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    Clinical Trial Results:
    A 12 Week, Randomized, Open-Label, Parallel Group Study to Evaluate the Mastery of Inhaler Technique for Budesonide Formoterol (BF) Spiromax(160/4.5 and 320/9 mcg) as Compared to SYMBICORT® TURBOHALER® (200/6 and 400/12 mcg) as Treatment for Adult Patients with Asthma (the Easy Low Instruction Over Time [ELIOT] Study)

    Summary
    EudraCT number
    		 2013-004630-14
    Trial protocol
    		 GB  
    Global end of trial date
    13 Mar 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 May 2017
    First version publication date
    13 May 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BFS-AS-40035
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02062463
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Teva Branded Pharmaceutical Products R&D, Inc.
    Sponsor organisation address
    41 Moores Road, Frazer, Pennsylvania, United States, 19355
    Public contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc, 001 215 591 3000,
    Scientific contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc, 001 215 591 3000,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Oct 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Mar 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a 2-stage study. The primary objectives of the study are as follows: •Stage 1: to determine the proportion of subjects achieving device mastery by the end of Step 3 of a 6-step standardized device training protocol for empty SPIROMAX is superior to empty TURBOHALER devices. Device mastery is defined as absence of nurse-observed errors. •Stage 2: to determine whether the proportion of subjects maintaining device mastery, in subjects receiving inhaled corticosteroids/long-acting beta agonists (ICS/LABA) via BF SPIROMAX, is superior to ICS/LABA received via SYMBICORT TURBOHALER. Maintenance of device mastery is defined as absence of nurse-observed errors after 12 weeks of device use.
    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.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 May 2014
    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
    United Kingdom: 540
    Worldwide total number of subjects
    540
    EEA total number of subjects
    540
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    390
    From 65 to 84 years
    150
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 540 patients with asthma were screened for enrollment into stage 1 of this study and 485 were enrolled.

    Period 1
    Period 1 title
    Stage 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Empty SPIROMAX Followed by Empty TURBOHALER
    Arm description
    		 Subjects were randomly assigned to training with empty SPIROMAX followed by empty SYMBICORT TURBOHALER devices. Subjects were educated on each device using empty training devices containing no active drug and no excipients.
    Arm type
    		 Empty device

    Investigational medicinal product name
    Empty Budesonide/Formoterol (BF) SPIROMAX
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Subjects were educated on the device using empty training devices containing no active drug and no excipients.

    Investigational medicinal product name
    Empty SYMBICORT TURBOHALER
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Subjects were educated on the device using empty training devices containing no active drug excipients.

    Arm title
    		 Empty TURBOHALER Followed by Empty SPIROMAX
    Arm description
    		 Subjects were randomly assigned to training with empty SYMBICORT TURBOHALER followed by empty SPIROMAX devices. Subjects were educated on each device using empty training devices containing no active drug and no excipients.
    Arm type
    		 Empty device

    Investigational medicinal product name
    Empty SYMBICORT TURBOHALER
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Subjects were educated on the device using empty training devices containing no active drug excipients.

    Investigational medicinal product name
    Empty Budesonide/Formoterol (BF) SPIROMAX
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Subjects were educated on the device using empty training devices containing no active drug and no excipients.

    Number of subjects in period 1
    		Empty SPIROMAX Followed by Empty TURBOHALER Empty TURBOHALER Followed by Empty SPIROMAX
    Started
    243
    242
    Completed
    240
    241
    Not completed
    3
    1
         Consent withdrawn by subject
    1
    -
         Reason not collected per protocol
    2
    1
    Period 2
    Period 2 title
    Stage 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BF SPIROMAX
    Arm description
    		 ICS/LABA via the BF SPIROMAX device for 12 weeks of therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Budesonide/Formoterol (BF) SPIROMAX
    Investigational medicinal product code
    Other name
    budesonide/formoterol fumarate dihydrate
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    The doses in stage 2 were equivalent to that received via the subject’s current device at baseline. Subjects who had had been receiving 800 to 1000 μg beclometasone-equivalent ICS per day were randomly assigned to receive 2 doses of budesonide/formoterol twice daily using the BF SPIROMAX 160/4.5 μg device. Subjects who had been receiving 1600 to 2000 μg beclometasone-equivalent ICS per day were randomly assigned to receive 2 doses of budesonide/formoterol twice daily using the BF SPIROMAX 320/9 μg device.

