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    Clinical Trial Results:
    Randomized, double-blind, double-dummy, active-controlled, 4 period complete cross-over study to compare the effect on lung function of 6 weeks once daily treatment with orally inhaled Tiotropium+Olodaterol fixed dose combination delivered by the Respimat® inhaler vs. 6 weeks twice daily treatment with Fluticasone Propionate+Salmeterol fixed dose combination delivered by the Accuhaler® in patients with Chronic Obstructive Pulmonary Disease (COPD). [ENERGITO™]

    Summary
    EudraCT number
    		 2013-000808-41
    Trial protocol
    		 ES   NL   CZ   BE   DK   SE   HU   DE  
    Global end of trial date
    04 Feb 2015

    Results information
    Results version number
    		 v2(current)
    This version publication date
    16 Sep 2016
    First version publication date
    01 Jul 2016
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    One value for endpoint "FEV1 AUC (12−24h) Change from Patient Baseline after 6 Weeks of Treatment" needs correction

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1237.11
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01969721
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    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
    20 Mar 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Jan 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Feb 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of the trial is to compare the lung function profile of once daily treatment with Tiotropium+Olodaterol (Tio+Olo) Fixed Dose Combination (FDC) [2.5/5μg and 5/5μg] delivered by the Respimat® with the lung function profile of twice daily treatment with Fluticasone propionate+Salmeterol (F+S) FDC [250/50μg and 500/50μg] delivered by the Accuhaler® after 6 weeks of treatment in patients with COPD.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all patients as required.
    Background therapy
    		 -
    Evidence for comparator
    		 Placebo matching Tiotropium + Olodaterol inhalation solution via Respimat® inhaler inhaled orally. Fluticasone+Salmeterol FDC (inhalation powder) via Accuhaler® inhaled orally as 250 μg/50 μg or 500 μg/50 μg per inhalation, twice daily. Placebo matching Fluticasone+Salmeterol inhalation powder via Accuhaler® inhaled orally.
    Actual start date of recruitment
    29 Oct 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
    Belgium: 16
    Country: Number of subjects enrolled
    Czech Republic: 39
    Country: Number of subjects enrolled
    Germany: 54
    Country: Number of subjects enrolled
    Denmark: 23
    Country: Number of subjects enrolled
    Spain: 23
    Country: Number of subjects enrolled
    Hungary: 36
    Country: Number of subjects enrolled
    Netherlands: 78
    Country: Number of subjects enrolled
    Sweden: 19
    Worldwide total number of subjects
    288
    EEA total number of subjects
    288
    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)
    159
    From 65 to 84 years
    129
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 This was a randomized, double-blind, double-dummy, active-controlled, 4-treatment, 4-period, complete cross-over design. The treatments were A: T+O 2.5/5; B: T+O 5/5; C: F+S 250/50; D: F+S 500/50. ABCD, BDAC, CADB, and DCBA were four treatment sequences.

    Pre-assignment
    Screening details
    		 All subjects were screened for eligibility to participate in trial. Subjects attended specialist sites to ensure that they met all implemented inclusion/exclusion criteria. Subjects were not randomised to trial drug if any of the specific entry criteria was violated. In this study, 288 subjects were enrolled.

    Period 1
    Period 1 title
    Overall trial by sequence
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 T+O 2.5/5 / T+O 5/5 / F+S 250/50 / F+S 500/50
    Arm description
    		 Tiotropium+Olodaterol (T+O) FDC (2.5 μg/5 μg) inhalation solution via Respimat® inhaler once daily in the morning and placebo Diskus® matching Fluticasone propionate+Salmeterol (F+S) FDC inhalation powder via Accuhaler® twice daily in period 1, followed with T+O FDC (5 μg/5 μg) inhalation solution via Respimat® inhaler once daily in the morning and placebo Diskus® matching F+S FDC inhalation powder via Accuhaler® twice daily in period 2, followed with F+S FDC (250 μg/50 μg) inhalation powder via Accuhaler® twice daily and placebo matching T+O FDC inhalation solution via Respimat® inhaler once daily in the morning in period 3, then followed with F+S FDC (500 μg/50 μg) inhalation powder via Accuhaler® twice daily and placebo matching T+O FDC inhalation solution via Respimat® inhaler once daily in the morning in period 4. Each treatment period was 6 weeks (wks) and washing-out period 3 wks. Treatment sequence was 33 wks including 4 treatment periods and 3 washing-out periods.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Tiotropium 2.5 μg / Olodaterol 5 μg_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium+Olodaterol (2.5/5 μg) FDC inhalation solution was administered via the Respimat® inhaler once daily.

    Investigational medicinal product name
    Tiotropium 5 μg / Olodaterol 5 μg_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium+Olodaterol (5/5 μg) FDC inhalation solution was administered via the Respimat® inhaler once daily.

    Investigational medicinal product name
    Fluticasone propionate 250 μg / Salmeterol 50 μg_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone propionate+Salmeterol (250/50 μg) FDC inhalation powder was inhaled orally twice daily via Accuhaler® in accordance with predefined treatment administration times.

    Investigational medicinal product name
    Fluticasone propionate 500 μg / Salmeterol 50 μg_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone propionate+Salmeterol (500/50 μg) FDC inhalation powder was inhaled orally twice daily via Accuhaler® in accordance with predefined treatment administration times.

    Investigational medicinal product name
    Placebo matching Tiotropium / Oladaterol_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium+Olodaterol placebo inhalation solution was administered via the Respimat® inhaler once daily.

