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    Clinical Trial Results:
    A Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, Parallel-Group, 12-Week Clinical Study to Assess the Efficacy and Safety of 80 or 160 mcg/Day of Beclomethasone Dipropionate Delivered via Breath-Actuated Inhaler (BAI) or Metered-Dose Inhaler (MDI) in Pediatric Patients 4 Through 11 Years of Age with Persistent Asthma

    Summary
    EudraCT number
    		 2013-004632-30
    Trial protocol
    		 PL   HR  
    Global end of trial date
    11 Feb 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Jul 2018
    First version publication date
    26 Jul 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    BDB-AS-302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02040766
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Teva Branded Pharmaceutical Products R&D
    Sponsor organisation address
    41 Moores Road, Frazer, United States, 19355
    Public contact
    Director, Clinical Research, MD, Teva Branded Pharmaceutical Products R&D, 001 888-483-8279, Info.era-clinical@teva.de
    Scientific contact
    Director, Clinical Research, MD, Teva Branded Pharmaceutical Products R&D, 001 888-483-8279, Info.era-clinical@teva.de
    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
    01 Aug 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Feb 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the efficacy of beclomethasone dipropionate administered via breath-activated inhaler (BAI) andmetered-dose inhaler (MDI) (80 or 160 mcg/day) compared with placebo treatment in pediatric patients 4 through 11 years of age with persistent asthma as assessed by the standardized baseline-adjusted trough morning (pre-dose and pre-rescue bronchodilator) percent predicted forced expiratory volume in 1 second (FEV1) area under the effect curve from time 0 to 12 weeks (FEV1 AUEC 0-12wk).
    Protection of trial subjects
    Written and/or oral information about the study was provided to all patients and their caregivers in a language understandable by the patients. The information included an adequate explanation of the aims, methods, anticipated benefits, potential hazards, and insurance arrangements in force. Written informed consent/assent was obtained from each caregiver/patient before any study procedures or assessments were done. It was explained to the caregivers/patients that they were free to refuse entry into the study and free to withdraw from the study at any time without prejudice to future treatment. Each patient’s willingness to participate in the study was documented in writing in a consent/assent form that was signed by the caregiver/patient with the date of that signature indicated. Each investigator kept the original consent forms, and copies were given to the caregivers/patients.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Dec 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
    Poland: 65
    Country: Number of subjects enrolled
    Croatia: 7
    Country: Number of subjects enrolled
    Mexico: 67
    Country: Number of subjects enrolled
    Ukraine: 23
    Country: Number of subjects enrolled
    United States: 466
    Worldwide total number of subjects
    628
    EEA total number of subjects
    72
    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)
    628
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Patients were screened at 123 centers in Croatia, Mexico, Poland, Ukraine, and the United States. The intent-to-treat (ITT) population included all randomly assigned patients

    Pre-assignment
    Screening details
    		 Patients were randomly assigned to treatment through a qualified randomization service provider. This system was used to ensure a balance across treatment groups, within each stratum.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Patients were randomly assigned to treatment through a qualified randomization service provider (ie, IRT). This system was used to ensure a balance across treatment groups, within each stratum (prior ICS therapy and prior NCS therapy groups). To maintain the study blind there was no discernible difference between beclomethasone dipropionate and placebo within each configuration (BAI or MDI).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo BAI and MDI
    Arm description
    		 Placebo was administered via breath-actuated inhaler (BAI) twice daily. Additionally placebo was administered via metered-dose inhaler (MDI) twice daily. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) at 90 mcg ex-actuator) or equivalent was used as rescue medication throughout the study.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo BAI
    Investigational medicinal product code
    Other name
    breath-activated inhaler
    Pharmaceutical forms
    Inhalation vapour, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo was delivered by a single inhalation using a breath-actuated inhaler (BAI) twice each day.

    Investigational medicinal product name
    Placebo MDI
    Investigational medicinal product code
    Other name
    metererd-dose inhaler
    Pharmaceutical forms
    Inhalation vapour, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo was delivered by a single inhalation using a metered-dose inhaler (MDI) twice each day.

    Investigational medicinal product name
    albuterol/salbutamol 90 mcg
    Investigational medicinal product code
    Other name
    bronchodilators, Ventolin, ProAir®
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Rescue medication (albuterol/salbutamol hydrofluoroalkane (HFA) MDI [90 mcg ex-actuator] or equivalent) for use on an as-needed basis for the immediate relief of asthma symptoms throughout the treatment period.