    Arm title
    		 SYMBICORT TURBOHALER
    Arm description
    		 ICS/LABA via the SYMBICORT TURBOHALER device for 12 weeks of therapy.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    SYMBICORT TURBOHALER
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    The doses in stage 2 were equivalent to that received via the subject’s current device at baseline. Subjects who had had been receiving 800 to 1000 μg beclometasone-equivalent ICS per day were randomly assigned to receive 2 doses of budesonide/formoterol twice daily using the SYMBICORT TURBOHALER 200/6 μg device. Subjects who had been receiving 1600 to 2000 μg beclometasone equivalent ICS per day were randomly assigned to receive 2 doses of budesonide/formoterol twice daily using the SYMBICORT TURBOHALER 400/12 μg device.

    Number of subjects in period 2
    		BF SPIROMAX SYMBICORT TURBOHALER
    Started
    197
    197
    Completed
    144
    141
    Not completed
    53
    56
         Consent withdrawn by subject
    15
    10
         Not specified
    3
    1
         Adverse event
    12
    20
         Non-compliance
    -
    1
         Lost to follow-up
    20
    20
         Lack of efficacy
    3
    4

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Empty SPIROMAX Followed by Empty TURBOHALER
    Reporting group description
    		 Subjects were randomly assigned to training with empty SPIROMAX followed by empty SYMBICORT TURBOHALER devices. Subjects were educated on each device using empty training devices containing no active drug and no excipients.

    Reporting group title
    Empty TURBOHALER Followed by Empty SPIROMAX
    Reporting group description
    		 Subjects were randomly assigned to training with empty SYMBICORT TURBOHALER followed by empty SPIROMAX devices. Subjects were educated on each device using empty training devices containing no active drug and no excipients.

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 485 of the enrolled subjects were randomized and entered Stage 1.
    Reporting group values
    		 Empty SPIROMAX Followed by Empty TURBOHALER Empty TURBOHALER Followed by Empty SPIROMAX Total
    Number of subjects
    		 243 242
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.4 ( 13.8 ) 53.1 ( 14.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 152 134 286
        Male
    		 91 108 199

    End points

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    End points reporting groups
    Reporting group title
    Empty SPIROMAX Followed by Empty TURBOHALER
    Reporting group description
    		 Subjects were randomly assigned to training with empty SPIROMAX followed by empty SYMBICORT TURBOHALER devices. Subjects were educated on each device using empty training devices containing no active drug and no excipients.

    Reporting group title
    Empty TURBOHALER Followed by Empty SPIROMAX
    Reporting group description
    		 Subjects were randomly assigned to training with empty SYMBICORT TURBOHALER followed by empty SPIROMAX devices. Subjects were educated on each device using empty training devices containing no active drug and no excipients.
    Reporting group title
    BF SPIROMAX
    Reporting group description
    		 ICS/LABA via the BF SPIROMAX device for 12 weeks of therapy.

    Reporting group title
    SYMBICORT TURBOHALER
    Reporting group description
    		 ICS/LABA via the SYMBICORT TURBOHALER device for 12 weeks of therapy.

    Subject analysis set title
    Stage 1 Full Analysis Set: Empty SPIROMAX
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomized subjects who completed both assessments (so permitting a paired analysis of results).

    Subject analysis set title
    Stage 1 Full Analysis Set: Empty TURBOHALER
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomized subjects who completed both assessments (so permitting a paired analysis of results).

    Subject analysis set title
    Stage 2 Full Analysis Set: BF SPIROMAX
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomized subjects who return for assessment of maintenance of inhaler technique at Week 12 using the inhaler (treatment) to which they were randomly assigned (BF SPIROMAX).