    Investigational medicinal product name
    Placebo matching Fluticasone propionate / Salmeterol_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone propionate+Salmeterol placebo inhalation powder was inhaled orally twice daily via Accuhaler® in accordance with predefined treatment administration times.

    Arm title
    		 T+O 5/5 / F+S 500/50 / T+O 2.5/5 / F+S 250/50
    Arm description
    		 Tiotropium+Olodaterol (T+O) FDC (5 μg/5 μg) inhalation solution via Respimat® inhaler once daily in the morning and placebo Diskus® matching Fluticasone propionate+Salmeterol (F+S) FDC inhalation powder via Accuhaler® twice daily in period 1, followed with F+S FDC (500 μg/50 μg) inhalation powder via Accuhaler® twice daily followed and placebo matching T+O FDC inhalation solution via Respimat® inhaler once daily in the morning in period 2, followed with T+O FDC (2.5 μg/5 μg) inhalation solution via Respimat® inhaler once daily in the morning and placebo Diskus® matching F+S FDC inhalation powder via Accuhaler® twice daily in period 3, then followed with F+S FDC (250 μg/50 μg) inhalation powder via Accuhaler® twice daily and placebo matching T+O FDC inhalation solution via Respimat® inhaler once daily in the morning in period 4. Each treatment period was 6 wks and washing-out period 3 wks. Treatment sequence was 33 wks including 4 treatment periods and 3 washing-out periods.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Tiotropium 2.5 μg / Olodaterol 5 μg_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium+Olodaterol (2.5/5 μg) FDC inhalation solution was administered via the Respimat® inhaler once daily.

    Investigational medicinal product name
    Tiotropium 5 μg / Olodaterol 5 μg_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium+Olodaterol (2.5/5 μg) FDC inhalation solution was administered via the Respimat® inhaler once daily.

    Investigational medicinal product name
    Fluticasone propionate 250 μg / Salmeterol 50 μg_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone propionate+Salmeterol (250/50 μg) FDC inhalation powder was inhaled orally twice daily via Accuhaler® in accordance with predefined treatment administration times.

    Investigational medicinal product name
    Fluticasone propionate 500 μg / Salmeterol 50 μg_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone propionate+Salmeterol (500/50 μg) FDC inhalation powder was inhaled orally twice daily via Accuhaler® in accordance with predefined treatment administration times.

    Investigational medicinal product name
    Placebo matching Tiotropium / Oladaterol_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium+Olodaterol placebo inhalation solution was administered via the Respimat® inhaler once daily.

    Investigational medicinal product name
    Placebo matching Fluticasone propionate / Salmeterol_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone propionate+Salmeterol placebo inhalation powder was inhaled orally twice daily via Accuhaler® in accordance with predefined treatment administration times.

    Arm title
    		 F+S 250/50 / T+O 2.5/5 / F+S 500/50 / T+O 5/5
    Arm description
    		 Fluticasone propionate+Salmeterol (F+S) FDC (250 μg/50 μg) inhalation powder via Accuhaler® twice daily and placebo matching Tiotropium+Olodaterol (T+O) FDC inhalation solution via Respimat® inhaler once daily in the morning in period 1, followed with T+O FDC (2.5 μg/5 μg) inhalation solution via Respimat® inhaler once daily in the morning and placebo Diskus® matching F+S FDC inhalation powder via Accuhaler® twice daily in period 2, followed with F+S FDC (500 μg/50 μg) inhalation powder via Accuhaler® twice daily and placebo matching T+O FDC inhalation solution via Respimat® inhaler once daily in the morning in period 3, then followed T+O FDC (5 μg/5 μg) inhalation solution via Respimat® inhaler once daily in the morning with placebo Diskus® matching F+S FDC inhalation powder via Accuhaler® twice daily in period 4. Each treatment period was 6 wks and washing-out period 3 wks. Treatment sequence was 33 wks including 4 treatment periods and 3 washing-out periods.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Tiotropium 5 μg / Olodaterol 5 μg_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium+Olodaterol (5/5 μg) FDC inhalation solution was administered via the Respimat® inhaler once daily.

    Investigational medicinal product name
    Tiotropium 2.5 μg / Olodaterol 5 μg_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium+Olodaterol (2.5/5 μg) FDC inhalation solution was administered via the Respimat® inhaler once daily.

    Investigational medicinal product name
    Fluticasone propionate 250 μg / Salmeterol 50 μg_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone propionate+Salmeterol (250/50 μg) FDC inhalation powder was inhaled orally twice daily via Accuhaler® in accordance with predefined treatment administration times.

    Investigational medicinal product name
    Fluticasone propionate 500 μg / Salmeterol 50 μg_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone propionate+Salmeterol (500/50 μg) FDC inhalation powder was inhaled orally twice daily via Accuhaler® in accordance with predefined treatment administration times.

    Investigational medicinal product name
    Placebo matching Tiotropium / Oladaterol_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium+Olodaterol placebo inhalation solution was administered via the Respimat® inhaler once daily.

    Investigational medicinal product name
    Placebo matching Fluticasone propionate / Salmeterol_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone propionate+Salmeterol placebo inhalation powder was inhaled orally twice daily via Accuhaler® in accordance with predefined treatment administration times.