    Arm title
    		 BDP 80 mcg BAI
    Arm description
    		 Beclomethasone dipropionate (BDP) was administered via a breath-actuated inhaler (BAI) twice daily (40 mcg twice a day). Placebo MDI twice daily for blinding. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) at 90 mcg ex-actuator) or equivalent was used as rescue medication throughout the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Beclomethasone dipropionate BAI
    Investigational medicinal product code
    Other name
    BDP, breath-actuated inhaler
    Pharmaceutical forms
    Inhalation vapour, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Beclomethasone dipropionate (BDP), was delivered by a single inhalation using a breath-actuated inhaler (BAI) at levels of 40 mcg or 80 mcg per inhalation, twice each day.

    Investigational medicinal product name
    Placebo MDI
    Investigational medicinal product code
    Other name
    metererd-dose inhaler
    Pharmaceutical forms
    Inhalation vapour, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo was delivered by a single inhalation using a metered-dose inhaler (MDI) twice each day.

    Investigational medicinal product name
    albuterol/salbutamol 90 mcg
    Investigational medicinal product code
    Other name
    bronchodilators, Ventolin, ProAir®
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Rescue medication (albuterol/salbutamol hydrofluoroalkane (HFA) MDI [90 mcg ex-actuator] or equivalent) for use on an as-needed basis for the immediate relief of asthma symptoms throughout the treatment period.

    Arm title
    		 BDP 160 mcg BAI
    Arm description
    		 Beclomethasone dipropionate (BDP) was administered via a breath-actuated inhaler (BAI) twice daily (80 mcg twice a day). Placebo MDI twice daily for blinding. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) at 90 mcg ex-actuator) or equivalent was used as rescue medication throughout the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Beclomethasone dipropionate BAI
    Investigational medicinal product code
    Other name
    BDP, breath-actuated inhaler
    Pharmaceutical forms
    Inhalation vapour, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Beclomethasone dipropionate (BDP), was delivered by a single inhalation using a breath-actuated inhaler (BAI) at levels of 40 mcg or 80 mcg per inhalation, twice each day.

    Investigational medicinal product name
    Placebo MDI
    Investigational medicinal product code
    Other name
    metererd-dose inhaler
    Pharmaceutical forms
    Inhalation vapour, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo was delivered by a single inhalation using a metered-dose inhaler (MDI) twice each day.

    Investigational medicinal product name
    albuterol/salbutamol 90 mcg
    Investigational medicinal product code
    Other name
    bronchodilators, Ventolin, ProAir®
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Rescue medication (albuterol/salbutamol hydrofluoroalkane (HFA) MDI [90 mcg ex-actuator] or equivalent) for use on an as-needed basis for the immediate relief of asthma symptoms throughout the treatment period.

    Arm title
    		 BDP 80 mcg MDI
    Arm description
    		 Beclomethasone dipropionate (BDP) was administered via a metered-dose inhaler (MDI) twice daily (40 mcg twice a day). Placebo BAI twice daily for blinding. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) at 90 mcg ex-actuator) or equivalent was used as rescue medication throughout the study.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Beclomethasone dipropionate MDI
    Investigational medicinal product code
    Other name
    BDP, metered-dose inhaler, QVAR®
    Pharmaceutical forms
    Inhalation vapour, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Beclomethasone dipropionate (BDP), was delivered by a single inhalation using a metered-dose inhaler (MDI) at levels of 40 mcg or 80 mcg per inhalation, twice each day.

    Investigational medicinal product name
    Placebo BAI
    Investigational medicinal product code
    Other name
    breath-activated inhaler
    Pharmaceutical forms
    Inhalation vapour, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo was delivered by a single inhalation using a breath-actuated inhaler (BAI) twice each day.

    Investigational medicinal product name
    albuterol/salbutamol 90 mcg
    Investigational medicinal product code
    Other name
    bronchodilators, Ventolin, ProAir®
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Rescue medication (albuterol/salbutamol hydrofluoroalkane (HFA) MDI [90 mcg ex-actuator] or equivalent) for use on an as-needed basis for the immediate relief of asthma symptoms throughout the treatment period.

