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    Clinical Trial Results:
    Proof of concept study to evaluate single and chronic dosing effects of ultra-long acting bronchodilator therapy on mannitol challenge in asthmatic patients taking inhaled corticosteroids

    Summary
    EudraCT number
    		 2013-001953-28
    Trial protocol
    		 GB  
    Global end of trial date
    15 Jul 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Jul 2017
    First version publication date
    29 Jul 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2012RC15
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02039011
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Dundee - NHS Tayside
    Sponsor organisation address
    Residency Block, Level 3, Ninewells Hospital, George Pirie Way, Dundee, United Kingdom, DD1 9SY
    Public contact
    Professor Brian Lipworth, Scottish Centre for Respiratory Research, 44 01382 383188, b.j.lipworth@dundee.ac.uk
    Scientific contact
    Professor Brian Lipworth, Scottish Centre for Respiratory Research, 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
    15 Jul 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Jul 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare first and last dose protection against mannitol challenge for indacaterol alone versus indacaterol plus tiotropium given once daily as add-on therapy to pre-existing inhaled corticosteroids.
    Protection of trial subjects
    The study was approved the Tayside committee for medical ethics (reference: 13/ES/0072) and full informed consent was obtained from all patients. Participants were only selected if they fulfilled the pre-determined inclusion criteria. Medical histories were obtained and physical examinations conducted prior to randomisation into the study, and a medically qualified person confirmed that it was safe for participants to receive the study drug. A screening blood sample was taken at screening with tests appropriate to the risk of the study. An emergency card was issued to each subject, detailing the study, fthe Chief Investigator, the drug under investigation and emergency contact numbers. An emergency mobile was kept 24 hours a day by the study doctor, and participants were advised to phone if they felt that their asthma was worsening during the step-down/run-in period. Only subjects deemed clinically stable were recruited into the study. They received a written PIS detailing the trial requirements and the extent of their participation before attending for a screening visit. They had the PIS for at least 24 hours and were encouraged to discuss the study and their potential involvement with both study staff and others, such as family and friends If participant becomes clinically unstable as assessed by the study physician then they will revert to their usual asthma medication and be withdrawn from the study A pre-Sponsorship study risk assessment was carried out by the TASC Research Governance Manager prior to Sponsorship approval being granted.
    Background therapy
    		 After initial screening, any LABA therapy was first withdrawn for 2 weeks followed by halving the ICS dose, to a minimum of 400μg/day (as beclometasone equivalent dose). If patients were on secondary controllers such as leukotriene receptor antagonists, these were also stopped. Participants then entered a 2 week run in on this dose of ICS, which was then continued throughout the study.
    Evidence for comparator
    		 Tiotropium (TIO) is a long acting muscarinic antagonists (LAMA), which is functionally selective for the post junctional M3 muscarinic receptor, found on airway smooth muscle. TIO reduces asthma exacerbations by 21% in patients when used as add on therapy in patients receiving inhaled corticosteroids and long-acting beta-agonists (ICS/LABA). TIO exhibits only modest improvements in FEV1, which amounts to approximately 100ml at trough, which is less than the minimally important difference of 230ml. It is therefore hard to explain the protective effect on exacerbations on solely the basis of this small improvement in airway calibre alone. No studies have looked at effects of TIO on AHR assessed by bronchial challenge using non cholinergic agents. One study showed that as expected TIO produced prolonged functional antagonism of M3 mediated smooth muscle constriction induced by the cholinergic agonist methacholine. As TIO is only currently indicated as add-on therapy to ICS/LABA , the objective of this study was to evaluate the impact of adding TIO to ICS/LABA on AHR, in patients with persistent asthma and whether TIO might also prevent against LABA induced subsensitivity. We chose an indirect bronchial challenge, namely mannitol, as this is thought to more closely reflect physiological stimuli and acts by release of pro-inflammatory mediators. Moreover mannitol challenge has been shown to be related to an inflammatory phenotype in asthma.
    Actual start date of recruitment
    24 Mar 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: 39
    Worldwide total number of subjects
    39
    EEA total number of subjects
    39
    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
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were recruited from March 2014 to May 2016. Of the 39 patients screened, 18 were randomised, and 14 completed per protocol.