    Arm title
    		 F+S 500/50 / F+S 250/50 / T+O 5/5 / T+O 2.5/5
    Arm description
    		 Fluticasone propionate+Salmeterol (F+S) FDC (500 μg/50 μg) inhalation powder via Accuhaler® twice daily and placebo matching Tiotropium+Olodaterol (T+O) FDC inhalation solution via Respimat® inhaler once daily in the morning in period 1, followed with F+S FDC (250 μg/50 μg) inhalation powder via Accuhaler® twice daily and placebo matching T+O FDC inhalation solution via Respimat® inhaler once daily in the morning in period 2, followed with T+O FDC (5 μg/5 μg) inhalation solution via Respimat® inhaler once daily in the morning and placebo Diskus® matching F+S FDC inhalation powder via Accuhaler® twice daily in period 3, then followed with T+O FDC (2.5 μg/5 μg) inhalation solution via Respimat® inhaler once daily in the morning and placebo Diskus® matching F+S FDC inhalation powder via Accuhaler® twice daily in period 4. Each treatment period was 6 wks and washing-out period 3 wks. Treatment sequence was 33 wks including 4 treatment periods and 3 washing-out periods.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Tiotropium 2.5 μg / Olodaterol 5 μg_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium+Olodaterol (2.5/5 μg) FDC inhalation solution was administered via the Respimat® inhaler once daily.

    Investigational medicinal product name
    Tiotropium 5 μg / Olodaterol 5 μg_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium+Olodaterol (5/5 μg) FDC inhalation solution was administered via the Respimat® inhaler once daily.

    Investigational medicinal product name
    Fluticasone propionate 250 μg / Salmeterol 50 μg_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone propionate+Salmeterol (250/50 μg) FDC inhalation powder was inhaled orally twice daily via Accuhaler® in accordance with predefined treatment administration times.

    Investigational medicinal product name
    Fluticasone propionate 500 μg / Salmeterol 50 μg_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone propionate+Salmeterol (500/50 μg) FDC inhalation powder was inhaled orally twice daily via Accuhaler® in accordance with predefined treatment administration times.

    Investigational medicinal product name
    Placebo matching Tiotropium / Oladaterol_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium+Olodaterol placebo inhalation solution was administered via the Respimat® inhaler once daily.

    Investigational medicinal product name
    Placebo matching Fluticasone propionate / Salmeterol_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone propionate+Salmeterol placebo inhalation powder was inhaled orally twice daily via Accuhaler® in accordance with predefined treatment administration times.

    Number of subjects in period 1
    		T+O 2.5/5 / T+O 5/5 / F+S 250/50 / F+S 500/50 T+O 5/5 / F+S 500/50 / T+O 2.5/5 / F+S 250/50 F+S 250/50 / T+O 2.5/5 / F+S 500/50 / T+O 5/5 F+S 500/50 / F+S 250/50 / T+O 5/5 / T+O 2.5/5
    Started
    58
    69
    50
    52
    Completed
    54
    57
    45
    46
    Not completed
    4
    12
    5
    6
         Adverse event, serious fatal
    -
    -
    1
    -
         Non compliant with protocol
    1
    1
    -
    2
         Adverse event, non-fatal
    3
    8
    2
    2
         Other not defined
    -
    2
    -
    -
         Discontinued during washout periods.
    -
    1
    1
    2
         Lack of efficacy
    -
    -
    1
    -
    Period 2
    Period 2 title
    Overall trial (treatment period)
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 T+O 2.5/5 / F+S placebo
    Arm description
    		 Subjects were administered with Fixed Dose Combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg. Tiotropium+Olodaterol FDC inhalation solutions were administered via the Respimat® inhaler once daily. Fluticasone propionate+Salmeterol placebo inhalation powders were inhaled orally twice daily via Accuhaler® in accordance with predefined treatment administration times. Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium 2.5 μg / Olodaterol 5 μg_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium+Olodaterol (2.5/5 μg) FDC inhalation solutions were administered via the Respimat® inhaler once daily.

    Investigational medicinal product name
    Placebo matching Fluticasone propionate / Salmeterol_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone propionate+Salmeterol placebo inhalation powders were inhaled orally twice daily via Accuhaler® in accordance with predefined treatment administration times.

    Arm title
    		 T+O 5/5 / F+S placebo
    Arm description
    		 Subjects were administered with Fixed dose combination (FDC) of Tiotropium 5 μg and Olodaterol 5 μg. Tiotropium+Olodaterol FDC inhalation solutions were administered via the Respimat® inhaler once daily. Fluticasone propionate+Salmeterol placebo inhalation powders were inhaled orally twice daily via Accuhaler® in accordance with predefined treatment administration times. Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tiotropium 5 μg / Olodaterol 5 μg_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium+Olodaterol (5 μg/5 μg) FDC inhalation solutions were administered via the Respimat® inhaler once daily.

    Investigational medicinal product name
    Placebo matching Fluticasone propionate / Salmeterol_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone propionate+Salmeterol placebo inhalation powders were inhaled orally twice daily via Accuhaler® in accordance with predefined treatment administration times.

    Arm title
    		 F+S 250/50 / T+O placebo
    Arm description
    		 Subjects were administered with Fixed dose combination (FDC) of Fluticasone propionate 250 μg and Salmeterol 50 μg. Fluticasone propionate+Salmeterol FDC inhalation powders were inhaled orally twice daily via Accuhaler®. Tiotropium+Olodaterol placebo inhalation solutions were administered via the Respimat® inhaler once daily. Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Fluticasone propionate 250 μg / Salmeterol 50 μg_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone propionate+Salmeterol (250/50 μg) FDC inhalation powders were inhaled orally twice daily via Accuhaler®.

    Investigational medicinal product name
    Placebo matching Tiotropium / Oladaterol_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium+Olodaterol placebo inhalation solutions were administered via the Respimat® inhaler once daily.