    Arm title
    		 BDP 160 mcg MDI
    Arm description
    		 Beclomethasone dipropionate (BDP) was administered via a metered-dose inhaler (MDI) twice daily (80 mcg twice a day). Placebo BAI twice daily for blinding. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) at 90 mcg ex-actuator) or equivalent was used as rescue medication throughout the study.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Beclomethasone dipropionate MDI
    Investigational medicinal product code
    Other name
    BDP, metered-dose inhaler, QVAR®
    Pharmaceutical forms
    Inhalation vapour, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Beclomethasone dipropionate (BDP), was delivered by a single inhalation using a metered-dose inhaler (MDI) at levels of 40 mcg or 80 mcg per inhalation, twice each day.

    Investigational medicinal product name
    Placebo BAI
    Investigational medicinal product code
    Other name
    breath-activated inhaler
    Pharmaceutical forms
    Inhalation vapour, solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo was delivered by a single inhalation using a breath-actuated inhaler (BAI) twice each day.

    Investigational medicinal product name
    albuterol/salbutamol 90 mcg
    Investigational medicinal product code
    Other name
    bronchodilators, Ventolin, ProAir®
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Rescue medication (albuterol/salbutamol hydrofluoroalkane (HFA) MDI [90 mcg ex-actuator] or equivalent) for use on an as-needed basis for the immediate relief of asthma symptoms throughout the treatment period.

    Number of subjects in period 1
    		Placebo BAI and MDI BDP 80 mcg BAI BDP 160 mcg BAI BDP 80 mcg MDI BDP 160 mcg MDI
    Started
    127
    126
    125
    125
    125
    Completed
    109
    116
    113
    112
    112
    Not completed
    18
    10
    12
    13
    13
         Consent withdrawn by subject
    4
    3
    2
    3
    2
         Adverse event, non-fatal
    1
    1
    1
    -
    2
         Not reported
    1
    -
    -
    -
    -
         Non-compliance
    -
    1
    -
    -
    -
         Lost to follow-up
    4
    1
    3
    1
    4
         Protocol deviation
    2
    1
    2
    3
    -
         Lack of efficacy
    6
    3
    4
    6
    5

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Placebo BAI and MDI
    Reporting group description
    		 Placebo was administered via breath-actuated inhaler (BAI) twice daily. Additionally placebo was administered via metered-dose inhaler (MDI) twice daily. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) at 90 mcg ex-actuator) or equivalent was used as rescue medication throughout the study.

    Reporting group title
    BDP 80 mcg BAI
    Reporting group description
    		 Beclomethasone dipropionate (BDP) was administered via a breath-actuated inhaler (BAI) twice daily (40 mcg twice a day). Placebo MDI twice daily for blinding. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) at 90 mcg ex-actuator) or equivalent was used as rescue medication throughout the study.

    Reporting group title
    BDP 160 mcg BAI
    Reporting group description
    		 Beclomethasone dipropionate (BDP) was administered via a breath-actuated inhaler (BAI) twice daily (80 mcg twice a day). Placebo MDI twice daily for blinding. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) at 90 mcg ex-actuator) or equivalent was used as rescue medication throughout the study.

    Reporting group title
    BDP 80 mcg MDI
    Reporting group description
    		 Beclomethasone dipropionate (BDP) was administered via a metered-dose inhaler (MDI) twice daily (40 mcg twice a day). Placebo BAI twice daily for blinding. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) at 90 mcg ex-actuator) or equivalent was used as rescue medication throughout the study.

    Reporting group title
    BDP 160 mcg MDI
    Reporting group description
    		 Beclomethasone dipropionate (BDP) was administered via a metered-dose inhaler (MDI) twice daily (80 mcg twice a day). Placebo BAI twice daily for blinding. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) at 90 mcg ex-actuator) or equivalent was used as rescue medication throughout the study.

    Reporting group values
    		 Placebo BAI and MDI BDP 80 mcg BAI BDP 160 mcg BAI BDP 80 mcg MDI BDP 160 mcg MDI Total
    Number of subjects
    		 127 126 125 125 125 628
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0
        Children (2-11 years)
    		 127 126 125 125 125 628
        Adolescents (12-17 years)
    		 0 0 0 0 0 0
        Adults (18-64 years)
    		 0 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 8.2 ( 2.06 ) 8.5 ( 2.10 ) 8.4 ( 1.84 ) 8.2 ( 1.78 ) 8.4 ( 1.86 ) -
    Gender categorical
    Units: Subjects
        Female
    		 41 52 46 49 50 238
        Male
    		 86 74 79 76 75 390
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 3 4 4 3 1 15
        Asian
    		 0 2 2 0 0 4
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0
        Black or African American
    		 42 34 33 37 49 195
        White
    		 71 69 69 76 63 348
        More than one race
    		 0 0 0 0 0 0
        Unknown or Not Reported
    		 11 17 17 9 12 66

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Placebo BAI and MDI
    Reporting group description
    		 Placebo was administered via breath-actuated inhaler (BAI) twice daily. Additionally placebo was administered via metered-dose inhaler (MDI) twice daily. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) at 90 mcg ex-actuator) or equivalent was used as rescue medication throughout the study.

