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    Clinical Trial Results:
    A 12-Week Efficacy and Safety Evaluation of Budesonide/Formoterol SPIROMAX® 160/4.5 mcg Inhalation Powder Versus SYMBICORT® TURBOHALER® 200/6 mcg in Adult and Adolescent Patients with Persistent Asthma

    Summary
    EudraCT number
    		 2013-000081-11
    Trial protocol
    		 HU   AT   DE   BE   IT   SE   CZ   FI   ES   PL   NL   DK  
    Global end of trial date
    20 Mar 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 May 2016
    First version publication date
    27 May 2016
    Other versions
    Summary report(s)
    		 Nonserious AEs During Run-in Period

    Trial information

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    Trial identification
    Sponsor protocol code
    BFS-AS-306
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01803555
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Teva Branded Pharmaceutical Products R&D, Inc.
    Sponsor organisation address
    41 Moores Road, Frazer, United States, 19355
    Public contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc, 215 591 3000, ustevatrials@tevapharm.com
    Scientific contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc, 215 591 3000, ustevatrials@tevapharm.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
    20 Mar 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Mar 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to establish the non-inferiority of BF SPIROMAX 160/4.5 mcg with that of SYMBICORT TURBOHALER 200/6 mcg administered twice daily in patients 12 years of age and older with persistent asthma, as assessed by the change from baseline in average daily trough (predose and pre-rescue bronchodilator) morning (AM) peak expiratory flow (PEF) rate over a 12-week treatment period. The secondary objectives of the study were to evaluate subject preference and ease of use of the BF SPIROMAX 160/4.5 mcg device compared to SYMBICORT TURBOHALER 200/6 mcg.
    Protection of trial subjects
    For adult subjects, written informed consent signed and dated by the subject before conducting any study-related procedures; for minor subjects, written informed consent signed and dated by the parent/legal guardian and written assent signed and dated by the subject before conducting any study-related procedure. Stopping criteria for worsening asthma were designed to assure subject safety. The study drug was stopped and the patient was withdrawn from the study if any of the criteria listed below were met: • clinic forced expiratory volume (FEV1) fell below the FEV1 stability limit value calculated at Visit 2 • during the 7 days immediately preceding any treatment visits (Visits 2 to 5), if the patient experienced: - more than 3 days in which the peak expiratory flow (PEF) fell below the PEF stability limit calculated at visit 2 - more than 2 days in which ≥ 12 inhalations/day of albuterol/salbutamol were used - more than 1 night with awakening due to asthma symptoms requiring use of rescue albuterol/salbutamol - clinical asthma exacerbation, defined as worsening asthma requiring any treatment other than study drug or rescue albuterol/salbutamol, including the use of systemic corticosteroids and/or emergency room visit or hospitalization.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Jul 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 12
    Country: Number of subjects enrolled
    Poland: 236
    Country: Number of subjects enrolled
    Spain: 16
    Country: Number of subjects enrolled
    Sweden: 10
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    Austria: 23
    Country: Number of subjects enrolled
    Belgium: 16
    Country: Number of subjects enrolled
    Czech Republic: 27
    Country: Number of subjects enrolled
    Denmark: 6
    Country: Number of subjects enrolled
    Finland: 8
    Country: Number of subjects enrolled
    France: 20
    Country: Number of subjects enrolled
    Germany: 105
    Country: Number of subjects enrolled
    Hungary: 85
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Israel: 18
    Country: Number of subjects enrolled
    Russian Federation: 71
    Worldwide total number of subjects
    671
    EEA total number of subjects
    582
    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)
    38
    Adults (18-64 years)
    539
    From 65 to 84 years
    94
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 725 subjects with persistent asthma were screened for enrollment into this study. Of these, 671 subjects at 112 study centers worldwide met entry criteria and were considered to be eligible for enrollment into the run-in period of the study.

    Pre-assignment
    Screening details
    		 During the run-in period, all subjects continued to use their current daily asthma medications at fixed doses. The rescue medication (albuterol/salbutamol) dispensed at visit 1 was provided by TEVA and permitted for symptomatic relief of asthma symptoms during the run-in period and replaced the subject’s current rescue therapy.

