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    Clinical Trial Results:
    INvestigating COPD Outcomes, Genomics and Neutrophilic Inflammation with Tiotropium and Olodaterol (INCOGNITO trial)

    Summary
    EudraCT number
    		 2016-004473-41
    Trial protocol
    		 GB  
    Global end of trial date
    26 Nov 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Jul 2022
    First version publication date
    12 Jul 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    2016RC22
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03152149
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Dundee
    Sponsor organisation address
    University of Dundee, Mailbox 12, Ninewells Hospital, Dundee, United Kingdom, DD1 9SY
    Public contact
    Chalmers, University of Dundee, 0044 01382 383642, jchalmers@dundee.ac.uk
    Scientific contact
    Chalmers, University of Dundee, 7435254338 01382 383642, jchalmers@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
    03 Dec 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Nov 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the effects of the Tiotropium and olodaterol combination (Spiolto respimat 2.5/2.5ug) 2 puffs once daily vs Relvar Ellipta (fluticasone furoate 92 micrograms, vilaterol 22 micrograms) 1 puff once daily on airway bacterial load (the numbers of bacteria found) from induced sputum
    Protection of trial subjects
    Patients were excluded if they were unable to give informed consent, had a known allergy, intolerance or contraindication to any of the study drugs, or had any unstable co-morbidities (cardiovascular disease, active malignancy) which in the opinion of the investigator would make the patient unsuitable to be enrolled in the study
    Background therapy
    		 Participants were permitted to continue all other medications during the trial that would not be expected to interfere with the upper airway microbiota (i.e., short acting beta2-adrenoceptor agonists, theophylline and carbocisteine)
    Evidence for comparator
    		 We hypothesised that the combination of tiotropium and olodaterol may be an ideal treatment option for patients with neutrophilic COPD because - Tiotropium and olodaterol have both been shown to have potentially beneficial effects in suppressing neutrophilic inflammation without impairing bacterial killing - These effects may reverse the detrimental impact of inhaled corticosteroids on airway neutrophil function and the microbiome. In particular olodaterol was evaluated in cigarette smoke- and Lipolpolysaccharide - induced- models of neutrophil lung inflammation in mice and guinea pigs. The results showed Olodaterol to suppress neutrophil recruitment to the lung (by up to 90%) while preserving chemotactic function (which is required for effective phagocytosis of pathogens)(1). Tiotropium has also been extensively investigated and is known to suppress neutrophil recruitment and neutrophil dependent remodelling in a number of in-vivo models and may work synergistically with olodaterol in reducing neutrophil retention in the lung.(2-4) This extensive preclinical work justified a study of olodaterol/tiotropium in human subjects evaluating its impact on neutrophilic inflammation. 1. Wex E, Kollak I, Duechs MJ et al. The long-acting B2-adrenoceptor agonist olodaterol attenuates pulmonary inflammation. Br J Pharmacol 2015;172(14):3537-47. 2. Profita M, Bonanno A, Montalbano AM et al. B2-long acting and anticholinergic drugs control TGF-B1-mediated neutrophilic inflammation in COPD. Biochim Biophys Acta2012;1822(7):1079-89. 3. Arai N, Kondo M, Izumo T et al. Inihibitoon of neutrophil elastase-induced goblet cell metaplasia by tiotropium in mice. Eur Respir J 2010;35(5):1164-71. 4. Pera T, Zuidhof A, Valadas J et al. Tiotropium inhibits pulmonary inflammation and remodelling in a guinea pig model of COPD. Eur Respir J 2011;38(4):789-96.
    Actual start date of recruitment
    03 Apr 2017
    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: 80
    Worldwide total number of subjects
    80
    EEA total number of subjects
    0
    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)
    23
    From 65 to 84 years
    55
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited at 4 NHS sites in the UK (Dundee, Glasgow, North Tyneside and Nottingham) between July 2017 until November 2019.