    Reporting group title
    BDP 80 mcg BAI
    Reporting group description
    		 Beclomethasone dipropionate (BDP) was administered via a breath-actuated inhaler (BAI) twice daily (40 mcg twice a day). Placebo MDI twice daily for blinding. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) at 90 mcg ex-actuator) or equivalent was used as rescue medication throughout the study.

    Reporting group title
    BDP 160 mcg BAI
    Reporting group description
    		 Beclomethasone dipropionate (BDP) was administered via a breath-actuated inhaler (BAI) twice daily (80 mcg twice a day). Placebo MDI twice daily for blinding. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) at 90 mcg ex-actuator) or equivalent was used as rescue medication throughout the study.

    Reporting group title
    BDP 80 mcg MDI
    Reporting group description
    		 Beclomethasone dipropionate (BDP) was administered via a metered-dose inhaler (MDI) twice daily (40 mcg twice a day). Placebo BAI twice daily for blinding. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) at 90 mcg ex-actuator) or equivalent was used as rescue medication throughout the study.

    Reporting group title
    BDP 160 mcg MDI
    Reporting group description
    		 Beclomethasone dipropionate (BDP) was administered via a metered-dose inhaler (MDI) twice daily (80 mcg twice a day). Placebo BAI twice daily for blinding. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) at 90 mcg ex-actuator) or equivalent was used as rescue medication throughout the study.

    Primary: Standardized Baseline-adjusted Trough Morning Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Effect Curve From Time 0 to 12 Weeks (AUEC(0-12wk))

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    End point title
    		 Standardized Baseline-adjusted Trough Morning Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Effect Curve From Time 0 to 12 Weeks (AUEC(0-12wk))
    End point description
    Trough morning FEV1 measurements were taken pre-dose and pre-rescue bronchodilator treatment for asthma. Baseline was defined as baseline trough morning percent predicted FEV1. Pulmonary function measurements (including FEV1) were obtained electronically by spirometry. All pulmonary function test data were submitted to a central reading center for evaluation. The highest ('best attempt') FEV1 value from 3 acceptable and 2 repeatable maneuvers (maximum of 8 attempts) was used. The full analysis set (FAS) included all patients in the ITT population who received at least 1 dose of study drug and had at least 1 post baseline trough morning (pre-dose and pre-rescue bronchodilator) assessment of percent predicted FEV1.
    End point type
    Primary
    End point timeframe
    Day 1 (baseline), Weeks 2, 4, 8, 12
    End point values
    		 Placebo BAI and MDI BDP 80 mcg BAI BDP 160 mcg BAI BDP 80 mcg MDI BDP 160 mcg MDI
    Number of subjects analysed
    113 [1]
    111 [2]
    116 [3]
    114 [4]
    114 [5]
    Units: liters
        least squares mean (standard error)
    2.62 ( 0.744 )
    5.43 ( 0.742 )
    3.25 ( 0.732 )
    3.54 ( 0.734 )
    3.71 ( 0.734 )
    Notes
    [1] - FAS
    [2] - FAS
    [3] - FAS
    [4] - FAS
    [5] - FAS
    Statistical analysis title
    		 % Pred FEV1 AUEC(0-12wk): 80 mcg BAI-Placebo
    Statistical analysis description
    ANCOVA model with effects due to baseline trough morning percent predicted FEV1, sex, age, current protocol-allowed asthma therapy (inhaled corticosteroid (ICS) or noncorticosteroid (NCS) therapy) at the time of screening visit, during the run-in period, and during treatment.
    Comparison groups
    BDP 80 mcg BAI v Placebo BAI and MDI
    Number of subjects included in analysis
    224
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0063 [6]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.796
         upper limit
    		 4.821
    Notes
    [6] - significance of 0.05
    Statistical analysis title
    		 % Pred FEV1 AUEC(0-12wk): 160 mcg BAI-Placebo
    Statistical analysis description
    ANCOVA model with effects due to baseline trough morning percent predicted FEV1, sex, age, current protocol-allowed asthma therapy (inhaled corticosteroid (ICS) or noncorticosteroid (NCS) therapy) at the time of screening visit, during the run-in period, and during treatment.
    Comparison groups
    BDP 160 mcg BAI v Placebo BAI and MDI
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5332 [7]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.354
         upper limit
    		 2.614
    Notes
    [7] - significance of 0.05
    Statistical analysis title
    		 % Pred FEV1 AUEC(0-12wk): 80 mcg MDI-Placebo
    Statistical analysis description
    ANCOVA model with effects due to baseline trough morning percent predicted FEV1, sex, age, current protocol-allowed asthma therapy (inhaled corticosteroid (ICS) or noncorticosteroid (NCS) therapy) at the time of screening visit, during the run-in period, and during treatment.
    Comparison groups
    BDP 80 mcg MDI v Placebo BAI and MDI
    Number of subjects included in analysis
    227
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3649 [8]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.077
         upper limit
    		 2.924
    Notes
    [8] - significance of 0.05
    Statistical analysis title
    		 % Pred FEV1 AUEC(0-12wk): 160 mcg MDI-Placebo
    Statistical analysis description
    ANCOVA model with effects due to baseline trough morning percent predicted FEV1, sex, age, current protocol-allowed asthma therapy (inhaled corticosteroid (ICS) or noncorticosteroid (NCS) therapy) at the time of screening visit, during the run-in period, and during treatment.
    Comparison groups
    BDP 160 mcg MDI v Placebo BAI and MDI
    Number of subjects included in analysis
    227
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2823 [9]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.902
         upper limit
    		 3.088
    Notes
    [9] - significance of 0.05