    Subject analysis set title
    Stage 2 Full Analysis Set: SYMBICORT TURBOHALER
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomized subjects who return for assessment of maintenance of inhaler technique at Week 12 using the inhaler (treatment) to which they were randomly assigned (SYMBICORT TURBOHALER).

    Subject analysis set title
    Stage 2 Intent-to-treat: BF SPIROMAX
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized subjects taking BF SPIROMAX

    Subject analysis set title
    Stage 2 Intent-to-treat: SYMBICORT TURBOHALER
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized subjects taking SYMBICORT TURBOHALER.

    Primary: Stage 1: Number of Subjects Achieving Device Mastery

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    End point title
    		 Stage 1: Number of Subjects Achieving Device Mastery [1]
    End point description
    Device mastery was defined as the absence of nurse-observed errors by the end of Step 3 of a 6-step standardized device training protocol for each device. The 6 training steps were as follows: Step 1, intuitive use; Step 2, patient device information leaflet; Step 3, instructional video; Step 4, nurse tuition; Step 5, nurse tuition (1st repeat); Step 6, nurse tuition (2nd repeat). After each training step an assessment of device use was carried out by the nurse using a pre-defined list of inhaler errors.
    End point type
    Primary
    End point timeframe
    1 day
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Analysis offered as a PDF attachment.
    End point values
    		 Stage 1 Full Analysis Set: Empty SPIROMAX Stage 1 Full Analysis Set: Empty TURBOHALER
    Number of subjects analysed
    481
    481
    Units: subjects
        Yes
    454
    418
        No
    27
    63
    Attachments
    		 Untitled (Filename: Statistical Analysis_Primary Endpoint Stage 1 Device Mastery.pdf)
    No statistical analyses for this end point

    Primary: Stage 2: Number of Subjects Maintaining Device Mastery

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    End point title
    		 Stage 2: Number of Subjects Maintaining Device Mastery
    End point description
    Maintenance of device mastery was defined as absence of nurse-observed errors after 12 weeks of device use.
    End point type
    Primary
    End point timeframe
    12 weeks
    End point values
    		 Stage 2 Full Analysis Set: BF SPIROMAX Stage 2 Full Analysis Set: SYMBICORT TURBOHALER
    Number of subjects analysed
    151
    154
    Units: subjects
        Yes
    89
    82
        No
    62
    72
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Stage 2 Full Analysis Set: BF SPIROMAX v Stage 2 Full Analysis Set: SYMBICORT TURBOHALER
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.316 [3]
    Method
    		 Chi-squared
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.98
    Notes
    [2] - BF SPIROMAX relative to SYMBICORT TURBOHALER (SYMBICORT TURBOHALER=1.00).
    [3] - The p-value for the treatment comparison is based on chi-square; p<0.05 considered statistically significant.

    Secondary: Stage 1: Number of Subjects Achieving Device Mastery by Step 1

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    End point title
    		 Stage 1: Number of Subjects Achieving Device Mastery by Step 1
    End point description
    The number of subjects achieving device mastery by Step 1 (no training/intuitive use) of the device training process. Device mastery was defined as the absence of nurse-observed errors by the end of Step 3 of a 6-step standardized device training protocol for each device. The 6 training steps were as follows: Step 1, intuitive use; Step 2, patient device information leaflet; Step 3, instructional video; Step 4, nurse tuition; Step 5, nurse tuition (1st repeat); Step 6, nurse tuition (2nd repeat). After each training step an assessment of device use was carried out by the nurse using a pre-defined list of inhaler errors.
    End point type
    Secondary
    End point timeframe
    1 day
    End point values
    		 Stage 1 Full Analysis Set: Empty SPIROMAX Stage 1 Full Analysis Set: Empty TURBOHALER
    Number of subjects analysed
    481
    481
    Units: subjects
        Yes
    160
    55
        No
    321
    426
    Attachments
    		 Untitled (Filename: Statistical Analysis_Secondary Endpoint Device Mastery by Step 1 of Stage 1.pdf)
    No statistical analyses for this end point