    Pre-assignment
    Screening details
    		 133 participants were screened and 80 participants were randomized. There were 53 screen failures for: Asthma: 2 Antibiotics in the last 28 days: 4 Less than 10 year pack history: 1 No clinical diagnosis of COPD: 1 FEV1/FVC ratio >0.7: 7 FEV1 >80% predicted: 17 No ICS treatment for at least 12 months: 2 Blood eosinophil

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tiotropium olodaterol
    Arm description
    		 Tiotropium 2.5 micrograms and olodaterol 2.5 micrograms 2 puffs once daily soft mist inhaler.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tiotropium olodaterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation vapour
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium 2.5 micrograms and olodaterol 2.5 micrograms 2 puffs once daily soft mist inhaler.

    Arm title
    		 Fluticasone furoate vilanterol
    Arm description
    		 fluticasone furoate 92 micrograms, vilanterol 22 micrograms 1 puff once daily
    Arm type
    		 Active comparator

    Investigational medicinal product name
    fluticasone furoate vilanterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    fluticasone furoate 92 micrograms, vilanterol 22 micrograms 1 puff once daily

    Number of subjects in period 1
    		Tiotropium olodaterol Fluticasone furoate vilanterol
    Started
    38
    42
    Completed
    33
    34
    Not completed
    5
    8
         Consent withdrawn by subject
    3
    5
         Physician decision
    1
    1
         Adverse event, non-fatal
    1
    1
         Lost to follow-up
    -
    1

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 80 80
    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)
    		 23 23
        From 65-84 years
    		 55 55
        85 years and over
    		 2 2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69.3 ( 8.0 ) -
    Gender categorical
    Units: Subjects
        Female
    		 39 39
        Male
    		 41 41
    Smoking status
    Smoking status at enrolment
    Units: Subjects
        Current smoker
    		 26 26
        Ex-smoker
    		 54 54
    Blood eosinophil count at baseline
    Blood eosinophil count at baseline (cells/mL)
    Units: Subjects
        <150
    		 35 35
        150-299
    		 45 45
    Medication history
    Medication history at enrolment
    Units: Subjects
        ICS/LABA
    		 9 9
        ICS/LABA/LAMA
    		 67 67
        ICS/LAMA
    		 4 4
    Pack-years
    Smoking pack years
    Units: Years
        arithmetic mean (standard deviation)
    		 47.3 ( 24.3 ) -
    BMI
    Body mass index
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 29.4 ( 8.2 ) -
    CAT Score
    Chronic Obstructive Pulmonary Disease Assessment Test Score
    Units: NA
        arithmetic mean (standard deviation)
    		 20.6 ( 8.2 ) -
    Pre-bronchodilator FEV1 (L)
    Units: litre(s)
        arithmetic mean (standard deviation)
    		 1.3 ( 0.5 ) -
    Pre-bronchodilator FEV1 (%)
    Units: percent
        arithmetic mean (standard deviation)
    		 51.5 ( 16.1 ) -
    Pre-bronchodilator FVC (L)
    Units: litre(s)
        arithmetic mean (standard deviation)
    		 2.8 ( 0.8 ) -
    Pre-bronchodilator FVC (%)
    Units: percent
        arithmetic mean (standard deviation)
    		 89.6 ( 18.3 ) -
    FEV1/FVC ratio
    Units: NA
        arithmetic mean (standard deviation)
    		 46.5 ( 12.8 ) -
    Post-bronchodilator FEV1 (L)
    Units: litre(s)
        arithmetic mean (standard deviation)
    		 1.3 ( 0.5 ) -
    Post-bronchodilator FEV1 (%)
    Units: percent
        arithmetic mean (standard deviation)
    		 54.0 ( 15.8 ) -
    Post-bronchodilator FVC (L)
    Units: litre(s)
        arithmetic mean (standard deviation)
    		 2.8 ( 0.8 ) -
    Post-bronchodilator FVC (%)
    Units: percent
        arithmetic mean (standard deviation)
    		 91.1 ( 19.3 ) -
    Post-bronchodilator FEV1/FVC ratio
    Units: NA
        arithmetic mean (standard deviation)
    		 47.4 ( 12.5 ) -
    Oxygen saturations at rest
    Units: percent
        arithmetic mean (standard deviation)
    		 95.4 ( 2.3 ) -
    Subject analysis sets