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

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    End point title
    		 Change From Baseline in Weekly Average of Daily Trough Morning Peak Expiratory Flow (PEF) Over the 12-week Treatment Period
    End point description
    The analysis of change from baseline in weekly average of daily trough morning (pre-dose and pre-rescue bronchodilator) PEF calculated across the 12-week treatment period was performed using a mixed model for repeated measures (MMRM) with effects due to baseline weekly average of daily trough morning PEF.
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline), weeks 1-12
    End point values
    		 Placebo BAI and MDI BDP 80 mcg BAI BDP 160 mcg BAI BDP 80 mcg MDI BDP 160 mcg MDI
    Number of subjects analysed
    124 [10]
    124 [11]
    122 [12]
    121 [13]
    123 [14]
    Units: liters
        least squares mean (standard error)
    4.3 ( 2.11 )
    15.6 ( 2.08 )
    12.8 ( 2.12 )
    11.9 ( 2.11 )
    10.8 ( 2.11 )
    Notes
    [10] - FAS
    [11] - FAS
    [12] - FAS
    [13] - FAS
    [14] - FAS
    Statistical analysis title
    		 CFB Morning PEF: 80 mcg BAI-Placebo
    Comparison groups
    BDP 80 mcg BAI v Placebo BAI and MDI
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    11.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.58
         upper limit
    		 17.06
    Statistical analysis title
    		 CFB Morning PEF: 160 mcg BAI-Placebo
    Comparison groups
    BDP 160 mcg BAI v Placebo BAI and MDI
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0041
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    8.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.71
         upper limit
    		 14.24
    Statistical analysis title
    		 CFB Morning PEF: 80 mcg MDI-Placebo
    Comparison groups
    BDP 80 mcg MDI v Placebo BAI and MDI
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0103
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    7.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.79
         upper limit
    		 13.35
    Statistical analysis title
    		 CFB Morning PEF: 160 mcg MDI-Placebo
    Comparison groups
    BDP 160 mcg MDI v Placebo BAI and MDI
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0278
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    6.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 12.23