    Arm title
    		 F+S 500/50 / T+O placebo
    Arm description
    		 Subjects were administered with Fixed dose combination (FDC) of Fluticasone propionate 500 μg and Salmeterol 50 μg. Fluticasone propionate+Salmeterol FDC inhalation powders were inhaled orally twice daily via Accuhaler®. Tiotropium+Olodaterol placebo inhalation solutions were administered via the Respimat® inhaler once daily. Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Fluticasone propionate 500 μg / Salmeterol 50 μg_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone propionate+Salmeterol (500/50 μg) FDC inhalation powders were inhaled orally twice daily via Accuhaler®.

    Investigational medicinal product name
    Placebo matching Tiotropium / Oladaterol_FDC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium+Olodaterol placebo inhalation solutions were administered via the Respimat® inhaler once daily.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: In this study, Period 1 evaluates by sequence and baseline characteristics is defined based on overall trial by treatment period, thus period 2 was selected as a baseline period to define the baseline characteristics of this trial.
    Number of subjects in period 2
    		T+O 2.5/5 / F+S placebo T+O 5/5 / F+S placebo F+S 250/50 / T+O placebo F+S 500/50 / T+O placebo
    Started
    215
    221
    212
    219
    Completed
    210
    213
    209
    212
    Not completed
    5
    8
    3
    7
         Adverse event, serious fatal
    -
    1
    -
    -
         Non compliant with protocol
    1
    1
    -
    2
         Adverse event, non-fatal
    3
    5
    2
    5
         Other not defined
    1
    1
    -
    -
         Lack of efficacy
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Overall trial (treatment period)
    Reporting group description
    		 -

    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: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication.
    Reporting group values
    		 Overall trial (treatment period) Total
    Number of subjects
    		 229
    Age categorical
    Units: Subjects
    Age Continuous |
    Treated Set: All randomised patients who received any dose of the trial medication.
    Units: years
        arithmetic mean (standard deviation)
    		 63.6 ( 7.6 ) -
    Gender, Male/Female
    Units: Participants
        Female
    		 81 81
        Male
    		 148 148

    End points

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    End points reporting groups
    Reporting group title
    T+O 2.5/5 / T+O 5/5 / F+S 250/50 / F+S 500/50
    Reporting group description
    		 Tiotropium+Olodaterol (T+O) FDC (2.5 μg/5 μg) inhalation solution via Respimat® inhaler once daily in the morning and placebo Diskus® matching Fluticasone propionate+Salmeterol (F+S) FDC inhalation powder via Accuhaler® twice daily in period 1, followed with T+O FDC (5 μg/5 μg) inhalation solution via Respimat® inhaler once daily in the morning and placebo Diskus® matching F+S FDC inhalation powder via Accuhaler® twice daily in period 2, followed with F+S FDC (250 μg/50 μg) inhalation powder via Accuhaler® twice daily and placebo matching T+O FDC inhalation solution via Respimat® inhaler once daily in the morning in period 3, then followed with F+S FDC (500 μg/50 μg) inhalation powder via Accuhaler® twice daily and placebo matching T+O FDC inhalation solution via Respimat® inhaler once daily in the morning in period 4. Each treatment period was 6 weeks (wks) and washing-out period 3 wks. Treatment sequence was 33 wks including 4 treatment periods and 3 washing-out periods.

    Reporting group title
    T+O 5/5 / F+S 500/50 / T+O 2.5/5 / F+S 250/50
    Reporting group description
    		 Tiotropium+Olodaterol (T+O) FDC (5 μg/5 μg) inhalation solution via Respimat® inhaler once daily in the morning and placebo Diskus® matching Fluticasone propionate+Salmeterol (F+S) FDC inhalation powder via Accuhaler® twice daily in period 1, followed with F+S FDC (500 μg/50 μg) inhalation powder via Accuhaler® twice daily followed and placebo matching T+O FDC inhalation solution via Respimat® inhaler once daily in the morning in period 2, followed with T+O FDC (2.5 μg/5 μg) inhalation solution via Respimat® inhaler once daily in the morning and placebo Diskus® matching F+S FDC inhalation powder via Accuhaler® twice daily in period 3, then followed with F+S FDC (250 μg/50 μg) inhalation powder via Accuhaler® twice daily and placebo matching T+O FDC inhalation solution via Respimat® inhaler once daily in the morning in period 4. Each treatment period was 6 wks and washing-out period 3 wks. Treatment sequence was 33 wks including 4 treatment periods and 3 washing-out periods.

    Reporting group title
    F+S 250/50 / T+O 2.5/5 / F+S 500/50 / T+O 5/5
    Reporting group description
    		 Fluticasone propionate+Salmeterol (F+S) FDC (250 μg/50 μg) inhalation powder via Accuhaler® twice daily and placebo matching Tiotropium+Olodaterol (T+O) FDC inhalation solution via Respimat® inhaler once daily in the morning in period 1, followed with T+O FDC (2.5 μg/5 μg) inhalation solution via Respimat® inhaler once daily in the morning and placebo Diskus® matching F+S FDC inhalation powder via Accuhaler® twice daily in period 2, followed with F+S FDC (500 μg/50 μg) inhalation powder via Accuhaler® twice daily and placebo matching T+O FDC inhalation solution via Respimat® inhaler once daily in the morning in period 3, then followed T+O FDC (5 μg/5 μg) inhalation solution via Respimat® inhaler once daily in the morning with placebo Diskus® matching F+S FDC inhalation powder via Accuhaler® twice daily in period 4. Each treatment period was 6 wks and washing-out period 3 wks. Treatment sequence was 33 wks including 4 treatment periods and 3 washing-out periods.