    Subject analysis set title
    Arm 1 T/O
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Arm 1 - Tiotropium and Olodaterol

    Subject analysis set title
    Arm 2 FF/VI
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Arm 2 - fluticasone furoate/vilanterol

    Subject analysis sets values
    		 Arm 1 T/O Arm 2 FF/VI
    Number of subjects
    38
    42
    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)
    12
    11
        From 65-84 years
    25
    30
        85 years and over
    1
    1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    69.4 ( 8.1 )
    69.3 ( 8.0 )
    Gender categorical
    Units: Subjects
        Female
    20
    19
        Male
    18
    23
    Smoking status
    Smoking status at enrolment
    Units: Subjects
        Current smoker
    12
    14
        Ex-smoker
    26
    28
    Blood eosinophil count at baseline
    Blood eosinophil count at baseline (cells/mL)
    Units: Subjects
        <150
    18
    17
        150-299
    20
    25
    Medication history
    Medication history at enrolment
    Units: Subjects
        ICS/LABA
    3
    6
        ICS/LABA/LAMA
    34
    33
        ICS/LAMA
    1
    3
    Pack-years
    Smoking pack years
    Units: Years
        arithmetic mean (standard deviation)
    48.1 ( 24.3 )
    47.3 ( 24.4 )
    BMI
    Body mass index
    Units: kg/m^2
        arithmetic mean (standard deviation)
    29.5 ( 8.3 )
    29.5 ( 8.2 )
    CAT Score
    Chronic Obstructive Pulmonary Disease Assessment Test Score
    Units: NA
        arithmetic mean (standard deviation)
    20.7 ( 8.3 )
    20.6 ( 8.3 )
    Pre-bronchodilator FEV1 (L)
    Units: litre(s)
        arithmetic mean (standard deviation)
    1.3 ( 0.5 )
    1.3 ( 0.5 )
    Pre-bronchodilator FEV1 (%)
    Units: percent
        arithmetic mean (standard deviation)
    51.6 ( 16.4 )
    51.4 ( 16.1 )
    Pre-bronchodilator FVC (L)
    Units: litre(s)
        arithmetic mean (standard deviation)
    2.8 ( 0.7 )
    2.8 ( 0.8 )
    Pre-bronchodilator FVC (%)
    Units: percent
        arithmetic mean (standard deviation)
    89.7 ( 18.6 )
    89.4 ( 18.3 )
    FEV1/FVC ratio
    Units: NA
        arithmetic mean (standard deviation)
    46.6 ( 13.0 )
    46.4 ( 12.8 )
    Post-bronchodilator FEV1 (L)
    Units: litre(s)
        arithmetic mean (standard deviation)
    1.3 ( 0.5 )
    1.3 ( 0.5 )
    Post-bronchodilator FEV1 (%)
    Units: percent
        arithmetic mean (standard deviation)
    54.0 ( 16.1 )
    53.7 ( 17.8 )
    Post-bronchodilator FVC (L)
    Units: litre(s)
        arithmetic mean (standard deviation)
    2.9 ( 0.8 )
    2.8 ( 0.8 )
    Post-bronchodilator FVC (%)
    Units: percent
        arithmetic mean (standard deviation)
    91.1 ( 19.2 )
    90.8 ( 19.2 )
    Post-bronchodilator FEV1/FVC ratio
    Units: NA
        arithmetic mean (standard deviation)
    47.4 ( 12.\6 )
    47.3 ( 12.5 )
    Oxygen saturations at rest
    Units: percent
        arithmetic mean (standard deviation)
    95.4 ( 2.3 )
    95.4 ( 2.3 )

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Tiotropium olodaterol
    Reporting group description
    		 Tiotropium 2.5 micrograms and olodaterol 2.5 micrograms 2 puffs once daily soft mist inhaler.