    Secondary: Stage 1: Number of Subjects Achieving Device Mastery by Step 2

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    End point title
    		 Stage 1: Number of Subjects Achieving Device Mastery by Step 2
    End point description
    The number of subjects achieving device mastery by Step 2 (patient information leaflet) of the device training process. Device mastery was defined as the absence of nurse-observed errors by the end of Step 3 of a 6-step standardized device training protocol for each device. The 6 training steps were as follows: Step 1, intuitive use; Step 2, patient device information leaflet; Step 3, instructional video; Step 4, nurse tuition; Step 5, nurse tuition (1st repeat); Step 6, nurse tuition (2nd repeat). After each training step an assessment of device use was carried out by the nurse using a pre-defined list of inhaler errors.
    End point type
    Secondary
    End point timeframe
    1 day
    End point values
    		 Stage 1 Full Analysis Set: Empty SPIROMAX Stage 1 Full Analysis Set: Empty TURBOHALER
    Number of subjects analysed
    481
    481
    Units: subjects
        Yes
    386
    308
        No
    95
    173
    Attachments
    		 Untitled (Filename: Statistical Analysis_Secondary Endpoint Device Mastery by Step 2 of Stage 1.pdf)
    No statistical analyses for this end point

    Secondary: Stage 1: Number of Steps Required to Achieve Device Mastery

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    End point title
    		 Stage 1: Number of Steps Required to Achieve Device Mastery
    End point description
    Device mastery was defined as the absence of nurse-observed errors by the end of Step 3 of a 6-step standardized device training protocol for each device. The 6 training steps were as follows: Step 1, intuitive use; Step 2, patient device information leaflet; Step 3, instructional video; Step 4, nurse tuition; Step 5, nurse tuition (1st repeat); Step 6, nurse tuition (2nd repeat). After each training step an assessment of device use was carried out by the nurse using a pre-defined list of inhaler errors.
    End point type
    Secondary
    End point timeframe
    1 day
    End point values
    		 Stage 1 Full Analysis Set: Empty SPIROMAX Stage 1 Full Analysis Set: Empty TURBOHALER
    Number of subjects analysed
    481
    481
    Units: training steps
        median (full range (min-max))
    1 (0 to 12)
    2 (0 to 15)
    Attachments
    		 Untitled (Filename: Statistical Analysis_Secondary Endpoint Number of Steps Taken to Device Mastery.pdf)
    No statistical analyses for this end point

    Secondary: Stage 1: Number of Health Care Professional-Observed Errors

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    End point title
    		 Stage 1: Number of Health Care Professional-Observed Errors
    End point description
    Device mastery was defined as the absence of nurse-observed errors by the end of Step 3 of a 6-step standardized device training protocol for each device. The 6 training steps were as follows: Step 1, intuitive use; Step 2, patient device information leaflet; Step 3, instructional video; Step 4, nurse tuition; Step 5, nurse tuition (1st repeat); Step 6, nurse tuition (2nd repeat). After each training step an assessment of device use was carried out by the nurse using a pre-defined list of inhaler errors.
    End point type
    Secondary
    End point timeframe
    1 day
    End point values
    		 Stage 1 Full Analysis Set: Empty SPIROMAX Stage 1 Full Analysis Set: Empty TURBOHALER
    Number of subjects analysed
    481
    481
    Units: errors
        arithmetic mean (standard deviation)
    1.91 ( 0.89 )
    2.36 ( 0.92 )
    Attachments
    		 Untitled (Filename: Statistical Analysis_Secondary Endpoint Number of HCP-Observed Errors in Stage 1.pdf)
    No statistical analyses for this end point