    Pre-assignment
    Screening details
    		 Males & females, non-smokers, >18 years, persistent asthma on ICS or ICS/LABA, FEV1 >50% predicted, mannitol responsive, no chest infections or oral steroids in the last 3 months. After screening, LABAs were stopped for 2 weeks, then ICS dose halved to a minimum of 400μg/day BDP, which continued thoughout study. Secondary controllers were stopped.

    Pre-assignment period milestones
    Number of subjects started
    		 39
    Intermediate milestone: Number of subjects
    Screening Visit: 39
    Number of subjects completed
    		 18

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Did not meet inclusion criteria: 17
    Reason: Number of subjects
    		 Inability to comply with protocol: 4
    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
    		 INDACATEROL
    Arm description
    		 Patients received 4 weeks of indacaterol (Onbrez Breezhaler) alone at a dose of 150μg OD as add-on to pre-existing ICS. There was a 2 week washout in between treatments while continuing to take the same dose of ICS. Including screening, there were 7 visits in total. Visits were performed, in the mornings, at baseline after run-in and washout, and at 24 hours (i.e. trough) after the first and last doses of each randomised treatment period. Patients were allowed short acting beta-2 agonists (SABAs) as a reliever during the study, but were asked to abstain from SABA use at least 6 hours before each visit. The visits were conducted in the mornings (8am-10am). Cross-over design – Participants received both IMPs (participated in both arms) during the course of the study
    Arm type
    		 Experimental

    Investigational medicinal product name
    Indacaterol
    Investigational medicinal product code
    Other name
    Onbrez Breezhaler
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Inhalation use
    Dosage and administration details
    Indacaterol (Onbrez Breezhaler) 150μg OD was taken for 4 weeks.

    Arm title
    		 TIOTROPIUM + INDACATEROL
    Arm description
    		 Patients received 4 weeks of indacaterol (Onbrez Breezhaler) at a dose of 150μg OD, combined with tiotropium (Spiriva Handihaler) 18μg OD as add-on to pre-existing ICS. There was a 2 week washout in between treatments while continuing to take the same dose of ICS. Including screening, there were 7 visits in total. Visits were performed, in the mornings, at baseline after run-in and washout, and at 24 hours (i.e. trough) after the first and last doses of each randomised treatment period. Patients were allowed short acting beta-2 agonists (SABAs) as a reliever during the study, but were asked to abstain from SABA use at least 6 hours before each visit. The visits were conducted in the mornings (8am-10am). Cross-over design – Participants received both IMPs (participated in both arms) during the course of the study
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Spiriva Handihaler
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium (Spiriva Handihaler) 18μg OD was taken for 4 weeks.

    Investigational medicinal product name
    Indacaterol
    Investigational medicinal product code
    Other name
    Onbrez Breezhaler
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Inhalation use
    Dosage and administration details
    Indacaterol (Onbrez Breezhaler) 150μg OD was taken for 4 weeks.

    Number of subjects in period 1
    		INDACATEROL TIOTROPIUM + INDACATEROL
    Started
    18
    17
    Completed
    15
    17
    Not completed
    3
    0
         Adverse event, non-fatal
    2
    -
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Randomised Treatment (overall period)
    Reporting group description
    		 Inclusion Criteria: Non-smoking male or female patients, aged at least 18 years, with persistent asthma already receiving ICS or ICS/LABA. Minimum FEV1 of > 50% predicted, and mannitol responsive (i.e., provocative dose required to reduce FEV1 by 15% (PD15) <635 mg. Exclusion Criteria: History of respiratory tract infection or oral corticosteroid use in the last three months prior to screening.