    Reporting group title
    Fluticasone furoate vilanterol
    Reporting group description
    		 fluticasone furoate 92 micrograms, vilanterol 22 micrograms 1 puff once daily

    Subject analysis set title
    Arm 1 T/O
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Arm 1 - Tiotropium and Olodaterol

    Subject analysis set title
    Arm 2 FF/VI
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Arm 2 - fluticasone furoate/vilanterol

    Primary: Difference in sputum bacterial load between the T/O group and the FF/VI group

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    End point title
    		 Difference in sputum bacterial load between the T/O group and the FF/VI group
    End point description
    To determine the effects of the Tiotropium and olodaterol combination (Spiolto respimat 2.5/2.5ug) 2 puffs once daily vs Relvar Ellipta (fluticasone furoate 92 micrograms, vilanterol 22 micrograms) 1 puff once daily on airway bacterial load in sputum
    End point type
    Primary
    End point timeframe
    Treatment period, visit 3 to visit 6
    End point values
    		 Tiotropium olodaterol Fluticasone furoate vilanterol Arm 1 T/O Arm 2 FF/VI
    Number of subjects analysed
    38
    42
    38
    42
    Units: CFUs
        arithmetic mean (confidence interval 95%)
    10.5 (10.3 to 10.7)
    10.6 (10.4 to 10.8)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 mean difference
    Comparison groups
    Arm 1 T/O v Arm 2 FF/VI
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.99
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.25
         upper limit
    		 0.25
    Variability estimate
    Standard error of the mean

    Secondary: Sputum bacterial community composition as measured by the Shannon Weiner Diversity Index

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    End point title
    		 Sputum bacterial community composition as measured by the Shannon Weiner Diversity Index
    End point description
    To determine the effects of the Tiotropium and olodaterol combination (Spiolto respimat 2.52.5ug) 2 puffs once daily vs Relvar Ellipta (fluticasone furoate 92 micrograms, vilanterol 22 micrograms) 1 puff once daily on the airway sputum microbiota.
    End point type
    Secondary
    End point timeframe
    Treatment period, visit 3 to visit 6
    End point values
    		 Tiotropium olodaterol Fluticasone furoate vilanterol Arm 1 T/O Arm 2 FF/VI
    Number of subjects analysed
    38
    42
    38
    42
    Units: NA
        arithmetic mean (confidence interval 95%)
    1.51 (1.37 to 1.66)
    1.61 (1.44 to 1.79)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 mean difference
    Comparison groups
    Arm 1 T/O v Arm 2 FF/VI
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.04
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 0.54
    Variability estimate
    Standard error of the mean

    Secondary: Oropharyngeal bacterial community composition as measured by the Shannon Weiner Diversity Index

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    End point title
    		 Oropharyngeal bacterial community composition as measured by the Shannon Weiner Diversity Index
    End point description
    To determine the effects of the Tiotropium and olodaterol combination (Spiolto respimat 2.52.5ug) 2 puffs once daily vs Relvar Ellipta (fluticasone furoate 92 micrograms, vilanterol 22 micrograms) 1 puff once daily on the airway oropharyngeal microbiota.
    End point type
    Secondary
    End point timeframe
    Treatment period, visit 3 to visit 6
    End point values
    		 Tiotropium olodaterol Fluticasone furoate vilanterol Arm 1 T/O Arm 2 FF/VI
    Number of subjects analysed
    38
    42
    38
    42
    Units: NA
        arithmetic mean (confidence interval 95%)
    1.44 (1.25 to 1.63)
    1.72 (1.59 to 1.85)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 mean difference
    Comparison groups
    Arm 2 FF/VI v Arm 1 T/O
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.026
         upper limit
    		 0.37
    Variability estimate
    Standard error of the mean

    Secondary: Nasopharyngeal bacterial community composition as measured by the Shannon Weiner Diversity Index

