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    Clinical Trial Results:
    Randomised controlled single and chronic dosing crossover comparison of extra fine particle formoterol and coarse particle salmeterol in asthmatic patients with persistent small airways dysfunction

    Summary
    EudraCT number
    		 2013-001103-36
    Trial protocol
    		 GB  
    Global end of trial date
    17 Dec 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Jul 2016
    First version publication date
    20 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2013RC01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01892787
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Tayside Medical Sciences Centre on behalf of the University of Dundee & NHS Tayside
    Sponsor organisation address
    Residency Block, Level 3, Ninewells Hospital, George Pirie Way , Dundee, United Kingdom, DD1 9SY
    Public contact
    Prof Brian Lipworth, Scottish Centre for Respiratory Research University of Dundee , 44 01382 383188, b.j.lipworth@dundee.ac.uk
    Scientific contact
    Prof Brian Lipworth, Scottish Centre for Respiratory Research University of Dundee , 44 01382 383188, b.j.lipworth@dundee.ac.uk
    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
    17 Dec 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Dec 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effects of extra fine particle formoterol (Atimos) with coarse particle salmeterol (Serevent) on small airway function
    Protection of trial subjects
    Subjects were recruited from a database of volunteers who had agreed to be contacted with regard to participating in departmental research. Subjects received a written information sheet (PIS) with details of trial requirements, and had this for at least 24 hours before attending for a screening visit. They were encouraged to discuss the possibility of participation with study staff and others. Informed consent was obtained before any protocol-specific procedures were carried out. Subjects were given every opportunity to clarify points they did not understand, and ask for more information. It was emphasised that the subject could withdraw consent to participate at any time without loss of benefits to which they otherwise would be entitled. The Chief Investigator could also withdraw a participant at any point if they felt it would be unsafe or inappropriate for the subject to continue. An informed consent form was signed and dated by the subject and the person taking consent, and the volunteer received a copy. Subjects were only selected if they met the pre-determined inclusion criteria. Only subjects deemed clinically stable were recruited. Medical history and concomitant medications were reviewed by a medically qualified person to confirm it was safe for the subject to receive the study drug. A physical examination was conducted before randomisation. A screening blood sample was taken at screening with tests appropriate to the risk of the study. Participants received an emergency mobile phone number, carried by a study doctor 24 hours a day, to contact if they experienced any problems, and were advised to contact the department if they felt their asthma was worsening during the study. Participants on long-acting beta agonists (LABAs) or combination inhalers with a LABA component had to withhold the LABA during the run-in/washout period. The washout periods were for a very short duration (1-2 weeks), and reliever inhalers could be used as required.
    Background therapy
    		 At Screening, all subjects were on inhaled corticosteroid (ICS), either alone, or in a combination inhaler After screening, subjects were converted to a reference ICS therapy (Clenil Modulite) at an equivalent dose. LABAs were stopped during the run-in period, and subjects taking a LABA / ICS combination inhaler were switched to Clenil Modulite at an equivalent dose. Short acting beta-agonists (SABAs) were withheld for 6 hours prior to each visit Other second line controller drugs were permitted (e.g., LTRAs, theophyllines, cromones, and LAMAs) The average ICS dose for subjects was 500µg/day (74 SEM)
    Evidence for comparator
    		 This was an open label study comparing Atimos Modulite with Serevent Accuhaler Pathological abnormalities in the small airways have been demonstrated regardless of asthma severity and seem to persist even in patients with stable asthma. There is a lack of information on the potential benefits of extra fine formoterol on the small airways. The comparators selected represent the two extremes of available long-acting beta-agonist formulations – i.e. extra fine HFA formoterol ( Atimos ) versus coarse particle DPI salmeterol (i.e. Serevent Accuhaler). and their effects on the small airway function was assessed via impulse oscillometry (IOS).
    Actual start date of recruitment
    08 Jul 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 37
    Worldwide total number of subjects
    37
    EEA total number of subjects
    37
    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)
    34
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were recruited from July 2013 until November 2014. Sufficient numbers were recruited to ensure 16 subjects completed.