    Pre-assignment period milestones
    Number of subjects started
    		 671
    Number of subjects completed
    		 605

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Inclusion criteria not met: 5
    Reason: Number of subjects
    		 Consent withdrawn by subject: 5
    Reason: Number of subjects
    		 Randomization criteria not met: 2
    Reason: Number of subjects
    		 Adverse event: 1
    Reason: Number of subjects
    		 Lost to follow-up: 1
    Reason: Number of subjects
    		 Not specified: 52
    Period 1
    Period 1 title
    Randomized Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    At the baseline visit (Visit 2; end of the run-in period), subjects meeting the eligibility criteria were randomized to the 84-day treatment period. In the event of an emergency, if it was necessary to know what treatment a specific patient received, the investigator was allowed to determine the patient’s treatment with or without consulting the sponsor, depending on the nature and severity of the emergency.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BF SPIROMAX
    Arm description
    		 2 inhalations of BF SPIROMAX at a dosage of 160/4.5 mcg (budesonide/formoterol fumarate dihydrate 160/4.5 mcg) and 2 inhalations of placebo SYMBICORT administered twice daily (AM and PM) during the 12-week treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Budesonide/Formoterol (BF) SPIROMAX (budesonide/formoterol fumarate dihydrate 160/4.5 mcg)
    Investigational medicinal product code
    BF Spiromax
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    During the treatment period (Visit 2 through Visit 5), subjects administered the double-blind study medication twice daily. All subjects continued albuterol/salbutamol for use on an as needed basis for the relief of asthma symptoms throughout the treatment period.

    Investigational medicinal product name
    Placebo SYMBICORT
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    During the treatment period (Visit 2 through Visit 5), subjects administered the double-blind study medication twice daily. All subjects continued albuterol/salbutamol for use on an as needed basis for the relief of asthma symptoms throughout the treatment period.

    Arm title
    		 SYMBICORT TURBOHALER
    Arm description
    		 2 inhalations of SYMBICORT TURBOHALER at a dosage of 200/6 mcg and 2 inhalations of placebo SPIROMAX administered twice daily (AM and PM) during the 12-week treatment period.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    SYMBICORT® TURBOHALER® 200/6 mcg inhalation powder
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    During the treatment period (Visit 2 through Visit 5), subjects administered the double-blind study medication twice daily. All subjects continued albuterol/salbutamol for use on an as needed basis for the relief of asthma symptoms throughout the treatment period.

    Investigational medicinal product name
    Placebo SPIROMAX
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    During the treatment period (Visit 2 through Visit 5), subjects administered the double-blind study medication twice daily. All subjects continued albuterol/salbutamol for use on an as needed basis for the relief of asthma symptoms throughout the treatment period.

    Number of subjects in period 1 [1]
    		BF SPIROMAX SYMBICORT TURBOHALER
    Started
    303
    302
    Completed
    290
    284
    Not completed
    13
    18
         Consent withdrawn by subject
    3
    3
         Not specified
    3
    5
         Adverse event
    3
    2
         Lost to follow-up
    -
    2
         Noncompliance
    1
    1
         Protocol deviation
    3
    5
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of subjects accounted for in the Run-in period (ie, Pre-assignment period; n=671) equals the worldwide number enrolled in the trial.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BF SPIROMAX
    Reporting group description
    		 2 inhalations of BF SPIROMAX at a dosage of 160/4.5 mcg (budesonide/formoterol fumarate dihydrate 160/4.5 mcg) and 2 inhalations of placebo SYMBICORT administered twice daily (AM and PM) during the 12-week treatment period.

    Reporting group title
    SYMBICORT TURBOHALER
    Reporting group description
    		 2 inhalations of SYMBICORT TURBOHALER at a dosage of 200/6 mcg and 2 inhalations of placebo SPIROMAX administered twice daily (AM and PM) during the 12-week treatment period.

    Reporting group values
    		 BF SPIROMAX SYMBICORT TURBOHALER Total
    Number of subjects
    		 303 302 605
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 18 20 38
        Adults (18-64 years)
    		 242 242 484
        From 65-84 years
    		 43 40 83
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 48.1 ± 16.24 46.9 ± 16.89 -
    Gender categorical
    Units: Subjects
        Female
    		 172 161 333
        Male
    		 131 141 272

    End points

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    End points reporting groups
    Reporting group title
    BF SPIROMAX
    Reporting group description
    		 2 inhalations of BF SPIROMAX at a dosage of 160/4.5 mcg (budesonide/formoterol fumarate dihydrate 160/4.5 mcg) and 2 inhalations of placebo SYMBICORT administered twice daily (AM and PM) during the 12-week treatment period.

    Reporting group title
    SYMBICORT TURBOHALER
    Reporting group description
    		 2 inhalations of SYMBICORT TURBOHALER at a dosage of 200/6 mcg and 2 inhalations of placebo SPIROMAX administered twice daily (AM and PM) during the 12-week treatment period.

