetic mean (standard deviation)
        Baseline, FEV1
    2.218 ( 0.544 )
    2.127 ( 0.521 )
    2.158 ( 0.597 )
    2.221 ( 0.548 )
    2.226 ( 0.545 )
    2.127 ( 0.513 )
    2.154 ( 0.576 )
    2.239 ( 0.54 )
        Endpoint, FEV1
    2.595 ( 0.814 )
    2.57 ( 0.791 )
    2.574 ( 0.884 )
    2.742 ( 0.762 )
    2.611 ( 0.808 )
    2.541 ( 0.765 )
    2.587 ( 0.858 )
    2.752 ( 0.768 )
        Change from Baseline
    0.377 ( 0.472 )
    0.443 ( 0.475 )
    0.416 ( 0.477 )
    0.522 ( 0.486 )
    0.385 ( 0.47 )
    0.414 ( 0.458 )
    0.433 ( 0.478 )
    0.512 ( 0.491 )
    Statistical analysis title
    		 Statistical analysis 1: ANCOVA
    Statistical analysis description
    An Analysis of Covariance (ANCOVA) using treatment and centre as factors and baseline FEV1 and age as co-variables. The first null hypothesis was that with respect to the change from baseline FEV1 (mean of the 2 pre-dose values at Visit 0) the test formulation is inferior to the reference formulation (the difference in means, µtest - µref is smaller than -200mL) in favour of the alternative hypothesis that the test product is equivalent to or better than the reference product.
    Comparison groups
    Salmeterol/Fluticasone MDI HEXAL (25 µg/50 µg) - FAS v Seretide 50 Evohaler - FAS
    Number of subjects included in analysis
    382
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.9739
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.080611
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -0.161974
         upper limit
    		 -
    Statistical analysis title
    		 Statistical analysis 2: ANCOVA
    Statistical analysis description
    An Analysis of Covariance (ANCOVA) using treatment and centre as factors and baseline FEV1 and age as co-variables. The first null hypothesis was that with respect to the change from baseline FEV1 (mean of the 2 pre-dose values at Visit 0) the test formulation is inferior to the reference formulation (the difference in means, µtest - µref is smaller than -200mL) in favour of the alternative hypothesis that the test product is equivalent to or better than the reference product.
    Comparison groups
    Salmeterol/Fluticasone MDI HEXAL (25 µg/50 µg) - PPS v Seretide 50 Evohaler - PPS
    Number of subjects included in analysis
    360
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.9104
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.056504
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -0.139088
         upper limit
    		 -
    Statistical analysis title
    		 Statistical analysis 3: ANCOVA
    Statistical analysis description
    An Analysis of Covariance (ANCOVA) using treatment and centre as factors and baseline FEV1 and age as co-variables. The first null hypothesis was that with respect to the change from baseline FEV1 (mean of the 2 pre-dose values at Visit 0) the test formulation is inferior to the reference formulation (the difference in means, µtest - µref is smaller than -200mL) in favour of the alternative hypothesis that the test product is equivalent to or better than the reference product.
    Comparison groups
    Salmeterol/Fluticasone MDI HEXAL (25 µg/250 µg) - FAS v Seretide 250 Evohaler - FAS
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.9489
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.102292
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -0.225175
         upper limit
    		 -
    Statistical analysis title
    		 Statistical analysis 4: ANCOVA
    Statistical analysis description
    An Analysis of Covariance (ANCOVA) using treatment and centre as factors and baseline FEV1 and age as co-variables. The first null hypothesis was that with respect to the change from baseline FEV1 (mean of the 2 pre-dose values at Visit 0) the test formulation is inferior to the reference formulation (the difference in means, µtest - µref is smaller than -200mL) in favour of the alternative hypothesis that the test product is equivalent to or better than the reference product.
    Comparison groups
    Salmeterol/Fluticasone MDI HEXAL (25 µg/250 µg) - PPS v Seretide 250 Evohaler - PPS
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.8427
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.066329
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -0.196239
         upper limit
    		 -

    Primary: AUC(0—12)/12 at the end of 12-week study period (Visit 6) relative to baseline