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

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    End point title
    		 Change From Baseline in Weekly Average of Daily Evening Peak Expiratory Flow (PEF) Over the 12-week Treatment Period
    End point description
    The analysis of change from baseline in the weekly average of daily evening PEF across the 12-week treatment period was performed using a mixed model for repeated measures (MMRM) with effects due to baseline weekly average of daily evening PEF.
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline), weeks 1-12
    End point values
    		 Placebo BAI and MDI BDP 80 mcg BAI BDP 160 mcg BAI BDP 80 mcg MDI BDP 160 mcg MDI
    Number of subjects analysed
    124 [15]
    124 [16]
    122 [17]
    121 [18]
    123 [19]
    Units: liters
        least squares mean (standard error)
    1.4 ( 2.11 )
    13.1 ( 2.09 )
    11.4 ( 2.12 )
    11.3 ( 2.12 )
    10.1 ( 2.12 )
    Notes
    [15] - FAS
    [16] - FAS
    [17] - FAS
    [18] - FAS
    [19] - FAS
    Statistical analysis title
    		 CFB Evening PEF: 80 mcg BAI - Placebo
    Comparison groups
    BDP 80 mcg BAI v Placebo BAI and MDI
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    11.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.96
         upper limit
    		 17.45
    Statistical analysis title
    		 CFB Evening PEF: 160 mcg BAI - Placebo
    Comparison groups
    BDP 160 mcg BAI v Placebo BAI and MDI
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0007
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    10
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.2
         upper limit
    		 15.76
    Statistical analysis title
    		 CFB Evening PEF: 80 mcg MDI - Placebo
    Comparison groups
    BDP 80 mcg MDI v Placebo BAI and MDI
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0008
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    9.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.11
         upper limit
    		 15.68
    Statistical analysis title
    		 CFB Evening PEF: 160 mcg MDI - Placebo
    Comparison groups
    BDP 160 mcg MDI v Placebo BAI and MDI
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0031
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    8.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.95
         upper limit
    		 14.49

    Secondary: Change From Baseline in the Weekly Average of Total Daily (24-hour) Use of Albuterol/Salbutamol Inhalation Aerosol (Number of Inhalations) Over Weeks 1-12

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    End point title
    		 Change From Baseline in the Weekly Average of Total Daily (24-hour) Use of Albuterol/Salbutamol Inhalation Aerosol (Number of Inhalations) Over Weeks 1-12
    End point description
    The change from baseline in the weekly average of total daily (24-hour) use of albuterol/ salbutamol inhalation aerosol (number of inhalations) across the 12 weeks was analyzed using a mixed model for repeated measures (MMRM).
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline), weeks 1-12
    End point values
    		 Placebo BAI and MDI BDP 80 mcg BAI BDP 160 mcg BAI BDP 80 mcg MDI BDP 160 mcg MDI
    Number of subjects analysed
    124 [20]
    124 [21]
    122 [22]
    121 [23]
    123 [24]
    Units: number of inhalations
        least squares mean (standard error)
    -0.36 ( 0.069 )
    -0.72 ( 0.068 )
    -0.50 ( 0.069 )
    -0.41 ( 0.069 )
    -0.54 ( 0.069 )
    Notes
    [20] - FAS
    [21] - FAS
    [22] - FAS
    [23] - FAS
    [24] - FAS
    Statistical analysis title
    		 CFB Daily Use of Rescue Meds: 80 mcg BAi-Placebo
    Comparison groups
    BDP 80 mcg BAI v Placebo BAI and MDI
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.548
         upper limit
    		 -0.174
    Statistical analysis title
    		 CFB Daily Use of Rescue Meds: 160 mcg BAI-Placebo
    Comparison groups
    BDP 160 mcg BAI v Placebo BAI and MDI
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.132
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.331
         upper limit
    		 0.044
    Statistical analysis title
    		 CFB Daily Use of Rescue Meds: 80 mcg MDI-Placebo
    Comparison groups
    BDP 80 mcg MDI v Placebo BAI and MDI
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5866
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.24
         upper limit
    		 0.136
    Statistical analysis title
    		 CFB Daily Use of Rescue Meds: 160 mcg MDI-Placebo
    Comparison groups
    BDP 160 mcg MDI v Placebo BAI and MDI
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0587
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.369
         upper limit
    		 0.007

    Secondary: Change From Baseline in the Weekly Average of the Total Daily Asthma Symptom Score Over Weeks 1-12