    Reporting group title
    F+S 500/50 / F+S 250/50 / T+O 5/5 / T+O 2.5/5
    Reporting group description
    		 Fluticasone propionate+Salmeterol (F+S) FDC (500 μg/50 μg) inhalation powder via Accuhaler® twice daily and placebo matching Tiotropium+Olodaterol (T+O) FDC inhalation solution via Respimat® inhaler once daily in the morning in period 1, followed with F+S FDC (250 μg/50 μg) inhalation powder via Accuhaler® twice daily and placebo matching T+O FDC inhalation solution via Respimat® inhaler once daily in the morning in period 2, followed with T+O FDC (5 μg/5 μg) inhalation solution via Respimat® inhaler once daily in the morning and placebo Diskus® matching F+S FDC inhalation powder via Accuhaler® twice daily in period 3, then followed with T+O FDC (2.5 μg/5 μg) inhalation solution via Respimat® inhaler once daily in the morning and placebo Diskus® matching F+S FDC inhalation powder via Accuhaler® twice daily in period 4. Each treatment period was 6 wks and washing-out period 3 wks. Treatment sequence was 33 wks including 4 treatment periods and 3 washing-out periods.
    Reporting group title
    T+O 2.5/5 / F+S placebo
    Reporting group description
    		 Subjects were administered with Fixed Dose Combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg. Tiotropium+Olodaterol FDC inhalation solutions were administered via the Respimat® inhaler once daily. Fluticasone propionate+Salmeterol placebo inhalation powders were inhaled orally twice daily via Accuhaler® in accordance with predefined treatment administration times. Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days.

    Reporting group title
    T+O 5/5 / F+S placebo
    Reporting group description
    		 Subjects were administered with Fixed dose combination (FDC) of Tiotropium 5 μg and Olodaterol 5 μg. Tiotropium+Olodaterol FDC inhalation solutions were administered via the Respimat® inhaler once daily. Fluticasone propionate+Salmeterol placebo inhalation powders were inhaled orally twice daily via Accuhaler® in accordance with predefined treatment administration times. Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days.

    Reporting group title
    F+S 250/50 / T+O placebo
    Reporting group description
    		 Subjects were administered with Fixed dose combination (FDC) of Fluticasone propionate 250 μg and Salmeterol 50 μg. Fluticasone propionate+Salmeterol FDC inhalation powders were inhaled orally twice daily via Accuhaler®. Tiotropium+Olodaterol placebo inhalation solutions were administered via the Respimat® inhaler once daily. Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days.

    Reporting group title
    F+S 500/50 / T+O placebo
    Reporting group description
    		 Subjects were administered with Fixed dose combination (FDC) of Fluticasone propionate 500 μg and Salmeterol 50 μg. Fluticasone propionate+Salmeterol FDC inhalation powders were inhaled orally twice daily via Accuhaler®. Tiotropium+Olodaterol placebo inhalation solutions were administered via the Respimat® inhaler once daily. Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days.

    Primary: FEV1 AUC (0−12h) Change from Patient Baseline after 6 Weeks of Treatment

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    End point title
    		 FEV1 AUC (0−12h) Change from Patient Baseline after 6 Weeks of Treatment
    End point description
    Change from patient baseline in Forced Expiratory Volume in one second (FEV1) Area Under the FEV1-time Curve from 0 to 12hours post-dose (AUC 0-12h) [L] after 6 weeks of treatment. Measured values presented are actually adjusted means. The period baseline is defined as the pre-dose measurement taken at on the day 1 of each period. The patient baseline is defined as the mean of non-missing period baselines for each patient. Full Analysis Set (FAS): Included all randomised patients who were documented to have had received any dose of trial medication and who had both period baseline and any evaluable post-baseline measurement for the primary efficacy endpoint.
    End point type
    Primary
    End point timeframe
    Baseline and 6 weeks.
    End point values
    		 T+O 2.5/5 / F+S placebo T+O 5/5 / F+S placebo F+S 250/50 / T+O placebo F+S 500/50 / T+O placebo
    Number of subjects analysed
    214 [1]
    216 [2]
    211 [3]
    217 [4]
    Units: Litres
        arithmetic mean (standard error)
    0.295 ( 0.014 )
    0.317 ( 0.014 )
    0.192 ( 0.015 )
    0.188 ( 0.014 )
    Notes
    [1] - Full Analysis Set (FAS)
    [2] - Full Analysis Set (FAS)
    [3] - Full Analysis Set (FAS)
    [4] - Full Analysis Set (FAS)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    T+O 5/5 / F+S placebo v F+S 250/50 / T+O placebo
    Number of subjects included in analysis
    427
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.0001 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.125
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.103
         upper limit
    		 0.147
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.011
    Notes
    [5] - The actual number of subjects analyzed is 221. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis below (427) does not reflect the actual number. Difference calculated as T+O 5/5 / F+S placebo - F+S 250/50 / T+O placebo adjusted mean FEV1 AUC 0-12h change from patient baseline (L).
    [6] - p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    T+O 5/5 / F+S placebo v F+S 500/50 / T+O placebo
    Number of subjects included in analysis
    433
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.0001 [8]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.129
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.107
         upper limit
    		 0.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.011
    Notes
    [7] - The actual number of subjects analyzed is 221. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (433) does not reflect the actual number. Difference calculated as T+O 5/5 / F+S placebo - F+S 500/50 / T+O placebo adjusted mean FEV1 AUC 0-12h change from patient baseline (L).
    [8] - p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    T+O 2.5/5 / F+S placebo v F+S 250/50 / T+O placebo
    Number of subjects included in analysis
    425
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 < 0.0001 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.103
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.081
         upper limit
    		 0.124
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.011
    Notes
    [9] - The actual number of subjects analyzed is 221. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (425) does not reflect the actual number. Difference calculated as T+O 2.5/5 / F+S placebo - F+S 250/50 / T+O placebo adjusted mean FEV1 AUC 0-12h change from patient baseline (L).
    [10] - p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
    Statistical analysis title
    		 Statistical analysis 4
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    T+O 2.5/5 / F+S placebo v F+S 500/50 / T+O placebo
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 < 0.0001 [12]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.106
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.085
         upper limit
    		 0.128
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.011
    Notes
    [11] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (431) does not reflect the actual number. Difference calculated as T+O 2.5/5 / F+S placebo - F+S 500/50 / T+O placebo adjusted mean FEV1 AUC 0-12h change from patient baseline (L).
    [12] - p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.