    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 (39). The number of subjects in the baseline period is the number who were then randomised into the study (18). Of these 18 subjects, 14 completed both arms of the cross-over trial and were able to be analysed.
    Reporting group values
    		 Randomised Treatment (overall period) Total
    Number of subjects
    		 18 18
    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)
    		 17 17
        From 65-84 years
    		 1 1
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 48 ± 15 -
    Gender categorical
    Units: Subjects
        Female
    		 12 12
        Male
    		 6 6
    Subject analysis sets

    Subject analysis set title
    Completed Subjects
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Inclusion Criteria: Non-smoking male or female patients, aged at least 18 years, with persistent asthma already receiving ICS or ICS/LABA. Minimum FEV1 of > 50% predicted, and mannitol responsive (i.e., provocative dose required to reduce FEV1 by 15% (PD15) <635 mg. Exclusion Criteria: History of respiratory tract infection or oral corticosteroid use in the last three months prior to screening.

    Subject analysis sets values
    		 Completed Subjects
    Number of subjects
    14
    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
    1
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    46 ± 15
    Gender categorical
    Units: Subjects
        Female
    9
        Male
    5

    End points

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    End points reporting groups
    Reporting group title
    INDACATEROL
    Reporting group description
    		 Patients received 4 weeks of indacaterol (Onbrez Breezhaler) alone at a dose of 150μg OD as add-on to pre-existing ICS. There was a 2 week washout in between treatments while continuing to take the same dose of ICS. Including screening, there were 7 visits in total. Visits were performed, in the mornings, at baseline after run-in and washout, and at 24 hours (i.e. trough) after the first and last doses of each randomised treatment period. Patients were allowed short acting beta-2 agonists (SABAs) as a reliever during the study, but were asked to abstain from SABA use at least 6 hours before each visit. The visits were conducted in the mornings (8am-10am). Cross-over design – Participants received both IMPs (participated in both arms) during the course of the study

    Reporting group title
    TIOTROPIUM + INDACATEROL
    Reporting group description
    		 Patients received 4 weeks of indacaterol (Onbrez Breezhaler) at a dose of 150μg OD, combined with tiotropium (Spiriva Handihaler) 18μg OD as add-on to pre-existing ICS. There was a 2 week washout in between treatments while continuing to take the same dose of ICS. Including screening, there were 7 visits in total. Visits were performed, in the mornings, at baseline after run-in and washout, and at 24 hours (i.e. trough) after the first and last doses of each randomised treatment period. Patients were allowed short acting beta-2 agonists (SABAs) as a reliever during the study, but were asked to abstain from SABA use at least 6 hours before each visit. The visits were conducted in the mornings (8am-10am). 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: Non-smoking male or female patients, aged at least 18 years, with persistent asthma already receiving ICS or ICS/LABA. Minimum FEV1 of > 50% predicted, and mannitol responsive (i.e., provocative dose required to reduce FEV1 by 15% (PD15) <635 mg. Exclusion Criteria: History of respiratory tract infection or oral corticosteroid use in the last three months prior to screening.

    Primary: Mannitol PD15 (mg)

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    End point title
    		 Mannitol PD15 (mg)
    End point description
    single dose vs chronic dosing
    End point type
    Primary
    End point timeframe
    1 day to 28 days
    End point values
    		 INDACATEROL TIOTROPIUM + INDACATEROL
    Number of subjects analysed
    14
    14
    Units: mg
    arithmetic mean (confidence interval 95%)
        baseline
    390 (291 to 521)
    390 (291 to 521)
        single
    537 (438 to 619)
    487 (329 to 624)
        chronic
    455 (342 to 606)
    388 (255 to 593)
    Statistical analysis title
    		 per protocol
    Statistical analysis description
    The study was powered at 80% to detect a minimal important difference of one doubling dose in mannitol PD 15 (the primary outcome), as change from baseline, comparing indacaterol alone with indacaterol plus tiotropium, after single and chronic dosing, and a within-subject SD of 1.3 doubling dose, requiring a sample size of 14 using a crossover design, with alpha error of 0.05 (2 tailed). All data were first examined for normality and distribution. Repeated measures analysis of variance (ANO
    Comparison groups
    INDACATEROL v TIOTROPIUM + INDACATEROL
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval

    Secondary: FEV1 (L)