    Subject analysis set title
    BF SPIROMAX (per protocol)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects in the BF SPIROMAX treatment arm included in the per-protocol (PP) population. The PP population includes all data from randomized subjects obtained before experiencing major protocol violations, which were determined before unblinding.

    Subject analysis set title
    SYMBICORT TURBOHALER (per protocol)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects in the SYMBICORT TURBOHALER treatment arm included in the per-protocol (PP) population. The PP population includes all data from randomized subjects obtained before experiencing major protocol violations, which were determined before unblinding.

    Primary: Change in Weekly Average of Daily Trough Morning (AM) Peak Expiratory Flow (PEF) From Baseline Over the 12-week Treatment Period

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    End point title
    		 Change in Weekly Average of Daily Trough Morning (AM) Peak Expiratory Flow (PEF) From Baseline Over the 12-week Treatment Period
    End point description
    PEF was determined twice daily, in the AM and in the evening (PM), before administration of study or rescue medications during the run-in period and throughout the 12-week double-blind treatment period. A handheld electronic peak flow meter was provided to subjects at the screening visit (Visit 1) and used to determine AM and PM PEFs throughout the course of the study. The highest value of triplicate measurements obtained in the AM and PM was to be recorded by subjects into a paper diary.
    End point type
    Primary
    End point timeframe
    Baseline (defined as the last non-missing assessment prior to the 1st dose of study medication) through Week 12
    End point values
    		 BF SPIROMAX (per protocol) SYMBICORT TURBOHALER (per protocol)
    Number of subjects analysed
    290
    284
    Units: L/min
        least squares mean (standard error)
    18.839 ± 2.754
    21.796 ± 2.745
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Performed using a repeated measures mixed model with effects due to baseline weekly average of daily trough AM PEF, gender, age, treatment, time, and treatment-by-time interaction. It is noted that missing data were not implicitly imputed in the repeated measures mixed model analysis; however, all non-missing data were used within the analysis to estimate the time-averaged difference between treatment groups over 12 weeks.
    Comparison groups
    SYMBICORT TURBOHALER (per protocol) v BF SPIROMAX (per protocol)
    Number of subjects included in analysis
    574
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 = 0.3387 [2]
    Method
    		 repeated measures mixed model
    Parameter type
    		 least squares mean
    Point estimate
    -2.957
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.02
         upper limit
    		 3.11
    Notes
    [1] - The non-inferiority of BF SPIROMAX 160/4.5 mcg to SYMBICORT TURBOHALER 200/6 mcg was demonstrated if the lower limit of the 2 sided 95% CI for the treatment difference is greater than –15 L/min.
    [2] - No explicit structure was assumed for the covariance among the repeated measures. However, in case there was a convergence problem with the unstructured covariance, then a compound symmetry or AR(1) covariance structure was assumed.

    Secondary: Change in Weekly Average of Daily Trough Evening (PM) PEF From Baseline Over the 12-week Treatment Period

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    End point title
    		 Change in Weekly Average of Daily Trough Evening (PM) PEF From Baseline Over the 12-week Treatment Period
    End point description
    PEF was determined twice daily, in the AM and in the PM, before administration of study or rescue medications during the run-in period and throughout the 12-week double-blind treatment period. A handheld electronic peak flow meter was provided to subjects at the screening visit (Visit 1) and used to determine AM and PM PEFs throughout the course of the study. The highest value of triplicate measurements obtained in the AM and PM was to be recorded by subjects into a paper diary.
    End point type
    Secondary
    End point timeframe
    Baseline (defined as the last non-missing assessment prior to the 1st dose of study medication) through Week 12
    End point values
    		 BF SPIROMAX (per protocol) SYMBICORT TURBOHALER (per protocol)
    Number of subjects analysed
    290
    284
    Units: L/Min
        least squares mean (standard error)
    18.661 ± 2.631
    21.74 ± 2.622
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Performed using a repeated measures mixed model with effects due to baseline weekly average of daily trough PM PEF, gender, age, treatment, time, and treatment-by-time interaction. It is noted that missing data were not implicitly imputed in the repeated measures mixed model analysis; however, all non-missing data were used within the analysis to estimate the time-averaged difference between treatment groups over 12 weeks.
    Comparison groups
    SYMBICORT TURBOHALER (per protocol) v BF SPIROMAX (per protocol)
    Number of subjects included in analysis
    574
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.293 [3]
    Method
    		 repeated measures mixed model
    Parameter type
    		 least squares mean
    Point estimate
    -3.078
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.82
         upper limit
    		 2.67
    Notes
    [3] - No explicit structure was assumed for the covariance among the repeated measures. However, in case there was a convergence problem with the unstructured covariance, then a compound symmetry or AR(1) covariance structure was assumed.