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    End point title
    		 Nasopharyngeal bacterial community composition as measured by the Shannon Weiner Diversity Index
    End point description
    To determine the effects of the Tiotropium and olodaterol combination (Spiolto respimat 2.52.5ug) 2 puffs once daily vs Relvar Ellipta (fluticasone furoate 92 micrograms, vilanterol 22 micrograms) 1 puff once daily on the airway nasopharyngeal microbiota by Shannon Weiner Diversity Index
    End point type
    Secondary
    End point timeframe
    Treatment period, visit 3 to 6
    End point values
    		 Tiotropium olodaterol Fluticasone furoate vilanterol Arm 1 T/O Arm 2 FF/VI
    Number of subjects analysed
    38
    42
    38
    42
    Units: NA
        arithmetic mean (confidence interval 95%)
    1.23 (1.08 to 1.38)
    1.09 (0.92 to 1.26)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 mean difference
    Comparison groups
    Arm 1 T/O v Arm 2 FF/VI
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.44
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.25
         upper limit
    		 0.11
    Variability estimate
    Standard error of the mean

    Secondary: Difference in oropharngeal bacterial load between the T/O group and the FF/VI group

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    End point title
    		 Difference in oropharngeal bacterial load between the T/O group and the FF/VI group
    End point description
    To determine the effects of the Tiotropium and olodaterol combination (Spiolto respimat 2.5/2.5ug) 2 puffs once daily vs Relvar Ellipta (fluticasone furoate 92 micrograms, vilanterol 22 micrograms) 1 puff once daily on airway bacterial load in oropharyngeal samples
    End point type
    Secondary
    End point timeframe
    Treatment period, visit 3 to 6
    End point values
    		 Tiotropium olodaterol Fluticasone furoate vilanterol Arm 1 T/O Arm 2 FF/VI
    Number of subjects analysed
    38
    42
    38
    42
    Units: CFUs
        arithmetic mean (confidence interval 95%)
    8.55 (8.13 to 8.97)
    8.98 (8.65 to 9.30)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 mean difference
    Comparison groups
    Arm 1 T/O v Arm 2 FF/VI
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.09
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.68
    Variability estimate
    Standard error of the mean

    Secondary: Difference in nasopharyngeal bacterial load between the T/O group and the FF/VI group

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    End point title
    		 Difference in nasopharyngeal bacterial load between the T/O group and the FF/VI group
    End point description
    To determine the effects of the Tiotropium and olodaterol combination (Spiolto respimat 2.5/2.5ug) 2 puffs once daily vs Relvar Ellipta (fluticasone furoate 92 micrograms, vilanterol 22 micrograms) 1 puff once daily on airway bacterial load in nasopharyngeal samples
    End point type
    Secondary
    End point timeframe
    Treatment period, visit 3 to 6
    End point values
    		 Tiotropium olodaterol Fluticasone furoate vilanterol Arm 1 T/O Arm 2 FF/VI
    Number of subjects analysed
    38
    42
    38
    42
    Units: CFUs
        arithmetic mean (confidence interval 95%)
    0 (0 to 0)
    0.131 (-0.185 to 0.447)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 mean difference
    Comparison groups
    Arm 2 FF/VI v Arm 1 T/O
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.41
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.19
         upper limit
    		 0.45
    Variability estimate
    Standard error of the mean

    Secondary: Sputum bacterial community composition as measured by difference in Haemophilus OTUs

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    End point title
    		 Sputum bacterial community composition as measured by difference in Haemophilus OTUs
    End point description
    End point type
    Secondary
    End point timeframe
    To determine the effects of the T/O combination (Spiolto respimat 2.52.5ug) 2 puffs once daily vs Relvar Ellipta (FF 92 micrograms, VI 22 micrograms) 1 puff once daily on the airway sputum microbiota in difference in Haemophilus OTUs
    End point values
    		 Tiotropium olodaterol Fluticasone furoate vilanterol Arm 1 T/O Arm 2 FF/VI
    Number of subjects analysed
    38
    42
    38
    42
    Units: OTUs
        arithmetic mean (confidence interval 95%)
    0.04 (0.001 to 0.08)
    0.05 (0.01 to 0.10)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 mean difference
    Comparison groups
    Arm 1 T/O v Arm 2 FF/VI
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.21
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.09
         upper limit
    		 0.21
    Variability estimate
    Standard error of the mean