    Secondary: FEV1 AUC (0−24h) Change from Patient Baseline after 6 Weeks of Treatment

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    End point title
    		 FEV1 AUC (0−24h) Change from Patient Baseline after 6 Weeks of Treatment
    End point description
    Change from patient baseline in Forced Expiratory Volume in one second (FEV1) Area Under the FEV1-time Curve from 0 to 24 hours post-dose (AUC 0-24h) [L] after 6 weeks of treatment. Measured values presented are actually adjusted means. The period baseline is defined as the pre-dose measurement taken at on the day 1 of each period. The patient baseline is defined as the mean of non-missing period baselines for each patient.
    End point type
    Secondary
    End point timeframe
    Baseline and 6 weeks.
    End point values
    		 T+O 2.5/5 / F+S placebo T+O 5/5 / F+S placebo F+S 250/50 / T+O placebo F+S 500/50 / T+O placebo
    Number of subjects analysed
    214 [13]
    216 [14]
    211 [15]
    217 [16]
    Units: Litres
        arithmetic mean (standard error)
    0.228 ( 0.014 )
    0.244 ( 0.014 )
    0.162 ( 0.014 )
    0.159 ( 0.014 )
    Notes
    [13] - Full Analysis Set (FAS)
    [14] - Full Analysis Set (FAS)
    [15] - Full Analysis Set (FAS)
    [16] - Full Analysis Set (FAS)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    T+O 5/5 / F+S placebo v F+S 250/50 / T+O placebo
    Number of subjects included in analysis
    427
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 < 0.0001 [18]
    Method
    		 Mixed models analysis
    Parameter type
    		 Median difference (net)
    Point estimate
    0.082
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.061
         upper limit
    		 0.103
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.011
    Notes
    [17] - The actual number of subjects analyzed is 221. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (427) does not reflect the actual number. Difference calculated as T+O 5/5 / F+S Placebo - F+S 250/50 / T+O Placebo adjusted mean FEV1 AUC 0-24h change from patient baseline (L).
    [18] - p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    T+O 5/5 / F+S placebo v F+S 500/50 / T+O placebo
    Number of subjects included in analysis
    433
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 < 0.0001 [20]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.086
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.065
         upper limit
    		 0.107
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.011
    Notes
    [19] - The actual number of subjects analyzed is 221. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (433) does not reflect the actual number. Difference calculated as T+O 5/5 / F+S Placebo - F+S 500/50 / T+O Placebo adjusted mean FEV1 AUC 0-24h change from patient baseline (L).
    [20] - p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    T+O 2.5/5 / F+S placebo v F+S 250/50 / T+O placebo
    Number of subjects included in analysis
    425
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 < 0.0001 [22]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.065
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.045
         upper limit
    		 0.086
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.011
    Notes
    [21] - The actual number of subjects analyzed is 215. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (425) does not reflect the actual number. Difference calculated as T+O 2.5/5 / F+S Placebo - F+S 250/50 / T+O Placebo adjusted mean FEV1 AUC 0-24h change from patient baseline (L).
    [22] - p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
    Statistical analysis title
    		 Statistical analysis 4
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    T+O 2.5/5 / F+S placebo v F+S 500/50 / T+O placebo
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 < 0.0001 [24]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.069
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.048
         upper limit
    		 0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.011
    Notes
    [23] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (431) does not reflect the actual number. Difference calculated as T+O 2.5/5 / F+S Placebo - F+S 500/50 / T+O Placebo adjusted mean FEV1 AUC 0-24h change from patient baseline (L).
    [24] - p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.