    Secondary: Change From Baseline Over the 12-week Treatment Period in the Percentage of Symptom-free 24-hour Periods

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    End point title
    		 Change From Baseline Over the 12-week Treatment Period in the Percentage of Symptom-free 24-hour Periods
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (defined as the last non-missing assessment prior to the 1st dose of study medication) through Week 12
    End point values
    		 BF SPIROMAX (per protocol) SYMBICORT TURBOHALER (per protocol)
    Number of subjects analysed
    290
    284
    Units: percentage of symptom-free 24-hr periods
        median (full range (min-max))
    20.5 (-94 to 100)
    27.8 (-93.3 to 100)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    BF SPIROMAX (per protocol) v SYMBICORT TURBOHALER (per protocol)
    Number of subjects included in analysis
    574
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3082
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.97
         upper limit
    		 1.19

    Secondary: Change From Baseline Over the 12-Week Treatment Period in the Percentage of Rescue-Free 24-Hour Periods

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    End point title
    		 Change From Baseline Over the 12-Week Treatment Period in the Percentage of Rescue-Free 24-Hour Periods
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (defined as the last non-missing assessment prior to the 1st dose of study medication) through Week 12
    End point values
    		 BF SPIROMAX (per protocol) SYMBICORT TURBOHALER (per protocol)
    Number of subjects analysed
    290
    284
    Units: percentage of rescue-free 24-hr periods
        median (full range (min-max))
    32.7 (-49.5 to 100)
    35.7 (-73.5 to 100)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    BF SPIROMAX (per protocol) v SYMBICORT TURBOHALER (per protocol)
    Number of subjects included in analysis
    574
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.43
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.23
         upper limit
    		 2.38

    Secondary: Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) Over the 12-Week Treatment Period

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    End point title
    		 Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) Over the 12-Week Treatment Period
    End point description
    Change from baseline in trough (AM predose and pre-rescue bronchodilator) FEV1 over the 12-week treatment period
    End point type
    Secondary
    End point timeframe
    Baseline (defined as the last non-missing assessment prior to the 1st dose of study medication) through Week 12
    End point values
    		 BF SPIROMAX (per protocol) SYMBICORT TURBOHALER (per protocol)
    Number of subjects analysed
    283 [4]
    280 [5]
    Units: Liters
        least squares mean (standard error)
    0.325 ± 0.025
    0.318 ± 0.025
    Notes
    [4] - subjects who contributed at least once to the analysis
    [5] - subjects who contributed at least once to the analysis
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    BF SPIROMAX (per protocol) v SYMBICORT TURBOHALER (per protocol)
    Number of subjects included in analysis
    563
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7661 [6]
    Method
    		 repeated measures mixed model
    Parameter type
    		 least squares mean
    Point estimate
    0.008
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.06
    Notes
    [6] - analyzed using a repeated measures mixed model with effects due to baseline trough FEV1, gender, age, visit, treatment, and visit by treatment interaction

    Secondary: Change From Baseline in Patient Satisfaction and Preference Questionnaire for Inhalation Devices (PASAPQ) Overall Satisfaction Scores Over the 12-Week Treatment Period

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    End point title
    		 Change From Baseline in Patient Satisfaction and Preference Questionnaire for Inhalation Devices (PASAPQ) Overall Satisfaction Scores Over the 12-Week Treatment Period
    End point description
    Change from baseline in PASAPQ total satisfaction score (Part I of PASAPQ). The PASAPQ is a multi-item measure of inhalation device satisfaction and preference designed specifically for patients with asthma and chronic obstructive pulmonary disease. The PASAPQ includes a total of 14 device satisfaction items, including an overall satisfaction item, each rated on a 7-point response scale from “very dissatisfied” (1) to “very satisfied” (7). Each of the satisfaction items was asked twice, once for each study device. The mean of the 14 satisfaction items, including the overall satisfaction item, form a total satisfaction score.
    End point type
    Secondary
    End point timeframe
    Baseline (defined as the last non-missing assessment prior to the 1st dose of study medication) through Week 12
    End point values
    		 BF SPIROMAX (per protocol) SYMBICORT TURBOHALER (per protocol)
    Number of subjects analysed
    276 [7]
    266 [8]
    Units: units on a scale
        least squares mean (standard error)
    0.181 ± 0.082
    0.04 ± 0.082
    Notes
    [7] - subjects who contributed at least once to the analysis
    [8] - subjects who contributed at least once to the analysis
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    BF SPIROMAX (per protocol) v SYMBICORT TURBOHALER (per protocol)
    Number of subjects included in analysis
    542
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1016 [9]
    Method
    		 ANCOVA
    Parameter type
    		 least squares mean
    Point estimate
    0.141
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0.31
    Notes
    [9] - Analyzed using an analysis of covariance (ANCOVA) model with effects due to baseline score, gender, age, and treatment, imputing missing data via last observation carried forward. Both original scale and transformed scale were used.