    Pre-assignment
    Screening details
    		 Subjects were assessed at screening against pre-defined inclusion and exclusion criteria. Eligible subjects entered a 1 to 2 week run-in period during which their ICS dose was converted to a reference inhaler (Clenil Modulite) at an equivalent dose, and any LABAs were stopped.

    Pre-assignment period milestones
    Number of subjects started
    		 37
    Intermediate milestone: Number of subjects
    Screening Visit: 37
    Intermediate milestone: Number of subjects
    Run-In Period: 19
    Number of subjects completed
    		 17

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Did not meet inclusion criteria: 18
    Reason: Number of subjects
    		 Did not attend after screening visit: 2
    Period 1
    Period 1 title
    Randomised Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 HFA Formoterol (Cross-Over Design)
    Arm description
    		 Subjects randomised to HFA-formoterol solution 12µg bid, At start of treatment arm, baseline IOS, spirometry, ACQ & FeNO recorded. First IMP dose administered in department, and IOS & spirometry measured at 5,15,30,45 & 60 minutes post-dose. After 1 to 2 weeks on IMP, subjects returned to department, 12 hours post-dose. Baseline IOS, spirometry, ACQ & FeNO recorded. Final IMP dose administered in department. IOS and spirometry recorded at 5, 15, 30, 45 and 60 minutes post-dose Cross-over design - Participants received both IMPs (participated in both arms) during the course of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    HFA Formoterol
    Investigational medicinal product code
    Other name
    Atimos Modulite
    Pharmaceutical forms
    Pressurised inhalation
    Routes of administration
    Inhalation use
    Dosage and administration details
    Formoterol 12µg bid

    Arm title
    		 DPI Salmeterol (Crossover design)
    Arm description
    		 Subjects randomised to either DPI salmeterol 50µg bid. At start of treatment arm, baseline IOS, spirometry, ACQ & FeNO recorded. First IMP dose administered in department, and IOS & spirometry measured at 5,15,30,45 & 60 minutes post-dose. After 1 to 2 weeks on IMP, subjects returned to department, 12 hours post-dose. Baseline IOS, spirometry, ACQ & FeNO recorded. Final IMP dose administered in department. IOS and spirometry recorded at 5, 15, 30, 45 and 60 minutes post-dose Cross-over design - Participants received both IMPs (participated in both arms) during the course of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    DPI Salmeterol
    Investigational medicinal product code
    Other name
    Serevent
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Salmeterol 50µg bid

    Number of subjects in period 1
    		HFA Formoterol (Cross-Over Design) DPI Salmeterol (Crossover design)
    Started
    16
    17
    Completed
    16
    16
    Not completed
    0
    1
         Adverse event, non-fatal
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Randomised Treatment
    Reporting group description
    		 Inclusion Criteria: Male or female, aged > 16 years, with persistent asthma. R5 > 150% predicted, R5-R20 > 0.05 kPa·L·s-1, on ICS or ICS/LABA, with a FEV1 > 60%. Exclusion Criteria: other significant respiratory diseases, an asthma exacerbation or respiratory tract infection requiring systemic steroids and/or antibiotics within 3 months of the study commencement and smoking within one year or > 10 pack year history.

    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: The worldwide number enrolled is the number of subjects screened into the study (37). The number of subjects in the baseline period is the number who were then randomised into the study (17). Of these 17 subjects, 16 of them completed both arms of the cross-over trial per protocol and were able to be analysed. Total number of subjects analysed: 16
    Reporting group values
    		 Randomised Treatment Total
    Number of subjects
    		 17 17
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 14 14
        From 65-84 years
    		 3 3
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 43 ( 4.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 8 8
        Male
    		 9 9
    Subject analysis sets

    Subject analysis set title
    Completed Subjects
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Inclusion Criteria: Male or female, aged > 16 years, with persistent asthma. R5 > 150% predicted, R5-R20 > 0.05 kPa·L·s-1, on ICS or ICS/LABA, with a FEV1 > 60%. Exclusion Criteria: other significant respiratory diseases, an asthma exacerbation or respiratory tract infection requiring systemic steroids and/or antibiotics within 3 months of the study commencement and smoking within one year or > 10 pack year history.