    Secondary: Trough FEV1 Change from Patient Baseline after 6 Weeks of Treatment

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    End point title
    		 Trough FEV1 Change from Patient Baseline after 6 Weeks of Treatment
    End point description
    Change from patient baseline in trough Forced Expiratory Volume in one second (FEV1) after 6 weeks of treatment. Trough FEV1 was defined as the mean of the 23h and 23h 50min (minutes) post-dose FEV1 measurements. Measured values presented are actually adjusted means. The period baseline is defined as the pre-dose measurement taken at on the day 1 of each period. The patient baseline is defined as the mean of non-missing period baselines for each patient.
    End point type
    Secondary
    End point timeframe
    Baseline and 6 weeks.
    End point values
    		 T+O 2.5/5 / F+S placebo T+O 5/5 / F+S placebo F+S 250/50 / T+O placebo F+S 500/50 / T+O placebo
    Number of subjects analysed
    214 [25]
    216 [26]
    211 [27]
    217 [28]
    Units: Litres
        arithmetic mean (standard error)
    0.192 ( 0.014 )
    0.197 ( 0.014 )
    0.15 ( 0.014 )
    0.139 ( 0.014 )
    Notes
    [25] - Full Analysis Set (FAS)
    [26] - Full Analysis Set (FAS)
    [27] - Full Analysis Set (FAS)
    [28] - Full Analysis Set (FAS)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    T+O 5/5 / F+S placebo v F+S 250/50 / T+O placebo
    Number of subjects included in analysis
    427
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 = 0.0002 [30]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.047
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.022
         upper limit
    		 0.071
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    Notes
    [29] - The actual number of subjects analyzed is 221. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (427) does not reflect the actual number. Difference calculated as T+O 5/5 / F+S Placebo - F+S 250/50 / T+O Placebo adjusted mean trough FEV1 change from patient baseline (L).
    [30] - p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    T+O 5/5 / F+S placebo v F+S 500/50 / T+O placebo
    Number of subjects included in analysis
    433
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [31]
    P-value
    		 < 0.0001 [32]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.058
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.034
         upper limit
    		 0.082
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    Notes
    [31] - The actual number of subjects analyzed is 221. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (433) does not reflect the actual number. Difference calculated as T+O 5/5 / F+S Placebo - F+S 500/50 / T+O Placebo adjusted mean trough FEV1 change from patient baseline (L).
    [32] - p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    T+O 2.5/5 / F+S placebo v F+S 250/50 / T+O placebo
    Number of subjects included in analysis
    425
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [33]
    P-value
    		 = 0.0007 [34]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.042
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.018
         upper limit
    		 0.067
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    Notes
    [33] - The actual number of subjects analyzed is 215. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (425) does not reflect the actual number. Difference calculated as T+O 2.5/5 / F+S Placebo - F+S 250/50 / T+O Placebo adjusted mean trough FEV1 change from patient baseline (L).
    [34] - p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
    Statistical analysis title
    		 Statistical analysis 4
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    T+O 2.5/5 / F+S placebo v F+S 500/50 / T+O placebo
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [35]
    P-value
    		 < 0.0001 [36]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.054
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.029
         upper limit
    		 0.078
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    Notes
    [35] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (431) does not reflect the actual number. Difference calculated as T+O 2.5/5 / F+S Placebo - F+S 500/50 / T+O Placebo adjusted mean trough FEV1 change from patient baseline (L).
    [36] - p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.

    Secondary: FEV1 AUC (12−24h) Change from Patient Baseline after 6 Weeks of Treatment

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    End point title
    		 FEV1 AUC (12−24h) Change from Patient Baseline after 6 Weeks of Treatment
    End point description
    Change from patient baseline in Forced Expiratory Volume in one second (FEV1) Area Under the FEV1-time Curve from 12 to 24 hours post-dose (AUC 12-24h) [L] after 6 weeks of treatment. Measured values presented are actually adjusted means. The period baseline is defined as the pre-dose measurement taken at on the day 1 of each period. The patient baseline is defined as the mean of non-missing period baselines for each patient.
    End point type
    Secondary
    End point timeframe
    Baseline and 6 weeks.
    End point values
    		 T+O 2.5/5 / F+S placebo T+O 5/5 / F+S placebo F+S 250/50 / T+O placebo F+S 500/50 / T+O placebo
    Number of subjects analysed
    214 [37]
    216 [38]
    211 [39]
    217 [40]
    Units: Litres
        arithmetic mean (standard error)
    0.164 ( 0.014 )
    0.172 ( 0.014 )
    0.132 ( 0.014 )
    0.129 ( 0.014 )
    Notes
    [37] - Full Analysis Set (FAS)
    [38] - Full Analysis Set (FAS)
    [39] - Full Analysis Set (FAS)
    [40] - Full Analysis Set (FAS)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    T+O 5/5 / F+S placebo v F+S 250/50 / T+O placebo
    Number of subjects included in analysis
    427
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [41]
    P-value
    		 = 0.0007 [42]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.039
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.017
         upper limit
    		 0.062
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    Notes
    [41] - The actual number of subjects analyzed is 221. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (427) does not reflect the actual number. Difference calculated as T+O 5/5 / F+S Placebo - F+S 250/50 / T+O Placebo adjusted mean FEV1 AUC (12−24h) change from patient baseline (L).
    [42] - p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    T+O 5/5 / F+S placebo v F+S 500/50 / T+O placebo
    Number of subjects included in analysis
    433
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [43]
    P-value
    		 = 0.0002 [44]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.043
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.021
         upper limit
    		 0.065
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.011
    Notes
    [43] - The actual number of subjects analyzed is 221. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (433) does not reflect the actual number. Difference calculated as T+O 5/5 / F+S Placebo - F+S 500/50 / T+O Placebo adjusted mean FEV1 AUC (12−24h) change from patient baseline (L).
    [44] - p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    T+O 2.5/5 / F+S placebo v F+S 250/50 / T+O placebo
    Number of subjects included in analysis
    425
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [45]
    P-value
    		 = 0.0146 [46]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.028
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.006
         upper limit
    		 0.051
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.011
    Notes
    [45] - The actual number of subjects analyzed is 215. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (425) does not reflect the actual number. Difference calculated as T+O 2.5/5 / F+S Placebo - F+S 250/50 / T+O Placebo adjusted mean FEV1 AUC (12−24h) change from patient baseline (L).
    [46] - p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
    Statistical analysis title
    		 Statistical analysis 4
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    T+O 2.5/5 / F+S placebo v F+S 500/50 / T+O placebo
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [47]
    P-value
    		 = 0.0055 [48]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.032
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.009
         upper limit
    		 0.054
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.011
    Notes
    [47] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (431) does not reflect the actual number. Difference calculated as T+O 2.5/5 / F+S Placebo - F+S 500/50 / T+O Placebo adjusted mean FEV1 AUC (12−24h) change from patient baseline (L).
    [48] - p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.