    Secondary: Stage 1: Subject Preference for the Device

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    End point title
    		 Stage 1: Subject Preference for the Device
    End point description
    Total Patient Satisfaction and Preference Questionnaire (PASAPQ) score. The PASAPQ is a multi-item measure of respiratory inhalation device satisfaction and preference designed to be easy to understand and administer to asthma and COPD patients (Kozma et al 2005). The PASAPQ is a two-part questionnaire. Part I consists of 14 questions, the first 13 generating the Performance, Convenience and Total Score domains, and a standalone question for Overall Satisfaction. Part II consists of standalone questions concerning a subject’s device preference and willingness to continue use.
    End point type
    Secondary
    End point timeframe
    1 day
    End point values
    		 Stage 1 Full Analysis Set: Empty SPIROMAX Stage 1 Full Analysis Set: Empty TURBOHALER
    Number of subjects analysed
    477 [4]
    477 [5]
    Units: units on a scale
        median (full range (min-max))
    89.8 (18.37 to 100)
    85.71 (14.29 to 100)
    Attachments
    		 Untitled (Filename: Statistical Analysis_Secondary Endpoint Subject Preference for the device in Stage 1.pdf)
    Notes
    [4] - subjects with an assessment
    [5] - subjects with an assessment
    No statistical analyses for this end point

    Secondary: Stage 2: Total Number of Observed Errors

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    End point title
    		 Stage 2: Total Number of Observed Errors
    End point description
    The total number of observed errors (as observed by health care providers and technology [Vitalograph™ pneumotrac spirometer]).
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Stage 2 Full Analysis Set: BF SPIROMAX Stage 2 Full Analysis Set: SYMBICORT TURBOHALER
    Number of subjects analysed
    151
    154
    Units: observed errors
        arithmetic mean (standard deviation)
    0.5 ( 0.68 )
    0.82 ( 1.1 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Stage 2 Full Analysis Set: BF SPIROMAX v Stage 2 Full Analysis Set: SYMBICORT TURBOHALER
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    Method
    Parameter type
    		 rate ratio
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 0.84
    Notes
    [6] - BF SPIROMAX relative to SYMBICORT TURBOHALER (SYMBICORT TURBOHALER=1.00). Negative binomial regression was used.

    Secondary: Stage 2: Total Number of Technology-Observed Errors

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    End point title
    		 Stage 2: Total Number of Technology-Observed Errors
    End point description
    The total number of technology-observed errors (by Vitalograph™ pneumotrac spirometer).
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Stage 2 Full Analysis Set: BF SPIROMAX Stage 2 Full Analysis Set: SYMBICORT TURBOHALER
    Number of subjects analysed
    151
    154
    Units: errors
        arithmetic mean (standard deviation)
    0.01 ( 0.08 )
    0.01 ( 0.08 )
    No statistical analyses for this end point

    Secondary: Stage 2: Total Number of Handling Errors

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    End point title
    		 Stage 2: Total Number of Handling Errors
    End point description
    The total number of observed handling errors (as observed by health care providers).
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Stage 2 Full Analysis Set: BF SPIROMAX Stage 2 Full Analysis Set: SYMBICORT TURBOHALER
    Number of subjects analysed
    151
    154
    Units: errors
        arithmetic mean (standard deviation)
    0.5 ( 0.67 )
    0.81 ( 1.1 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Stage 2 Full Analysis Set: BF SPIROMAX v Stage 2 Full Analysis Set: SYMBICORT TURBOHALER
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    Method
    Parameter type
    		 rate ratio
    Point estimate
    0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 0.84
    Notes
    [7] - Negative binomial regression model was used.

    Secondary: Stage 2: Difference in Handling Errors from Stage 1 to Stage 2 (12 weeks)

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    End point title
    		 Stage 2: Difference in Handling Errors from Stage 1 to Stage 2 (12 weeks)
    End point description
    The difference in number of handling errors identified following training using patient device information leaflet at Stage 1 and after 12 weeks of treatment (end of Stage 2).
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Stage 2 Full Analysis Set: BF SPIROMAX Stage 2 Full Analysis Set: SYMBICORT TURBOHALER
    Number of subjects analysed
    151
    154
    Units: errors
        arithmetic mean (standard deviation)
    -0.95 ( 1.72 )
    -2.01 ( 2.52 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Stage 2 Full Analysis Set: BF SPIROMAX v Stage 2 Full Analysis Set: SYMBICORT TURBOHALER
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    Method
    Parameter type
    		 rate ratio
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 1.54
    Notes
    [8] - Negative binomial regression model was used.