    Secondary: Oropharyngeal bacterial community composition as measured by difference in Haemophilus OTUs

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    End point title
    		 Oropharyngeal bacterial community composition as measured by difference in Haemophilus OTUs
    End point description
    To determine the effects of FF/VI compared to T/O on relative abundance of Haemophilus OTUs in oropharyngeal samples
    End point type
    Secondary
    End point timeframe
    Treatment period, visit 3 to 6
    End point values
    		 Tiotropium olodaterol Fluticasone furoate vilanterol Arm 1 T/O Arm 2 FF/VI
    Number of subjects analysed
    38
    42
    38
    42
    Units: OTUs
        arithmetic mean (confidence interval 95%)
    0.002 (0 to 0.004)
    0.0006 (0.0002 to 0.009)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 mean difference
    Comparison groups
    Arm 1 T/O v Arm 2 FF/VI
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.035
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.011
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.001
         upper limit
    		 0.022
    Variability estimate
    Standard error of the mean

    Secondary: Nasopharyngeal bacterial community composition as measured by difference in Haemophilus OTUs

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    End point title
    		 Nasopharyngeal bacterial community composition as measured by difference in Haemophilus OTUs
    End point description
    End point type
    Secondary
    End point timeframe
    To determine the effects of FF/VI compared to T/O treatment on the relative abundance of Haemophilus OTUs in nasopharyngeal samples
    End point values
    		 Tiotropium olodaterol Fluticasone furoate vilanterol Arm 1 T/O Arm 2 FF/VI
    Number of subjects analysed
    38
    42
    38
    42
    Units: OTUs
        arithmetic mean (confidence interval 95%)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 mean difference
    Comparison groups
    Arm 1 T/O v Arm 2 FF/VI
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.52
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.0002
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0003
         upper limit
    		 0.0007
    Variability estimate
    Standard error of the mean

    Secondary: Sputum bacterial community composition as measured by difference in Streptococcus OTUs

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    End point title
    		 Sputum bacterial community composition as measured by difference in Streptococcus OTUs
    End point description
    To determine the effect of FF/VI compared to T/O on the relative abundance of Streptococcus OTUs
    End point type
    Secondary
    End point timeframe
    Treatment period, visit 3 to 6
    End point values
    		 Tiotropium olodaterol Fluticasone furoate vilanterol Arm 1 T/O Arm 2 FF/VI
    Number of subjects analysed
    38
    42
    38
    42
    Units: OTUs
        arithmetic mean (confidence interval 95%)
    0.55 (0.50 to 0.59)
    0.52 (0.47 to 0.57)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 mean difference
    Comparison groups
    Arm 1 T/O v Arm 2 FF/VI
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≥ 0.01
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 -0.02
    Variability estimate
    Standard error of the mean

    Secondary: Oropharyngeal bacterial community composition as measured by difference in Streptococcus OTUs

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    End point title
    		 Oropharyngeal bacterial community composition as measured by difference in Streptococcus OTUs
    End point description
    To determine the effect of FF/VI compared to T/O on the relative abundance of Streptococcus OTUs
    End point type
    Secondary
    End point timeframe
    Treatment period, visit 3 to 6
    End point values
    		 Tiotropium olodaterol Fluticasone furoate vilanterol Arm 1 T/O Arm 2 FF/VI
    Number of subjects analysed
    38
    42
    38
    42
    Units: OTUs
        arithmetic mean (confidence interval 95%)
    0.56 (0.49 to 0.62)
    0.46 (0.41 to 0.51)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 mean difference
    Comparison groups
    Arm 1 T/O v Arm 2 FF/VI
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.055
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.12
         upper limit
    		 0.01
    Variability estimate
    Standard error of the mean