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    End point title
    		 FEV1 (L)
    End point description
    single (1 day) vs chronic (28 day) dosing
    End point type
    Secondary
    End point timeframe
    1 day - 28 days
    End point values
    		 INDACATEROL TIOTROPIUM + INDACATEROL
    Number of subjects analysed
    14
    14
    Units: litre(s)
    arithmetic mean (confidence interval 95%)
        baseline
    2.56 (2.18 to 2.95)
    2.56 (2.18 to 2.95)
        single
    2.69 (2.28 to 3.1)
    2.78 (2.38 to 3.19)
        chronic
    2.64 (2.26 to 3.02)
    2.71 (2.33 to 3.09)
    No statistical analyses for this end point

    Secondary: FEV1 Predicted (%)

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    End point title
    		 FEV1 Predicted (%)
    End point description
    single (1 day) vs chronic (28 day) dosing
    End point type
    Secondary
    End point timeframe
    1 day - 28 days
    End point values
    		 INDACATEROL TIOTROPIUM + INDACATEROL
    Number of subjects analysed
    14
    14
    Units: percent
    arithmetic mean (confidence interval 95%)
        baseline
    87 (78 to 97)
    87 (78 to 97)
        single
    91 (82 to 100)
    95 (85 to 105)
        chronic
    90 (81 to 100)
    93 (83 to 102)
    No statistical analyses for this end point

    Secondary: FEF25-75 (L)

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    End point title
    		 FEF25-75 (L)
    End point description
    single (1 day) vs chronic (28 day) dosing
    End point type
    Secondary
    End point timeframe
    1 day - 28 days
    End point values
    		 INDACATEROL TIOTROPIUM + INDACATEROL
    Number of subjects analysed
    14
    14
    Units: litre(s)
    arithmetic mean (confidence interval 95%)
        baseline
    1.79 (1.22 to 2.36)
    1.79 (1.22 to 2.36)
        single
    2.02 (1.93 to 2.65)
    2.22 (1.49 to 2.95)
        chronic
    1.91 (1.25 to 2.57)
    1.94 (1.38 to 2.49)
    No statistical analyses for this end point

    Secondary: R5 (kPA/l.s)

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    End point title
    		 R5 (kPA/l.s)
    End point description
    Single (1 day) vs chronic (28 days) dosing
    End point type
    Secondary
    End point timeframe
    1 day - 28 days
    End point values
    		 INDACATEROL TIOTROPIUM + INDACATEROL
    Number of subjects analysed
    14
    14
    Units: kPA/l.s
    arithmetic mean (confidence interval 95%)
        baseline
    0.54 (0.44 to 0.64)
    0.54 (0.44 to 0.64)
        single
    0.45 (0.37 to 0.52)
    0.39 (0.34 to 0.43)
        chronic
    0.44 (0.37 to 0.5)
    0.45 (0.39 to 0.5)
    No statistical analyses for this end point

    Secondary: R5-R20 (kPA/l.s)

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    End point title
    		 R5-R20 (kPA/l.s)
    End point description
    Single (1 day) vs chronic (28 days) dosing
    End point type
    Secondary
    End point timeframe
    1 - 28 days
    End point values
    		 INDACATEROL TIOTROPIUM + INDACATEROL
    Number of subjects analysed
    14
    14
    Units: kPa/l.s
    arithmetic mean (confidence interval 95%)
        baseline
    0.14 (0.07 to 0.22)
    0.14 (0.07 to 0.22)
        single
    0.07 (0.03 to 0.11)
    0.05 (0.03 to 0.07)
        chronic
    0.07 (0.04 to 0.1)
    0.08 (0.04 to 0.11)
    No statistical analyses for this end point

    Secondary: AX (kPa/l)

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    End point title
    		 AX (kPa/l)
    End point description
    Single (1 day) vs chronic (28 days) dosing
    End point type
    Secondary
    End point timeframe
    1- 28 days
    End point values
    		 INDACATEROL TIOTROPIUM + INDACATEROL
    Number of subjects analysed
    14
    14
    Units: kPa/l
    arithmetic mean (confidence interval 95%)
        baseline
    1.63 (0.58 to 2.68)
    1.63 (0.58 to 2.68)
        single
    0.76 (0.34 to 1.19)
    0.44 (0.25 to 0.63)
        chronic
    0.68 (0.43 to 0.92)
    0.78 (0.48 to 1.09)
    No statistical analyses for this end point