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    End point title
    		 AUC(0—12)/12 at the end of 12-week study period (Visit 6) relative to baseline
    End point description
    The area under the 12-hour serial FEV1 curve (AUC0-12) at the end of the 12-week treatment period (Visit 6) relative to baseline FEV1 (mean of the 2 pre-dose values at Visit 0). Missing values of the second primary endpoint ‘FEV1 AUC(0-12)’ were replaced using linear interpolation.
    End point type
    Primary
    End point timeframe
    From baseline (Visit 0) to end of 12 weeks study period (Visit 6)
    End point values
    		 Salmeterol/Fluticasone MDI HEXAL (25 µg/50 µg) - FAS Seretide 50 Evohaler - FAS Salmeterol/Fluticasone MDI HEXAL (25 µg/250 µg) - FAS Seretide 250 Evohaler - FAS Salmeterol/Fluticasone MDI HEXAL (25 µg/50 µg) - PPS Seretide 50 Evohaler - PPS Salmeterol/Fluticasone MDI HEXAL (25 µg/250 µg) - PPS Seretide 250 Evohaler - PPS
    Number of subjects analysed
    192
    190
    95
    88
    183
    177
    89
    81
    Units: Litre
    arithmetic mean (standard deviation)
        Baseline, FEV1
    2.218 ( 0.544 )
    2.127 ( 0.521 )
    2.158 ( 0.597 )
    2.221 ( 0.548 )
    2.226 ( 0.545 )
    2.127 ( 0.513 )
    2.154 ( 0.576 )
    2.239 ( 0.54 )
        AUC(0—12)/12 (L) at V6/ET
    2.733 ( 0.825 )
    2.702 ( 0.813 )
    2.682 ( 0.868 )
    2.896 ( 0.849 )
    2.732 ( 0.829 )
    2.677 ( 0.792 )
    2.693 ( 0.865 )
    2.899 ( 0.854 )
        Ratio of AUC(0—12)/12 and Baseline
    1.225 ( 0.21 )
    1.262 ( 0.227 )
    1.246 ( 0.221 )
    1.303 ( 0.229 )
    1.223 ( 0.209 )
    1.255 ( 0.223 )
    1.248 ( 0.222 )
    1.299 ( 0.228 )
        Log of Ratio of AUC(0—12)/12 and Baseline
    0.189 ( 0.165 )
    0.217 ( 0.179 )
    0.205 ( 0.168 )
    0.25 ( 0.17 )
    0.187 ( 0.165 )
    0.212 ( 0.177 )
    0.207 ( 0.169 )
    0.247 ( 0.169 )
    Statistical analysis title
    		 Statistical analysis 5: ANCOVA
    Statistical analysis description
    Analysis of Covariance (ANCOVA) using treatment and centre as factors and log transformed baseline FEV1 and age as co-variables. The second null hypothesis was that with respect to the FEV1 AUC(0-12) after 12 weeks of treatment relative to baseline FEV1 the test formulation is inferior to the reference formulation (the ratio in means, µtest/µref, is smaller than 80%) in favour of the alternative hypothesis that the test formulation is equivalent to or better than the reference formulation.
    Comparison groups
    Salmeterol/Fluticasone MDI HEXAL (25 µg/50 µg) - FAS v Seretide 50 Evohaler - FAS
    Number of subjects included in analysis
    382
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.9818
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.968004
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 0.938962
         upper limit
    		 -
    Statistical analysis title
    		 Statistical analysis 6: ANCOVA
    Statistical analysis description
    Analysis of Covariance (ANCOVA) using treatment and centre as factors and log transformed baseline FEV1 and age as co-variables. The second null hypothesis was that with respect to the FEV1 AUC(0-12) after 12 weeks of treatment relative to baseline FEV1 the test formulation is inferior to the reference formulation (the ratio in means, µtest/µref, is smaller than 80%) in favour of the alternative hypothesis that the test formulation is equivalent to or better than the reference formulation.
    Comparison groups
    Salmeterol/Fluticasone MDI HEXAL (25 µg/50 µg) - PPS v Seretide 50 Evohaler - PPS
    Number of subjects included in analysis
    360
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.9721
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.970518
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 0.941211
         upper limit
    		 -
    Statistical analysis title
    		 Statistical analysis 7: ANCOVA
    Statistical analysis description
    Analysis of Covariance (ANCOVA) using treatment and centre as factors and log transformed baseline FEV1 and age as co-variables. The second null hypothesis was that with respect to the FEV1 AUC(0-12) after 12 weeks of treatment relative to baseline FEV1 the test formulation is inferior to the reference formulation (the ratio in means, µtest/µref, is smaller than 80%) in favour of the alternative hypothesis that the test formulation is equivalent to or better than the reference formulation.
    Comparison groups
    Salmeterol/Fluticasone MDI HEXAL (25 µg/250 µg) - FAS v Seretide 250 Evohaler - FAS
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.9822
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.952911
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 0.911031
         upper limit
    		 -
    Statistical analysis title
    		 Statistical analysis 8: ANCOVA
    Statistical analysis description
    Analysis of Covariance (ANCOVA) using treatment and centre as factors and log transformed baseline FEV1 and age as co-variables. The second null hypothesis was that with respect to the FEV1 AUC(0-12) after 12 weeks of treatment relative to baseline FEV1 the test formulation is inferior to the reference formulation (the ratio in means, µtest/µref, is smaller than 80%) in favour of the alternative hypothesis that the test formulation is equivalent to or better than the reference formulation.
    Comparison groups
    Salmeterol/Fluticasone MDI HEXAL (25 µg/250 µg) - PPS v Seretide 250 Evohaler - PPS
    Number of subjects included in analysis
    170
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.9621
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.960046
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 0.917738
         upper limit
    		 -