    Secondary: Stage 2: Treatment Adherence

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    End point title
    		 Stage 2: Treatment Adherence
    End point description
    Percentage of treatment adherence by subject as assessed by device dose counters.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Stage 2 Full Analysis Set: BF SPIROMAX Stage 2 Full Analysis Set: SYMBICORT TURBOHALER
    Number of subjects analysed
    151
    154
    Units: subjects
        </= 50% adherence
    60
    61
        51% to 70% adherence
    19
    16
        71% to 99% adherence
    70
    71
        100% adherence
    2
    6
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Stage 2 Full Analysis Set: BF SPIROMAX v Stage 2 Full Analysis Set: SYMBICORT TURBOHALER
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.523 [9]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [9] - p < 0.05 is considered statistically significant.

    Secondary: Stage 2: Change in 6-item Asthma Control Questionnaire (ACQ) From Baseline to 4, 8, and 12 Weeks

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    End point title
    		 Stage 2: Change in 6-item Asthma Control Questionnaire (ACQ) From Baseline to 4, 8, and 12 Weeks
    End point description
    Change in the 6-item ACQ from Baseline to 4, 8, and 12 weeks. The ACQ is a 7-item, validated tool for assessing asthma control (Juniper et al 1999). Thinking about their asthma for the last 7 days,subjects were asked to evaluate their asthma against 5 symptom items and a rescue bronchodilator use question using a 7-point scale (0=no impairment and 6=maximum impairment). Spirometry data were used to grade the percent predicted forced expiratory volume in 1 second (FEV1) on a 7-point scale (0 to 6). The score is the mean of the first 6 questions (excluding the FEV1 question), generating a value from 0 (totally controlled) to 6 (severely uncontrolled). A negative change from Baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, 4, 8, and 12 weeks
    End point values
    		 Stage 2 Full Analysis Set: BF SPIROMAX Stage 2 Full Analysis Set: SYMBICORT TURBOHALER
    Number of subjects analysed
    151 [10]
    154 [11]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Week 4; n=142, 140
    -0.22 ( 0.83 )
    -0.33 ( 0.81 )
        Week 8; n=140, 143
    -0.2 ( 0.98 )
    -0.3 ( 1.04 )
        Week 12; n=137, 147
    -0.22 ( 0.95 )
    -0.36 ( 1.05 )
    Notes
    [10] - n=number of subjects with an assessment at Baseline and given time point
    [11] - n=number of subjects with an assessment at Baseline and given time point
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Week 4
    Comparison groups
    Stage 2 Full Analysis Set: BF SPIROMAX v Stage 2 Full Analysis Set: SYMBICORT TURBOHALER
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 treatment difference
    Point estimate
    0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 0.3
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Week 8
    Comparison groups
    Stage 2 Full Analysis Set: BF SPIROMAX v Stage 2 Full Analysis Set: SYMBICORT TURBOHALER
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 treatment difference
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.14
         upper limit
    		 0.33
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Week 12
    Comparison groups
    Stage 2 Full Analysis Set: BF SPIROMAX v Stage 2 Full Analysis Set: SYMBICORT TURBOHALER
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 treatment difference
    Point estimate
    0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.37