    Secondary: Change From Baseline in PASAPQ Performance and Convenience Domain Scores Over the 12-Week Treatment Period

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    End point title
    		 Change From Baseline in PASAPQ Performance and Convenience Domain Scores Over the 12-Week Treatment Period
    End point description
    Change from baseline in PASAPQ domain scores of performance (7 items) and convenience (6 items; Part I). The PASAPQ is a multi-item measure of inhalation device satisfaction and preference designed specifically for patients with asthma and chronic obstructive pulmonary disease. The PASAPQ The PASAPQ has 2 subscale scores: performance (7 items) and convenience (6 items), each rated on a 7-point response scale from “very dissatisfied” (1) to “very satisfied” (7). Each of the items was asked twice, once for each study device.
    End point type
    Secondary
    End point timeframe
    Baseline (defined as the last non-missing assessment prior to the 1st dose of study medication) through Week 12
    End point values
    		 BF SPIROMAX (per protocol) SYMBICORT TURBOHALER (per protocol)
    Number of subjects analysed
    276 [10]
    266 [11]
    Units: units on a scale
    least squares mean (standard error)
        Change in performance domain scores
    0.212 ± 0.065
    0.012 ± 0.066
        Change in convenience domain scores
    0.042 ± 0.06
    0.118 ± 0.06
    Notes
    [10] - subjects who contributed at least once to the analysis
    [11] - subjects who contributed at least once to the analysis
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Performance domain score difference
    Comparison groups
    BF SPIROMAX (per protocol) v SYMBICORT TURBOHALER (per protocol)
    Number of subjects included in analysis
    542
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0038 [12]
    Method
    		 ANCOVA
    Parameter type
    		 least squares mean
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.07
         upper limit
    		 0.34
    Notes
    [12] - Analyzed using an ANCOVA model with effects due to baseline score, gender, age, and treatment, imputing missing data via last observation carried forward. Both original scale and transformed scale were used.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Convenience domain score difference
    Comparison groups
    BF SPIROMAX (per protocol) v SYMBICORT TURBOHALER (per protocol)
    Number of subjects included in analysis
    542
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2206 [13]
    Method
    		 ANCOVA
    Parameter type
    		 least squares mean
    Point estimate
    -0.077
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.05
    Notes
    [13] - Analyzed using an ANCOVA model with effects due to baseline score, gender, age, and treatment, imputing missing data via last observation carried forward. Both original scale and transformed scale were used.

    Secondary: Change From Baseline in PASAPQ Device Preference Scores Over the 12-Week Treatment Period

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    End point title
    		 Change From Baseline in PASAPQ Device Preference Scores Over the 12-Week Treatment Period
    End point description
    Number of subjects with a change from baseline (BL) in device preference, using the PASAPQ device preference score (Part II). The PASAPQ is a multi-item measure of inhalation device satisfaction and preference designed specifically for patients with asthma and chronic obstructive pulmonary disease. The PASAPQ includes a device preference item, which is rated using a 3-level categorical response scale: “I prefer inhaler 1,” “I prefer inhaler 2,” “no preference.” Inhaler 1 was used for BF SPIROMAX and its placebo. Inhaler 2 was used for SYMBICORT TURBOHALER and its placebo.
    End point type
    Secondary
    End point timeframe
    Baseline (defined as the last non-missing assessment prior to the 1st dose of study medication) through Week 12
    End point values
    		 BF SPIROMAX (per protocol) SYMBICORT TURBOHALER (per protocol)
    Number of subjects analysed
    274 [14]
    263 [15]
    Units: subjects
        BL no preference / Week 12 no preference
    26
    26
        BL no preference / Week 12 prefer inhaler 1
    14
    26
        BL no preference / Week 12 prefer inhaler 2
    9
    14
        BL prefer inhaler 1 / Week 12 no preference
    38
    33
        BL prefer inhaler 1 / Week 12 prefer inhaler 1
    96
    88
        BL prefer inhaler 1 / Week 12 prefer inhaler 2
    31
    18
        BL prefer inhaler 2 / Week 12 no preference
    18
    14
        BL prefer inhaler 2 / Week 12 prefer inhaler 1
    17
    15
        BL prefer inhaler 2 / Week 12 prefer inhaler 2
    25
    29
    Notes
    [14] - subjects with an assessment at Baseline and Week 12
    [15] - subjects with an assessment at Baseline and Week 12
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    BF SPIROMAX (per protocol) v SYMBICORT TURBOHALER (per protocol)
    Number of subjects included in analysis
    537
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2011
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Change From Baseline in PASAPQ Willingness to Continue Using the Device Scores Over the 12-Week Treatment Period