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first intake of investigational product (IP) till the 28 days after the last intake of IP
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.0
    Reporting groups
    Reporting group title
    Salmeterol/Fluticasone MDI HEXAL (25 µg/50 µg) - Safety Set
    Reporting group description
    		 -

    Reporting group title
    Seretide 50 Evohaler - Safety Set
    Reporting group description
    		 -

    Reporting group title
    Salmeterol/Fluticasone MDI HEXAL (25 µg/250 µg) - Safety Set
    Reporting group description
    		 -

    Reporting group title
    Seretide 250 Evohaler - Safety Set
    Reporting group description
    		 -

    Serious adverse events
    		 Salmeterol/Fluticasone MDI HEXAL (25 µg/50 µg) - Safety Set Seretide 50 Evohaler - Safety Set Salmeterol/Fluticasone MDI HEXAL (25 µg/250 µg) - Safety Set Seretide 250 Evohaler - Safety Set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Salmeterol/Fluticasone MDI HEXAL (25 µg/50 µg) - Safety Set Seretide 50 Evohaler - Safety Set Salmeterol/Fluticasone MDI HEXAL (25 µg/250 µg) - Safety Set Seretide 250 Evohaler - Safety Set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    60 / 195 (30.77%)
    41 / 192 (21.35%)
    22 / 96 (22.92%)
    24 / 89 (26.97%)
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Chills
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 192 (0.00%)
    1 / 96 (1.04%)
    0 / 89 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oedema
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    1 / 89 (1.12%)
         occurrences all number
    0
    0
    0
    1
    Fatigue
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    1 / 89 (1.12%)
         occurrences all number
    1
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    3 / 195 (1.54%)
    2 / 192 (1.04%)
    2 / 96 (2.08%)
    1 / 89 (1.12%)
         occurrences all number
    3
    2
    2
    1
    Dysphonia
         subjects affected / exposed
    7 / 195 (3.59%)
    2 / 192 (1.04%)
    3 / 96 (3.13%)
    3 / 89 (3.37%)
         occurrences all number
    7
    3
    3
    3
    Epistaxis
         subjects affected / exposed
    1 / 195 (0.51%)
    1 / 192 (0.52%)
    1 / 96 (1.04%)
    0 / 89 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Pharyngolaryngeal pain
         subjects affected / exposed
    2 / 195 (1.03%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    2 / 89 (2.25%)
         occurrences all number
    0
    0
    0
    6
    Sneezing
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Wheezing
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Psychiatric disorders
    Nervousness
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    1 / 89 (1.12%)
         occurrences all number
    0
    0
    0
    1
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    2 / 89 (2.25%)
         occurrences all number
    1
    0
    0
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cortisol free urine increased
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Electrocardiogram t wave inversion
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Weight increased
         subjects affected / exposed
    2 / 195 (1.03%)
    1 / 192 (0.52%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 192 (0.00%)
    1 / 96 (1.04%)
    0 / 89 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Fibula fracture
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hand fracture
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Joint sprain
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    1 / 89 (1.12%)
         occurrences all number
    0
    0
    0
    1
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Extrasystoles
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 192 (0.00%)
    1 / 96 (1.04%)
    0 / 89 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Headache
         subjects affected / exposed
    4 / 195 (2.05%)
    1 / 192 (0.52%)
    1 / 96 (1.04%)
    1 / 89 (1.12%)
         occurrences all number
    4
    3
    3
    1
    Intercostal neuralgia
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Somnolence
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tremor
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 96 (0.00%)
    1 / 89 (1.12%)
         occurrences all number
    0
    1
    0
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    1 / 96 (1.04%)
    0 / 89 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Gastrointestinal disorders
    Cheilitis
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    1 / 89 (1.12%)
         occurrences all number
    0
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    1 / 96 (1.04%)
    0 / 89 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Duodenitis