    Secondary: Stage 2: Change in the 7-item ACQ From Baseline to Week 12

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    End point title
    		 Stage 2: Change in the 7-item ACQ From Baseline to Week 12
    End point description
    Change in 7-item ACQ (including FEV1 question) from baseline to Week 12. The ACQ is a 7-item, validated tool for assessing asthma control (Juniper et al 1999). Thinking about their asthma for the last 7 days, subjects were asked to evaluate their asthma against 5 symptom items and a rescue bronchodilator use question using a 7-point scale (0=no impairment and 6=maximum impairment). Spirometry data were used to grade the percent predicted FEV1 on a 7-point scale (0 to 6). The ACQ score is the mean of the 7 questions, generating a value from 0 (totally controlled) to 6 (severely uncontrolled). A negative change from Baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Stage 2 Full Analysis Set: BF SPIROMAX Stage 2 Full Analysis Set: SYMBICORT TURBOHALER
    Number of subjects analysed
    145 [12]
    149 [13]
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.2 ( 0.78 )
    -0.31 ( 0.92 )
    Notes
    [12] - subjects with an assessment at Baseline and Week 12
    [13] - subjects with an assessment at Baseline and Week 12
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Stage 2 Full Analysis Set: BF SPIROMAX v Stage 2 Full Analysis Set: SYMBICORT TURBOHALER
    Number of subjects included in analysis
    294
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 treatment difference
    Point estimate
    0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.09
         upper limit
    		 0.3

    Secondary: Stage 2: Time to First Treatment Failure

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    End point title
    		 Stage 2: Time to First Treatment Failure
    End point description
    The time to treatment failure, defined as change of asthma treatment or treatment for an asthma exacerbation or lower respiratory tract infection.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Stage 2 Full Analysis Set: BF SPIROMAX Stage 2 Full Analysis Set: SYMBICORT TURBOHALER
    Number of subjects analysed
    151 [14]
    154 [15]
    Units: days
        arithmetic mean (standard deviation)
    76.38 ( 21.42 )
    73.95 ( 24.27 )
    Notes
    [14] - subjects with treatment failure=29
    [15] - subjects with treatment failure=40
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Stage 2 Full Analysis Set: BF SPIROMAX v Stage 2 Full Analysis Set: SYMBICORT TURBOHALER
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.159 [16]
    Method
    		 Log-rank (Mantel-Cox)
    Confidence interval
    Notes
    [16] - p < 0.05 is considered statistically significant.

    Secondary: Stage 2: Number of Severe Asthma Exacerbations

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    End point title
    		 Stage 2: Number of Severe Asthma Exacerbations
    End point description
    Number of severe asthma exacerbations, defined as a hospitalization or emergency room attendance for asthma, or an acute course of oral corticosteroids.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Stage 2 Intent-to-treat: BF SPIROMAX Stage 2 Intent-to-treat: SYMBICORT TURBOHALER
    Number of subjects analysed
    197
    197
    Units: subjects
        No exacerbations
    178
    176
        One exacerbation
    18
    20
        Two exacerbations
    1
    1
        Three or more exacerbaions
    0
    0
    No statistical analyses for this end point

    Secondary: Stage 2: Impact of Maintaining Device Mastery on Time to Treatment Failure

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    End point title
    		 Stage 2: Impact of Maintaining Device Mastery on Time to Treatment Failure
    End point description
    The impact of maintaining device mastery on time to treatment failure (defined as change of asthma treatment or treatment for an asthma exacerbation or lower respiratory tract infection) was assessed by comparing the time to treatment failure for subjects with and without device mastery. Device mastery was defined as the absence of nurse-observed errors by the end of Step 3 of a 6-step standardized device training protocol for each device.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Stage 2 Full Analysis Set: BF SPIROMAX Stage 2 Full Analysis Set: SYMBICORT TURBOHALER
    Number of subjects analysed
    151 [17]
    154 [18]
    Units: days
    arithmetic mean (standard deviation)
        Device mastery=yes; n=89, 82
    72.99 ( 22.38 )
    75.93 ( 22.59 )
        Device mastery=no; n=62, 72
    81.24 ( 19.11 )
    71.69 ( 26.03 )
    Notes
    [17] - n=subjects with or without device mastery
    [18] - n=subjects with or without device mastery
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Stage 2 Full Analysis Set: BF SPIROMAX v Stage 2 Full Analysis Set: SYMBICORT TURBOHALER
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.38
    Notes
    [19] - Cox Regression with device and device mastery as covariates.