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    End point title
    		 Change From Baseline in the Weekly Average of the Total Daily Asthma Symptom Score Over Weeks 1-12
    End point description
    The total daily asthma symptom score is the average of the daytime and nighttime scores analyzed using an mixed model for repeated measures (MMRM). Baseline was defined as the average of recorded morning and evening asthma symptom scores over the 7 days before randomization. Daytime Scores range from 0=No symptoms during the day to 5=Symptoms so severe that I could not go to work or perform normal daily activities; Nighttime Scores range from 0=No symptoms during the night to 4=Symptoms so severe that I did not sleep at all. The daily asthma symptom score was therefore 0 - 9 with 0=no symptoms during the day or night and 9=severe symptoms both day and night.
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline), weeks 1-12
    End point values
    		 Placebo BAI and MDI BDP 80 mcg BAI BDP 160 mcg BAI BDP 80 mcg MDI BDP 160 mcg MDI
    Number of subjects analysed
    124 [25]
    124 [26]
    122 [27]
    121 [28]
    123 [29]
    Units: units on a scae
        least squares mean (standard error)
    -0.27 ( 0.036 )
    -0.44 ( 0.036 )
    -0.36 ( 0.036 )
    -0.31 ( 0.036 )
    -0.36 ( 0.036 )
    Notes
    [25] - FAS
    [26] - FAS
    [27] - FAS
    [28] - FAS
    [29] - FAS
    Statistical analysis title
    		 Asthma Symptom Score: 80 mcg BAI-Placebo
    Comparison groups
    Placebo BAI and MDI v BDP 80 mcg BAI
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0011
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.261
         upper limit
    		 -0.065
    Statistical analysis title
    		 Asthma Symptom Score: 160 mcg BAI-Placebo
    Comparison groups
    BDP 160 mcg BAI v Placebo BAI and MDI
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0869
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.185
         upper limit
    		 0.013
    Statistical analysis title
    		 Asthma Symptom Score: 80 mcg MDI-Placebo
    Comparison groups
    BDP 80 mcg MDI v Placebo BAI and MDI
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4388
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.138
         upper limit
    		 0.06
    Statistical analysis title
    		 Asthma Symptom Score: 160 mcg MDI-Placebo
    Comparison groups
    BDP 160 mcg MDI v Placebo BAI and MDI
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1041
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.18
         upper limit
    		 0.017

    Secondary: Kaplan-Meier Estimates For Time to Withdrawal Due to Meeting Stopping Criteria for Worsening Asthma During the 12- week Treatment Period

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    End point title
    		 Kaplan-Meier Estimates For Time to Withdrawal Due to Meeting Stopping Criteria for Worsening Asthma During the 12- week Treatment Period
    End point description
    Time to withdrawal due to meeting stopping criteria was defined as number of days elapsed from the date of first dose of double-blind study treatment to the date of withdrawal due to meeting stopping criteria. Kaplan-Meier estimates (median and 95% CI of the median) are not applicable if the proportion of participants withdrawn is less than 0.5. Values of 9999 indicate the values could not be estimated because too few participants withdrew.
    End point type
    Secondary
    End point timeframe
    Day 1 to 12 weeks
    End point values
    		 Placebo BAI and MDI BDP 80 mcg BAI BDP 160 mcg BAI BDP 80 mcg MDI BDP 160 mcg MDI
    Number of subjects analysed
    124 [30]
    124 [31]
    122 [32]
    121 [33]
    123 [34]
    Units: days
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Notes
    [30] - FAS
    [31] - FAS
    [32] - FAS
    [33] - FAS
    [34] - FAS
    Statistical analysis title
    		 Time to Withdrawal: 80 mcg BAI-Placebo
    Comparison groups
    BDP 80 mcg BAI v Placebo BAI and MDI
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.287
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Time to Withdrawal: 160 mcg BAI-Placebo
    Comparison groups
    BDP 160 mcg BAI v Placebo BAI and MDI
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5257
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Time to Withdrawal: 80 mcg MDI-Placebo
    Comparison groups
    BDP 80 mcg MDI v Placebo BAI and MDI
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9982
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Time to Withdrawal: 160 mcg MDI-Placebo
    Comparison groups
    BDP 160 mcg MDI v Placebo BAI and MDI
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7633
    Method
    		 Logrank
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Double-blind Study Treatment: Day 1 to Week 12
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Placebo BAI and MDI
    Reporting group description
    		 Placebo was administered via breath-actuated inhaler (BAI) twice daily. Additionally placebo was administered via metered-dose inhaler (MDI) twice daily. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) at 90 mcg ex-actuator) or equivalent was used as rescue medication throughout the study.

    Reporting group title
    BDP 80 mcg BAI
    Reporting group description
    		 Beclomethasone dipropionate (BDP) was administered via a breath-actuated inhaler (BAI) twice daily (40 mcg twice a day). Placebo MDI twice daily for blinding. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) at 90 mcg ex-actuator) or equivalent was used as rescue medication throughout the study.