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    End point title
    		 Change From Baseline in PASAPQ Willingness to Continue Using the Device Scores Over the 12-Week Treatment Period
    End point description
    Change from baseline in PASAPQ willingness to continue using the device score (Part II) at Week 12. The PASAPQ is a multi-item measure of inhalation device satisfaction and preference designed specifically for patients with asthma and chronic obstructive pulmonary disease. The PASAPQ includes an item on willingness to continue using the device in the future, which is rated using a numerical rating scale from 0 to 100, once for each study device.
    End point type
    Secondary
    End point timeframe
    Baseline (defined as the last non-missing assessment prior to the 1st dose of study medication) through Week 12
    End point values
    		 BF SPIROMAX (per protocol) SYMBICORT TURBOHALER (per protocol)
    Number of subjects analysed
    272 [16]
    261 [17]
    Units: units on a scale
        least squares mean (standard error)
    3.65 ± 2.047
    -3.951 ± 2.066
    Notes
    [16] - subjects who contributed at least once to the analysis
    [17] - subjects who contributed at least once to the analysis
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    BF SPIROMAX (per protocol) v SYMBICORT TURBOHALER (per protocol)
    Number of subjects included in analysis
    533
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0005 [18]
    Method
    		 ANCOVA
    Parameter type
    		 least squares mean
    Point estimate
    7.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.33
         upper limit
    		 11.87
    Notes
    [18] - Analyzed using an ANCOVA model with effects due to baseline score, gender, age, and treatment, imputing missing data via LOCF.

    Secondary: Change From Baseline in Overall Inhaler Quickness Satisfaction at Week 12

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    End point title
    		 Change From Baseline in Overall Inhaler Quickness Satisfaction at Week 12
    End point description
    Participants responded to the overall device quickness satisfaction question "How satisfied are you with the overall quickness of using your inhaler?" at Baseline and Week 12. Answers were: very dissatisfied, dissatisfied, somewhat dissatisfied, neither satisfied nor dissatisfied, somewhat satisfied, satisfied, and very satisfied. Change from baseline in PASAPQ total satisfaction score (Part I of PASAPQ). The PASAPQ is a multi-item measure of inhalation device satisfaction and preference designed specifically for patients with asthma and chronic obstructive pulmonary disease. The PASAPQ includes a total of 14 device satisfaction items, including an overall quickness satisfaction item, each rated on a 7-point response scale from “very dissatisfied” (1) to “very satisfied” (7). Each of the satisfaction items was asked twice, once for each study device.
    End point type
    Secondary
    End point timeframe
    Baseline (defined as the last non-missing assessment prior to the 1st dose of study medication), Week 12
    End point values
    		 BF SPIROMAX (per protocol) SYMBICORT TURBOHALER (per protocol)
    Number of subjects analysed
    271 [19]
    265 [20]
    Units: units on a scale
        least squares mean (standard error)
    0.316 ± 0.088
    -0.012 ± 0.089
    Notes
    [19] - subjects who contributed at least once to the analysis
    [20] - subjects who contributed at least once to the analysis
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    BF SPIROMAX (per protocol) v SYMBICORT TURBOHALER (per protocol)
    Number of subjects included in analysis
    536
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0005 [21]
    Method
    		 ANCOVA
    Parameter type
    		 least squares mean
    Point estimate
    0.328
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.14
         upper limit
    		 0.51
    Notes
    [21] - Analyzed using an ANCOVA model with effects due to baseline score, gender, age, and treatment, imputing missing data via LOCF.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Screening visit (Day −14 ± 2 days) through Week 12 or early termination (up to Day 84 ±2 days)
    Adverse event reporting additional description
    Adverse events for Treatment Period are presented in this table. Non-serious adverse events for Run-in period are attached to this record (EudraCT system restrictions prevented their addition within the record). There were no serious adverse events during the run-in period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Treatment Period: BF SPIROMAX
    Reporting group description
    		 2 inhalations of BF Spiromax at a dosage of 160/4.5 mcg (budesonide/formoterol fumarate dihydrate 160/4.5 mcg) and 2 inhalations of SYMBICORT placebo administered twice daily (AM and PM) during the 12-week treatment period.