    Subject analysis sets values
    		 Completed Subjects
    Number of subjects
    16
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    13
        From 65-84 years
    3
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    Gender categorical
    Units: Subjects
        Female
    7
        Male
    9

    End points

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    End points reporting groups
    Reporting group title
    HFA Formoterol (Cross-Over Design)
    Reporting group description
    		 Subjects randomised to HFA-formoterol solution 12µg bid, At start of treatment arm, baseline IOS, spirometry, ACQ & FeNO recorded. First IMP dose administered in department, and IOS & spirometry measured at 5,15,30,45 & 60 minutes post-dose. After 1 to 2 weeks on IMP, subjects returned to department, 12 hours post-dose. Baseline IOS, spirometry, ACQ & FeNO recorded. Final IMP dose administered in department. IOS and spirometry recorded at 5, 15, 30, 45 and 60 minutes post-dose Cross-over design - Participants received both IMPs (participated in both arms) during the course of the study.

    Reporting group title
    DPI Salmeterol (Crossover design)
    Reporting group description
    		 Subjects randomised to either DPI salmeterol 50µg bid. At start of treatment arm, baseline IOS, spirometry, ACQ & FeNO recorded. First IMP dose administered in department, and IOS & spirometry measured at 5,15,30,45 & 60 minutes post-dose. After 1 to 2 weeks on IMP, subjects returned to department, 12 hours post-dose. Baseline IOS, spirometry, ACQ & FeNO recorded. Final IMP dose administered in department. IOS and spirometry recorded at 5, 15, 30, 45 and 60 minutes post-dose Cross-over design - Participants received both IMPs (participated in both arms) during the course of the study.

    Subject analysis set title
    Completed Subjects
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Inclusion Criteria: Male or female, aged > 16 years, with persistent asthma. R5 > 150% predicted, R5-R20 > 0.05 kPa·L·s-1, on ICS or ICS/LABA, with a FEV1 > 60%. Exclusion Criteria: other significant respiratory diseases, an asthma exacerbation or respiratory tract infection requiring systemic steroids and/or antibiotics within 3 months of the study commencement and smoking within one year or > 10 pack year history.

    Primary: % change in R5-R20 from baseline

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    End point title
    		 % change in R5-R20 from baseline
    End point description
    Effects on R5-R20 with either small particle formoterol or large particle salmeterol over a 60 minute period after acute and chronic dosing of the IMP, reported as % change from baseline.
    End point type
    Primary
    End point timeframe
    Timeframe started at the first visit of the treatment period (acute dosing) and extended 1 – 2 weeks until last visit of treatment period (chronic dosing)
    End point values
    		 HFA Formoterol (Cross-Over Design) DPI Salmeterol (Crossover design)
    Number of subjects analysed
    16
    16
    Units: Percentage
    number (not applicable)
        5 minutes
    53.05
    37.87
        60 minutes
    31.12
    18.36
    Statistical analysis title
    		 % change in R5-R20 from baseline
    Comparison groups
    HFA Formoterol (Cross-Over Design) v DPI Salmeterol (Crossover design)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard error of the mean

    Secondary: change in R5 from baseline

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    End point title
    		 change in R5 from baseline
    End point description
    Effects on R5 with either small particle formoterol or large particle salmeterol over a 60 minute period after acute and chronic dosing of the IMP, reported as change from baseline.
    End point type
    Secondary
    End point timeframe
    Timeframe started at the first visit of the treatment period (acute dosing) and extended 1 – 2 weeks until last visit of treatment period (chronic dosing)
    End point values
    		 HFA Formoterol (Cross-Over Design) DPI Salmeterol (Crossover design)
    Number of subjects analysed
    16
    16
    Units: percentage
        number (not applicable)
    13.6
    6.11
    Statistical analysis title
    		 change in R5 from baseline
    Comparison groups
    HFA Formoterol (Cross-Over Design) v DPI Salmeterol (Crossover design)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 Median difference (final values)
    Confidence interval
         level
    		 95%
    Variability estimate
    Standard error of the mean