    Secondary: Nasopharyngeal bacterial community composition as measured by difference in Streptococcus OTUs

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    End point title
    		 Nasopharyngeal bacterial community composition as measured by difference in Streptococcus OTUs
    End point description
    To determine the effect of FF/VI compared to T/O on the relative abundance of Streptococcus OTUs
    End point type
    Secondary
    End point timeframe
    Treatment period, visit 3 to visit 6
    End point values
    		 Tiotropium olodaterol Fluticasone furoate vilanterol Arm 1 T/O Arm 2 FF/VI
    Number of subjects analysed
    38
    42
    38
    42
    Units: OTUs
        arithmetic mean (confidence interval 95%)
    0.09 (0.03 to 0.16)
    0.05 (0.004 to 0.10)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 mean difference
    Comparison groups
    Arm 1 T/O v Arm 2 FF/VI
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.03
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 -0.003
    Variability estimate
    Standard error of the mean

    Secondary: Difference in sputum neutrophil elastase activity

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    End point title
    		 Difference in sputum neutrophil elastase activity
    End point description
    To determine the effect of FF/VI compared to T/O on sputum neutrophil elastase activity
    End point type
    Secondary
    End point timeframe
    Treatment period, visit 3 to 6
    End point values
    		 Tiotropium olodaterol Fluticasone furoate vilanterol Arm 1 T/O Arm 2 FF/VI
    Number of subjects analysed
    38
    42
    38
    42
    Units: ng/ml
        arithmetic mean (confidence interval 95%)
    230.9 (142.9 to 318.9)
    361.4 (171.8 to 550.9)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 mean difference
    Comparison groups
    Arm 1 T/O v Arm 2 FF/VI
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    6.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -148.8
         upper limit
    		 161.8
    Variability estimate
    Standard error of the mean

    Secondary: Difference in sputum neutrophil extracellular trap formation

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    End point title
    		 Difference in sputum neutrophil extracellular trap formation
    End point description
    To determine the effect of FF/VI compared to T/O on sputum neutrophil extracellular trap formation
    End point type
    Secondary
    End point timeframe
    Treatment period, visit 3 to 6
    End point values
    		 Tiotropium olodaterol Fluticasone furoate vilanterol Arm 1 T/O Arm 2 FF/VI
    Number of subjects analysed
    38
    42
    38
    42
    Units: units/ml
        arithmetic mean (confidence interval 95%)
    12.7 (4.7 to 20.7)
    9.1 (5.5 to 12.7)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 mean difference
    Comparison groups
    Arm 1 T/O v Arm 2 FF/VI
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.52
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.4
         upper limit
    		 3.2
    Variability estimate
    Standard error of the mean

    Secondary: Difference in sputum resistin

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    End point title
    		 Difference in sputum resistin
    End point description
    To determine the effect of FF/VI compared to T/O on sputum resistin
    End point type
    Secondary
    End point timeframe
    Treatment period, visit 3 to 6
    End point values
    		 Tiotropium olodaterol Fluticasone furoate vilanterol Arm 1 T/O Arm 2 FF/VI
    Number of subjects analysed
    38
    42
    38
    42
    Units: ng/ml
        arithmetic mean (confidence interval 95%)
    174 (46 to 302)
    118 (31 to 204)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 mean difference
    Comparison groups
    Arm 1 T/O v Arm 2 FF/VI
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.97
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.4
         upper limit
    		 3.2
    Variability estimate
    Standard error of the mean

    Secondary: Difference in sputum IL1-beta

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    End point title
    		 Difference in sputum IL1-beta
    End point description
    To determine the effect of FF/VI compared to T/O on sputum IL1-beta
    End point type
    Secondary
    End point timeframe
    Treatment period, visit 3 to 6
    End point values
    		 Tiotropium olodaterol Fluticasone furoate vilanterol Arm 1 T/O Arm 2 FF/VI
    Number of subjects analysed
    38
    42
    38
    42
    Units: pg/mL
        arithmetic mean (confidence interval 95%)
    251 (-11.6 to 513)
    178 (-48.6 to 403)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 mean difference
    Comparison groups
    Arm 1 T/O v Arm 2 FF/VI
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.53
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -45.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -190
         upper limit
    		 98.9
    Variability estimate
    Standard error of the mean