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Enterocolitis
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastritis
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Toothache
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 192 (0.00%)
    1 / 96 (1.04%)
    0 / 89 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Photodermatosis
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 192 (0.00%)
    1 / 96 (1.04%)
    0 / 89 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rash pruritic
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    1 / 89 (1.12%)
         occurrences all number
    0
    0
    0
    1
    Endocrine disorders
    Toxic nodular goitre
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 195 (1.54%)
    1 / 192 (0.52%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Intervertebral disc disorder
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Limb discomfort
         subjects affected / exposed
    1 / 195 (0.51%)
    1 / 192 (0.52%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    4
    1
    0
    0
    Muscle spasms
         subjects affected / exposed
    1 / 195 (0.51%)
    1 / 192 (0.52%)
    0 / 96 (0.00%)
    1 / 89 (1.12%)
         occurrences all number
    1
    3
    0
    1
    Muscular weakness
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    1 / 89 (1.12%)
         occurrences all number
    0
    0
    0
    1
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    1 / 89 (1.12%)
         occurrences all number
    0
    0
    0
    1
    Acute tonsillitis
         subjects affected / exposed
    2 / 195 (1.03%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Bronchitis
         subjects affected / exposed
    4 / 195 (2.05%)
    1 / 192 (0.52%)
    1 / 96 (1.04%)
    1 / 89 (1.12%)
         occurrences all number
    4
    1
    1
    1
    Candidiasis
         subjects affected / exposed
    2 / 195 (1.03%)
    2 / 192 (1.04%)
    0 / 96 (0.00%)
    2 / 89 (2.25%)
         occurrences all number
    2
    2
    0
    2
    Cystitis
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 192 (0.00%)
    1 / 96 (1.04%)
    0 / 89 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Influenza
         subjects affected / exposed
    4 / 195 (2.05%)
    1 / 192 (0.52%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    4
    1
    0
    0
    Laryngitis
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    1 / 89 (1.12%)
         occurrences all number
    1
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    10 / 195 (5.13%)
    7 / 192 (3.65%)
    3 / 96 (3.13%)
    0 / 89 (0.00%)
         occurrences all number
    10
    8
    3
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Oropharyngeal candidiasis
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Paronychia
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pharyngitis
         subjects affected / exposed
    1 / 195 (0.51%)
    3 / 192 (1.56%)
    0 / 96 (0.00%)
    4 / 89 (4.49%)
         occurrences all number
    1
    3
    0
    4
    Pneumonia
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    12 / 195 (6.15%)
    12 / 192 (6.25%)
    6 / 96 (6.25%)
    5 / 89 (5.62%)
         occurrences all number
    14
    12
    7
    5
    Respiratory tract infection viral
         subjects affected / exposed
    7 / 195 (3.59%)
    6 / 192 (3.13%)
    5 / 96 (5.21%)
    2 / 89 (2.25%)
         occurrences all number
    9
    6
    6
    2
    Rhinitis
         subjects affected / exposed
    2 / 195 (1.03%)
    1 / 192 (0.52%)
    2 / 96 (2.08%)
    0 / 89 (0.00%)
         occurrences all number
    2
    1
    2
    0
    Tracheitis
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    1 / 89 (1.12%)
         occurrences all number
    0
    0
    0
    1
    Tonsillitis
         subjects affected / exposed
    1 / 195 (0.51%)
    0 / 192 (0.00%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tracheobronchitis
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 192 (0.00%)
    1 / 96 (1.04%)
    0 / 89 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 195 (1.03%)
    3 / 192 (1.56%)
    2 / 96 (2.08%)
    1 / 89 (1.12%)
         occurrences all number
    2
    3
    2
    1
    Viral infection
         subjects affected / exposed
    1 / 195 (0.51%)
    1 / 192 (0.52%)
    1 / 96 (1.04%)
    0 / 89 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Viral rhinitis
         subjects affected / exposed
    0 / 195 (0.00%)
    1 / 192 (0.52%)
    0 / 96 (0.00%)
    0 / 89 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 195 (0.00%)
    0 / 192 (0.00%)
    1 / 96 (1.04%)
    0 / 89 (0.00%)
         occurrences all number
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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