    Reporting group title
    Treatment Period: SYMBICORT TURBOHALER
    Reporting group description
    		 -

    Serious adverse events
    		 Treatment Period: BF SPIROMAX Treatment Period: SYMBICORT TURBOHALER
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 303 (0.33%)
    3 / 299 (1.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Treatment Period: BF SPIROMAX Treatment Period: SYMBICORT TURBOHALER
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    116 / 303 (38.28%)
    104 / 299 (34.78%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 303 (0.33%)
    3 / 299 (1.00%)
         occurrences all number
    1
    3
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    6 / 303 (1.98%)
    2 / 299 (0.67%)
         occurrences all number
    8
    2
    Chest discomfort
         subjects affected / exposed
    2 / 303 (0.66%)
    0 / 299 (0.00%)
         occurrences all number
    2
    0
    Influenza like illness
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    1
    Chest pain
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    1
    Feeling cold
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    1
    Epididymitis
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    1
    Dysmenorrhoea
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 303 (3.63%)
    8 / 299 (2.68%)
         occurrences all number
    12
    9
    Oropharyngeal pain
         subjects affected / exposed
    7 / 303 (2.31%)
    5 / 299 (1.67%)
         occurrences all number
    7
    8
    Dysphonia
         subjects affected / exposed
    9 / 303 (2.97%)
    1 / 299 (0.33%)
         occurrences all number
    9
    1
    Dyspnoea
         subjects affected / exposed
    4 / 303 (1.32%)
    4 / 299 (1.34%)
         occurrences all number
    4
    9
    Rhinorrhoea
         subjects affected / exposed
    2 / 303 (0.66%)
    1 / 299 (0.33%)
         occurrences all number
    2
    1
    Epistaxis
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 299 (0.33%)
         occurrences all number
    1
    1
    Throat irritation
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    1
    Rhonchi
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    1
    Pulmonary congestion
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    1
    Productive cough
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    2
    Sneezing
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    1
    Nasal congestion
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    1
    Dry throat
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    1
    Aspiration
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    1
    Pharyngeal inflammation
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Nasal obstruction
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Increased upper airway secretion
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Rhinitis allergic
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Pleurisy
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    1
    Investigations
    Blood pressure increased
         subjects affected / exposed
    0 / 303 (0.00%)
    2 / 299 (0.67%)
         occurrences all number
    0
    4
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    3 / 303 (0.99%)
    0 / 299 (0.00%)
         occurrences all number
    3
    0
    Post-traumatic neck syndrome
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    1
    Head injury
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    1
    Wrist fracture
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Fall
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Arthropod bite
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Animal scratch
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    3 / 303 (0.99%)
    0 / 299 (0.00%)
         occurrences all number
    4
    0
    Angina pectoris
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    18 / 303 (5.94%)
    24 / 299 (8.03%)
         occurrences all number
    31
    57
    Dizziness
         subjects affected / exposed
    1 / 303 (0.33%)
    2 / 299 (0.67%)
         occurrences all number
    1
    2
    Migraine
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 299 (0.33%)
         occurrences all number
    3
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    2
    Hyposmia
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    1
    Radiculitis
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Aphonia
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    1
    Cataract
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    4 / 303 (1.32%)
    1 / 299 (0.33%)
         occurrences all number
    5
    1
    Diarrhoea
         subjects affected / exposed
    5 / 303 (1.65%)
    2 / 299 (0.67%)
         occurrences all number
    5
    3
    Abdominal pain
         subjects affected / exposed
    1 / 303 (0.33%)
    3 / 299 (1.00%)
         occurrences all number
    1
    3
    Nausea
         subjects affected / exposed
    2 / 303 (0.66%)
    1 / 299 (0.33%)
         occurrences all number
    4
    1
    Gastritis
         subjects affected / exposed
    2 / 303 (0.66%)
    1 / 299 (0.33%)
         occurrences all number
    2
    1
    Vomiting
         subjects affected / exposed
    0 / 303 (0.00%)
    2 / 299 (0.67%)
         occurrences all number
    0
    3
    Toothache
         subjects affected / exposed
    0 / 303 (0.00%)
    2 / 299 (0.67%)
         occurrences all number
    0
    2
    Dry mouth
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 299 (0.33%)
         occurrences all number