    Secondary: RDR (%/mg)

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    End point title
    		 RDR (%/mg)
    End point description
    Single (1 day) vs chronic (28 days) dosing
    End point type
    Secondary
    End point timeframe
    1- 28 days
    End point values
    		 INDACATEROL TIOTROPIUM + INDACATEROL
    Number of subjects analysed
    14
    14
    Units: %/mg
    arithmetic mean (confidence interval 95%)
        baseline
    0.037 (0.025 to 0.055)
    0.037 (0.025 to 0.055)
        single
    0.011 (0.005 to 0.026)
    0.015 (0.008 to 0.029)
        chronic
    0.037 (0.023 to 0.061)
    0.035 (0.018 to 0.07)
    No statistical analyses for this end point

    Secondary: FeNO (ppb)

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    End point title
    		 FeNO (ppb)
    End point description
    Single (1 day) vs chronic (28 days) dosing
    End point type
    Secondary
    End point timeframe
    1- 28 days
    End point values
    		 INDACATEROL TIOTROPIUM + INDACATEROL
    Number of subjects analysed
    14
    14
    Units: ppb
    arithmetic mean (confidence interval 95%)
        baseline
    30 (20 to 45)
    30 (20 to 45)
        single
    30 (20 to 44)
    32 (23 to 45)
        chronic
    30 (20 to 45)
    29 (19 to 44)
    No statistical analyses for this end point

    Secondary: Salbutamol Recovery (%.min)

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    End point title
    		 Salbutamol Recovery (%.min)
    End point description
    Single (1 day) vs chronic (28 days) dosing
    End point type
    Secondary
    End point timeframe
    1- 28 days
    End point values
    		 INDACATEROL TIOTROPIUM + INDACATEROL
    Number of subjects analysed
    14
    14
    Units: %/min
    arithmetic mean (confidence interval 95%)
        baseline
    47 (-79 to 172)
    47 (-79 to 172)
        single
    33 (-47 to 113)
    77 (19 to 136)
        chronic
    259 (196 to 322)
    239 (177 to 300)
    No statistical analyses for this end point

    Secondary: ACQ-7

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    End point title
    		 ACQ-7
    End point description
    Single (1 day) vs chronic (28 days) dosing
    End point type
    Secondary
    End point timeframe
    1- 28 days
    End point values
    		 INDACATEROL TIOTROPIUM + INDACATEROL
    Number of subjects analysed
    14
    14
    Units: units
    arithmetic mean (confidence interval 95%)
        baseline
    0.72 (0.48 to 0.95)
    0.72 (0.48 to 0.95)
        chronic
    0.44 (0.24 to 0.63)
    0.5 (0.27 to 0.73)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs 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 CRF.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    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 / 14 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Completed Subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 14 (78.57%)
    Investigations
    Delayed Recovery following Mannitol Challenge
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Surgical and medical procedures
    Root Canal
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    4
    Feeling Shaky
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Hangover
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Elevated INR
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    Diarrhoea
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    Vomiting
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    Abdominal pain
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Rhinovirus infection
         subjects affected / exposed
    4 / 14 (28.57%)
         occurrences all number
    5
    Pharyngitis
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    5
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Chest pain
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    3
    Cough
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    Rhinitis
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Foot Cramps
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    3
    Hand Cramps
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Painful Finger Joint
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Jaw Pain
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Toothache
         subjects affected / exposed
    1 / 14 (7.14%)
         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
    09 Jan 2014
    REC Amendment (AM01) Amendment to notify REC of changes made in response to MHRA’s grounds for non-acceptance and right to amend request during initial application process.
    19 Mar 2015
    REC Amendment (AM02) Amendment for use of additional sources for patient recruitment.
    20 Oct 2015
    REC Amendment (AM03) Amendment for prospective approval of patient diaries and emergency contact card

    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/28665534
    For support, Contact us.
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