    Secondary: change in R20 from baseline

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    End point title
    		 change in R20 from baseline
    End point description
    Effects on R20 with either small particle formoterol or large particle salmeterol over a 60 minute period after acute and chronic dosing of the IMP, reported as change from baseline.
    End point type
    Secondary
    End point timeframe
    Timeframe started at the first visit of the treatment period (acute dosing) and extended 1 – 2 weeks until last visit of treatment period (chronic dosing)
    End point values
    		 HFA Formoterol (Cross-Over Design) DPI Salmeterol (Crossover design)
    Number of subjects analysed
    16
    16
    Units: percentage
        number (not applicable)
    6.82
    1.45
    Statistical analysis title
    		 change in R20 from baseline
    Comparison groups
    HFA Formoterol (Cross-Over Design) v DPI Salmeterol (Crossover design)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 Median difference (final values)
    Confidence interval
         level
    		 95%
    Variability estimate
    Standard error of the mean

    Secondary: Change in X5 from baseline

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    End point title
    		 Change in X5 from baseline
    End point description
    Effects on X5 with either small particle formoterol or large particle salmeterol over a 60 minute period after acute and chronic dosing of the IMP, reported as change from baseline.
    End point type
    Secondary
    End point timeframe
    Timeframe started at the first visit of the treatment period (acute dosing) and extended 1 – 2 weeks until last visit of treatment period (chronic dosing)
    End point values
    		 HFA Formoterol (Cross-Over Design) DPI Salmeterol (Crossover design)
    Number of subjects analysed
    16
    16
    Units: percent
        number (not applicable)
    20.48
    9.29
    Statistical analysis title
    		 change in X5 from baseline
    Comparison groups
    HFA Formoterol (Cross-Over Design) v DPI Salmeterol (Crossover design)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard error of the mean

    Secondary: change in RF from baseline

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    End point title
    		 change in RF from baseline
    End point description
    Effects on RF with either small particle formoterol or large particle salmeterol over a 60 minute period after acute and chronic dosing of the IMP, reported as change from baseline.
    End point type
    Secondary
    End point timeframe
    Timeframe started at the first visit of the treatment period (acute dosing) and extended 1 – 2 weeks until last visit of treatment period (chronic dosing)
    End point values
    		 HFA Formoterol (Cross-Over Design) DPI Salmeterol (Crossover design)
    Number of subjects analysed
    16
    16
    Units: percent
        number (not applicable)
    18.04
    8.7
    Statistical analysis title
    		 change in RF from baseline
    Comparison groups
    HFA Formoterol (Cross-Over Design) v DPI Salmeterol (Crossover design)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard error of the mean

    Secondary: change in AX from baseline

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    End point title
    		 change in AX from baseline
    End point description
    Effects on AX with either small particle formoterol or large particle salmeterol over a 60 minute period after acute and chronic dosing of the IMP, reported as change from baseline.
    End point type
    Secondary
    End point timeframe
    Timeframe started at the first visit of the treatment period (acute dosing) and extended 1 – 2 weeks until last visit of treatment period (chronic dosing)
    End point values
    		 HFA Formoterol (Cross-Over Design) DPI Salmeterol (Crossover design)
    Number of subjects analysed
    16
    16
    Units: percent
        number (not applicable)
    38.27
    18.81
    Statistical analysis title
    		 change in AX from baseline
    Comparison groups
    HFA Formoterol (Cross-Over Design) v DPI Salmeterol (Crossover design)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%

    Secondary: change in FEV1 from baseline

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    End point title
    		 change in FEV1 from baseline
    End point description
    Effects on FEV1 with either small particle formoterol or large particle salmeterol over a 60 minute period after acute and chronic dosing of the IMP, reported as change from baseline.
    End point type
    Secondary
    End point timeframe
    Timeframe started at the first visit of the treatment period (acute dosing) and extended 1 – 2 weeks until last visit of treatment period (chronic dosing)
    End point values
    		 HFA Formoterol (Cross-Over Design) DPI Salmeterol (Crossover design)
    Number of subjects analysed
    16
    16
    Units: percent
        number (not applicable)
    5.81
    3.15
    Statistical analysis title
    		 change in FEV1 from baseline
    Comparison groups
    HFA Formoterol (Cross-Over Design) v DPI Salmeterol (Crossover design)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard error of the mean