    Reporting group title
    BDP 160 mcg BAI
    Reporting group description
    		 Beclomethasone dipropionate (BDP) was administered via a breath-actuated inhaler (BAI) twice daily (80 mcg twice a day). Placebo MDI twice daily for blinding. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) at 90 mcg ex-actuator) or equivalent was used as rescue medication throughout the study.

    Reporting group title
    BDP 80 mcg MDI
    Reporting group description
    		 Beclomethasone dipropionate (BDP) was administered via a metered-dose inhaler (MDI) twice daily (40 mcg twice a day). Placebo BAI twice daily for blinding. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) at 90 mcg ex-actuator) or equivalent was used as rescue medication throughout the study.

    Reporting group title
    BDP 160 mcg MDI
    Reporting group description
    		 Beclomethasone dipropionate (BDP) was administered via a metered-dose inhaler (MDI) twice daily (80 mcg twice a day). Placebo BAI twice daily for blinding. Albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) at 90 mcg ex-actuator) or equivalent was used as rescue medication throughout the study.

    Serious adverse events
    		 Placebo BAI and MDI BDP 80 mcg BAI BDP 160 mcg BAI BDP 80 mcg MDI BDP 160 mcg MDI
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 126 (0.00%)
    0 / 125 (0.00%)
    0 / 125 (0.00%)
    0 / 125 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo BAI and MDI BDP 80 mcg BAI BDP 160 mcg BAI BDP 80 mcg MDI BDP 160 mcg MDI
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 127 (6.30%)
    6 / 126 (4.76%)
    13 / 125 (10.40%)
    15 / 125 (12.00%)
    11 / 125 (8.80%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 127 (3.15%)
    1 / 126 (0.79%)
    3 / 125 (2.40%)
    9 / 125 (7.20%)
    6 / 125 (4.80%)
         occurrences all number
    7
    1
    3
    11
    7
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 127 (3.15%)
    5 / 126 (3.97%)
    11 / 125 (8.80%)
    6 / 125 (4.80%)
    6 / 125 (4.80%)
         occurrences all number
    5
    6
    14
    7
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 May 2014
    Amendment 1 (dated 21 May 2014) to the protocol was issued after 49 patients were enrolled into the study. Changes to the protocol were considered to have no negative impact on the safety of patients already enrolled into the study. The primary reasons for the amendment were modification of prohibited medications and clarification of study procedures. The following major procedural changes (not all-inclusive) were made to the protocol: • At the prescreening visit, dose of fluticasone propionate MDI adjusted from 88 mcg/day to 176 mcg/day to be consistent with ICS of combination therapy. • Changes to allow nebulizer treatment reversibility testing as standard of care and to clarify that historical spirometry data need only include the expiratory tracings. • Edited to allow PRN use of low-potency topical corticosteroids and aspirin use as standard of care, revised to indicate that aqueous formulations of intranasal steroids are allowable before SV but aerosol formulations are disallowed, clarified when ocular steroid use is permitted, removed tricyclic antidepressants as a prohibited medication, and added medicinal marijuana and inhaled nicotine to the list of prohibited medication.
    18 Dec 2014
    Amendment 2 (dated 18 December 2014) to the protocol was issued after 220 patients were enrolled into the study. Changes to the protocol were considered to have no negative impact on the safety of patients already enrolled into the study. The primary reasons for the amendment were the change in the primary efficacy variable, lowering of the minimum age for eligibility to participate in the study, the addition of the option to rescreen patients who failed to qualify for the study based on spirometry criteria, and permission of younger patients who were unable to perform spirometry to participate in the study on the basis of PEF criteria in place of spirometry criteria. The following major procedural changes (not all-inclusive) were made to the protocol: • The minimum age requirement for participation in the study was changed from 5 to 4 years of age. • A change in the primary efficacy measure at endpoint. The primary efficacy variable was changed to standardized baseline-adjusted trough morning (pre-dose and pre-rescue bronchodilator) percent predicted FEV1 AUEC(0-12wk) after discussions with the Food and Drug Administration indicated a concern over handling of missing data due to early dropouts. • The order of secondary objectives was changed to correspond with a change in the order of statistical testing of the secondary variables. • The number of attempts to perform acceptable and repeatable spirometry was increased from 5 to 8 and the option to rescreen patients who failed screening based on spirometry was added because younger patients were having difficulty performing spirometry measurements adequately. • Inclusion criterion C was changed to allow patients aged 4 to 5 years to participate in the study using PEF measurements.

    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/28710850
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