    1
    1
    Aphthous stomatitis
         subjects affected / exposed
    2 / 303 (0.66%)
    0 / 299 (0.00%)
         occurrences all number
    5
    0
    Constipation
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    1
    Tongue discolouration
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    1
    Diverticulum
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    1
    Tooth loss
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Stomatitis
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    1 / 303 (0.33%)
    2 / 299 (0.67%)
         occurrences all number
    1
    2
    Rash
         subjects affected / exposed
    0 / 303 (0.00%)
    2 / 299 (0.67%)
         occurrences all number
    0
    2
    Dermatitis contact
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    2
    Skin lesion
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 303 (1.32%)
    1 / 299 (0.33%)
         occurrences all number
    4
    1
    Muscle spasms
         subjects affected / exposed
    1 / 303 (0.33%)
    3 / 299 (1.00%)
         occurrences all number
    1
    4
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 299 (0.33%)
         occurrences all number
    1
    1
    Osteoarthritis
         subjects affected / exposed
    2 / 303 (0.66%)
    0 / 299 (0.00%)
         occurrences all number
    2
    0
    Myalgia
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    1
    Tendonitis
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    2
    0
    Pain in jaw
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Osteochondritis
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Neck pain
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Costochondritis
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Arthritis
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    6 / 303 (1.98%)
    7 / 299 (2.34%)
         occurrences all number
    7
    7
    Nasopharyngitis
         subjects affected / exposed
    31 / 303 (10.23%)
    25 / 299 (8.36%)
         occurrences all number
    36
    27
    Bronchitis
         subjects affected / exposed
    3 / 303 (0.99%)
    7 / 299 (2.34%)
         occurrences all number
    3
    8
    Influenza
         subjects affected / exposed
    2 / 303 (0.66%)
    6 / 299 (2.01%)
         occurrences all number
    2
    9
    Pharyngitis
         subjects affected / exposed
    4 / 303 (1.32%)
    4 / 299 (1.34%)
         occurrences all number
    4
    4
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 303 (1.32%)
    3 / 299 (1.00%)
         occurrences all number
    5
    3
    Sinusitis
         subjects affected / exposed
    1 / 303 (0.33%)
    3 / 299 (1.00%)
         occurrences all number
    1
    3
    Tonsillitis
         subjects affected / exposed
    1 / 303 (0.33%)
    3 / 299 (1.00%)
         occurrences all number
    1
    3
    Respiratory tract infection viral
         subjects affected / exposed
    2 / 303 (0.66%)
    2 / 299 (0.67%)
         occurrences all number
    3
    3
    Gastroenteritis
         subjects affected / exposed
    1 / 303 (0.33%)
    2 / 299 (0.67%)
         occurrences all number
    1
    2
    Laryngitis
         subjects affected / exposed
    1 / 303 (0.33%)
    2 / 299 (0.67%)
         occurrences all number
    1
    2
    Respiratory tract infection
         subjects affected / exposed
    1 / 303 (0.33%)
    2 / 299 (0.67%)
         occurrences all number
    1
    2
    Viral pharyngitis
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    1
    Viral infection
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 303 (0.00%)
    2 / 299 (0.67%)
         occurrences all number
    0
    2
    Oral candidiasis
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 299 (0.33%)
         occurrences all number
    1
    1
    Viral rhinitis
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 299 (0.33%)
         occurrences all number
    1
    1
    Gastrointestinal infection
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 299 (0.33%)
         occurrences all number
    1
    1
    Candidiasis
         subjects affected / exposed
    2 / 303 (0.66%)
    0 / 299 (0.00%)
         occurrences all number
    2
    0
    Acute tonsillitis
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    3
    Chronic sinusitis
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    1
    Otitis media
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    1
    Urethritis
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    1
    Pharyngotonsillitis
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    1
    Oral herpes
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    1
    Lice infestation
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    1
    Gingivitis
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 299 (0.33%)
         occurrences all number
    0
    1
    Respiratory tract infection bacterial
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Tracheitis
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Infected bites
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Gingival infection
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Folliculitis
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Ear infection
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 299 (0.00%)
         occurrences all number
    3
    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26987997
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    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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