    Secondary: change in FEF25-75 from baseline

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    End point title
    		 change in FEF25-75 from baseline
    End point description
    Effects on FEF25-75 with either small particle formoterol or large particle salmeterol over a 60 minute period after acute and chronic dosing of the IMP, reported as change from baseline.
    End point type
    Secondary
    End point timeframe
    Timeframe started at the first visit of the treatment period (acute dosing) and extended 1 – 2 weeks until last visit of treatment period (chronic dosing)
    End point values
    		 HFA Formoterol (Cross-Over Design) DPI Salmeterol (Crossover design)
    Number of subjects analysed
    16
    16
    Units: percent
        number (not applicable)
    13.5
    9.93
    Statistical analysis title
    		 change in FEF25-75 from baseline
    Comparison groups
    HFA Formoterol (Cross-Over Design) v DPI Salmeterol (Crossover design)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard error of the mean

    Secondary: mean ACQ

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    End point title
    		 mean ACQ
    End point description
    Effects on ACQ with either small particle formoterol or large particle salmeterol over a 60 minute period after acute and chronic dosing of the IMP, reported as change from baseline.
    End point type
    Secondary
    End point timeframe
    Timeframe started at the first visit of the treatment period (acute dosing) and extended 1 – 2 weeks until last visit of treatment period (chronic dosing)
    End point values
    		 HFA Formoterol (Cross-Over Design) DPI Salmeterol (Crossover design)
    Number of subjects analysed
    16
    16
    Units: units
        number (not applicable)
    0.48
    0.52
    Statistical analysis title
    		 Change from baseline in ACQ
    Comparison groups
    HFA Formoterol (Cross-Over Design) v DPI Salmeterol (Crossover design)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 Median difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard error of the mean

    Secondary: Change from baseline in FeNO.

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    End point title
    		 Change from baseline in FeNO.
    End point description
    Effects on FeNO with either small particle formoterol or large particle salmeterol over a 60 minute period after acute and chronic dosing of the IMP, reported as change from baseline.
    End point type
    Secondary
    End point timeframe
    Timeframe started at the first visit of the treatment period (acute dosing) and extended 1 – 2 weeks until last visit of treatment period (chronic dosing)
    End point values
    		 HFA Formoterol (Cross-Over Design) DPI Salmeterol (Crossover design)
    Number of subjects analysed
    16
    16
    Units: ppb
        number (not applicable)
    22.5
    23.6
    Statistical analysis title
    		 Change from baseline in FeNO
    Comparison groups
    HFA Formoterol (Cross-Over Design) v DPI Salmeterol (Crossover design)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard error of the mean

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs and SAEs were recorded from the time a participant consented to join the study until the last study visit.
    Adverse event reporting additional description
    Subjects were asked about the occurrence of AEs at each study visit and received training on how to record AEs and concomitant medications. All AEs were recorded on subject-specific logs in the CRFs.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    Completed Subjects
    Reporting group description
    		 -

    Serious adverse events
    		 Completed Subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 16 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Completed Subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 16 (56.25%)
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 16 (18.75%)
         occurrences all number
    3
    Migraine
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Sinusitis
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Immune system disorders
    Allergic Reaction
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Ear and labyrinth disorders
    earache
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Lightheaded
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Gastrointestinal disorders
    Reflux gastritis
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Irritable bowel syndrome
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Wheeze
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    2
    Worsening of respiratory symptoms
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Dry Cough
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    3
    pain in shoulder
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Muscle strain (back)
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1
    Infections and infestations
    Rhinovirus infection
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Sep 2014
    REC Amendment (AM01) / MHRA Amendment AM01 Amendment to Inclusion / Exclusion criteria intended to help with recruitment.

    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/26220533
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