    Secondary: Difference in sputum IL-13

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    End point title
    		 Difference in sputum IL-13
    End point description
    To determine the effect of FF/VI compared to T/O on sputum IL-13
    End point type
    Secondary
    End point timeframe
    Treatment period, visit 3 to 6
    End point values
    		 Tiotropium olodaterol Fluticasone furoate vilanterol Arm 1 T/O Arm 2 FF/VI
    Number of subjects analysed
    38
    42
    38
    42
    Units: pg/ml
        arithmetic mean (confidence interval 95%)
    0 (0 to 0)
    -0.98 (-2.62 to 0.67)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 mean difference
    Comparison groups
    Arm 1 T/O v Arm 2 FF/VI
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.24
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.6
         upper limit
    		 0.67
    Variability estimate
    Standard error of the mean

    Secondary: Difference in sputum IL-17A

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    End point title
    		 Difference in sputum IL-17A
    End point description
    To determine the effect of FF/VI compared to T/O on sputum IL-17A
    End point type
    Secondary
    End point timeframe
    Treatment period, visit 3 to 6
    End point values
    		 Tiotropium olodaterol Fluticasone furoate vilanterol Arm 1 T/O Arm 2 FF/VI
    Number of subjects analysed
    38
    42
    38
    42
    Units: pg/ml
        arithmetic mean (confidence interval 95%)
    1.58 (0.38 to 2.79)
    1.94 (0.58 to 3.31)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 mean difference
    Comparison groups
    Arm 1 T/O v Arm 2 FF/VI
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.98
         upper limit
    		 0.48
    Variability estimate
    Standard error of the mean

    Secondary: Difference in sputum CXCL-8

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    End point title
    		 Difference in sputum CXCL-8
    End point description
    To determine the effect of FF/VI compared to T/O on sputum CXCL-8
    End point type
    Secondary
    End point timeframe
    Treatment period, visit 3 to 6
    End point values
    		 Tiotropium olodaterol Fluticasone furoate vilanterol Arm 1 T/O Arm 2 FF/VI
    Number of subjects analysed
    38
    42
    38
    42
    Units: ng/ml
        arithmetic mean (confidence interval 95%)
    0 (0 to 0)
    -3.16 (-7.25 to 0.94)
    0 (0 to 0)
    0 (0 to 0)
    Statistical analysis title
    		 mean difference
    Comparison groups
    Arm 1 T/O v Arm 2 FF/VI
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.13
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.3
         upper limit
    		 0.94
    Variability estimate
    Standard error of the mean

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded from screening to end of study, from July 2017 until November 2019
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24
    Reporting groups
    Reporting group title
    Tiotropium/Olodaterol
    Reporting group description
    		 -

    Reporting group title
    Fluticasone furoate/Vilaterol
    Reporting group description
    		 -

    Serious adverse events
    		 Tiotropium/Olodaterol Fluticasone furoate/Vilaterol
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 38 (15.79%)
    1 / 42 (2.38%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Tiotropium/Olodaterol Fluticasone furoate/Vilaterol
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 38 (73.68%)
    22 / 42 (52.38%)
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    4 / 38 (10.53%)
    0 / 42 (0.00%)
         occurrences all number
    5
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 38 (18.42%)
    1 / 42 (2.38%)
         occurrences all number
    7
    1
    Dyspnoea
         subjects affected / exposed
    16 / 38 (42.11%)
    11 / 42 (26.19%)
         occurrences all number
    19
    11
    Epistaxis
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    3
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 38 (0.00%)
    4 / 42 (9.52%)
         occurrences all number
    0
    5
    Oropharyngeal pain
         subjects affected / exposed
    1 / 38 (2.63%)
    3 / 42 (7.14%)
         occurrences all number
    1
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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