    Secondary: Stage 2: Impact of Maintaining Device Mastery on Asthma Control

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    End point title
    		 Stage 2: Impact of Maintaining Device Mastery on Asthma Control
    End point description
    The impact of maintaining device mastery on asthma control was assessed by comparing the 7-item ACQ scores for subjects with and without device mastery. The ACQ is a 7-item, validated tool for assessing asthma control (Juniper et al 1999). Thinking about their asthma for the last 7 days, subjects were asked to evaluate their asthma against 5 symptom items and a rescue bronchodilator use question using a 7-point scale (0=no impairment and 6=maximum impairment). Spirometry data were used to grade the percent predicted FEV1 on a 7-point scale (0 to 6). The ACQ score is the mean of the 7 questions, generating a value from 0 (totally controlled) to 6 (severely uncontrolled). Device mastery was defined as the absence of nurse-observed errors by the end of Step 3 of a 6-step standardized device training protocol for each device.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Stage 2 Full Analysis Set: BF SPIROMAX Stage 2 Full Analysis Set: SYMBICORT TURBOHALER
    Number of subjects analysed
    151 [20]
    154 [21]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Device mastery=yes; n=85, 79
    1.25 ( 1.05 )
    1.35 ( 0.95 )
        Device mastery=no; n=60, 70
    1.46 ( 0.97 )
    1.37 ( 0.97 )
    Notes
    [20] - n=subjects with or without device mastery
    [21] - n=subjects with or without device mastery
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Stage 2 Full Analysis Set: BF SPIROMAX v Stage 2 Full Analysis Set: SYMBICORT TURBOHALER
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.64
         upper limit
    		 7.71

    Secondary: Stage 2: Percentage of Patients Maintaining Device Mastery Relating to Dose Preparation Errors

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    End point title
    		 Stage 2: Percentage of Patients Maintaining Device Mastery Relating to Dose Preparation Errors
    End point description
    Device mastery was defined as the absence of nurse-observed errors by the end of Step 3 of a 6-step standardized device training protocol for each device. This analysis is limited to errors affecting dose preparation, such as not twisting the base as far as possible, until it clicks and not turning it back to its original position.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Stage 2 Full Analysis Set: BF SPIROMAX Stage 2 Full Analysis Set: SYMBICORT TURBOHALER
    Number of subjects analysed
    151
    154
    Units: percentage of participants
    number (not applicable)
        Yes: maintained device mastery
    76.2
    69.5
        No: did not maintain device mastery
    23.8
    30.5
    Statistical analysis title
    		 Mastery: Dose Prep Errors Only
    Comparison groups
    Stage 2 Full Analysis Set: BF SPIROMAX v Stage 2 Full Analysis Set: SYMBICORT TURBOHALER
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.19
    Method
    		 Chi-squared
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 2.34

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Through Week 12
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    BF SPIROMAX
    Reporting group description
    		 Inhaled corticosteroid/long-acting β2-agonist via the BF SPIROMAX device for 12 weeks of therapy.

    Reporting group title
    SYMBICORT TURBOHALER
    Reporting group description
    		 Inhaled corticosteroid/long-acting β2-agonist via the SYMBICORT TURBOHALER device for 12 weeks of therapy.

    Serious adverse events
    		 BF SPIROMAX SYMBICORT TURBOHALER
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 197 (2.03%)
    8 / 197 (4.06%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Thermal burn
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 197 (0.00%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian mass
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    2 / 197 (1.02%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    0 / 197 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 197 (0.51%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 197 (0.51%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 BF SPIROMAX SYMBICORT TURBOHALER
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 197 (14.21%)
    39 / 197 (19.80%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 197 (5.58%)
    12 / 197 (6.09%)
         occurrences all number
    11
    12
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    16 / 197 (8.12%)
    29 / 197 (14.72%)
         occurrences all number
    16
    29

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jan 2014
    The following major procedural changes (not all-inclusive) were made to the protocol: • removal of allowance for subject rescreening • changing the ACQ and PASAPQ from verbally administered to written completion by the subject
    24 Mar 2014
    The following major procedural changes (not all-inclusive) were made to the protocol: • amended the errata associated with BF SPIROMAX devices resulting from recently available stability data • removed the collection of peripheral blood for eosinophil assessment as a procedure

    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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