    Secondary: FEV1 Peak (0−3h) Change from Patient Baseline after 6 Weeks of Treatment

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    End point title
    		 FEV1 Peak (0−3h) Change from Patient Baseline after 6 Weeks of Treatment
    End point description
    Change from patient baseline in Forced Expiratory Volume in one second (FEV1) peak (0-3 hours) after 6 weeks of treatment. FEV1 peak (0-3 hours) was defined as the maximum FEV1 value measured within the first three hours post dosing. Measured values presented are actually adjusted means.
    End point type
    Secondary
    End point timeframe
    Baseline and 6 weeks.
    End point values
    		 T+O 2.5/5 / F+S placebo T+O 5/5 / F+S placebo F+S 250/50 / T+O placebo F+S 500/50 / T+O placebo
    Number of subjects analysed
    214 [49]
    216 [50]
    211 [51]
    217 [52]
    Units: Litres
        arithmetic mean (standard error)
    0.401 ( 0.016 )
    0.432 ( 0.016 )
    0.291 ( 0.016 )
    0.285 ( 0.015 )
    Notes
    [49] - Full Analysis Set (FAS)
    [50] - Full Analysis Set (FAS)
    [51] - Full Analysis Set (FAS)
    [52] - Full Analysis Set (FAS)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    T+O 5/5 / F+S placebo v F+S 250/50 / T+O placebo
    Number of subjects included in analysis
    427
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [53]
    P-value
    		 < 0.0001 [54]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.142
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.118
         upper limit
    		 0.166
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    Notes
    [53] - The actual number of subjects analyzed is 221. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (427) does not reflect the actual number. Difference calculated as T+O 5/5 / F+S Placebo - F+S 250/50 / T+O placebo adjusted mean FEV1 peak (0−3h) change from patient baseline (L).
    [54] - p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    T+O 5/5 / F+S placebo v F+S 500/50 / T+O placebo
    Number of subjects included in analysis
    433
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [55]
    P-value
    		 < 0.0001 [56]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.147
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.123
         upper limit
    		 0.171
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    Notes
    [55] - The actual number of subjects analyzed is 221. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (433) does not reflect the actual number. Difference calculated as T+O 5/5 / F+S placebo - F+S 500/50 / T+O placebo adjusted mean FEV1 peak (0−3h) change from patient baseline (L).
    [56] - p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    T+O 2.5/5 / F+S placebo v F+S 250/50 / T+O placebo
    Number of subjects included in analysis
    425
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [57]
    P-value
    		 < 0.0001 [58]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.111
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.087
         upper limit
    		 0.135
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    Notes
    [57] - The actual number of subjects analyzed is 215. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (425) does not reflect the actual number. Difference calculated as T+O 2.5/5 / F+S placebo - F+S 250/50 / T+O placebo adjusted mean FEV1 peak (0−3h) change from patient baseline (L).
    [58] - p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.
    Statistical analysis title
    		 Statistical analysis 4
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting an MMRM model including fixed effects of treatment and period; period baseline and patient baseline as covariates; patient as a random effect; compound symmetry covariance structure for within−patient variation and Kenward−Roger approximation of denominator degrees of freedom.
    Comparison groups
    T+O 2.5/5 / F+S placebo v F+S 500/50 / T+O placebo
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [59]
    P-value
    		 < 0.0001 [60]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.116
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.092
         upper limit
    		 0.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.012
    Notes
    [59] - The actual number of subjects analyzed is 219. As this is a cross over study and arms are not mutually exclusive, the pre-specified, automatically calculated number that is provided in the statistical analysis (431) does not reflect the actual number. Difference calculated as T+O 2.5/5 / F+S placebo - F+S 500/50 / T+O placebo adjusted mean FEV1 peak (0−3h) change from patient baseline (L).
    [60] - p-value is not adjusted for multiple comparisons. A priori threshold for statistical significance is two-sided alpha=0.05.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first drug intake until 21 days after last drug intake, up to 88 days.
    Adverse event reporting additional description
    AEs are displayed by treatment, however in total patients were in the study for up to 223 days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    T+O 2.5/5 / F+S placebo
    Reporting group description
    		 Subjects were administered with Fixed Dose Combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg. Tiotropium+Olodaterol FDC inhalation solutions were administered via the Respimat® inhaler once daily. Fluticasone propionate+Salmeterol placebo inhalation powders were inhaled orally twice daily via Accuhaler® in accordance with predefined treatment administration times. Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days.

    Reporting group title
    F+S 250/50 / T+O placebo
    Reporting group description
    		 Subjects were administered with Fixed dose combination (FDC) of Fluticasone propionate 250 μg and Salmeterol 50 μg. Fluticasone propionate+Salmeterol FDC inhalation powders were inhaled orally twice daily via Accuhaler®. Tiotropium+Olodaterol placebo inhalation solutions were administered via the Respimat® inhaler once daily. Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days.

    Reporting group title
    F+S 500/50 / T+O placebo
    Reporting group description
    		 Subjects were administered with Fixed dose combination (FDC) of Fluticasone propionate 500 μg and Salmeterol 50 μg. Fluticasone propionate+Salmeterol FDC inhalation powders were inhaled orally twice daily via Accuhaler®. Tiotropium+Olodaterol placebo inhalation solutions were administered via the Respimat® inhaler once daily. Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days.

    Reporting group title
    T+O 5/5 / F+S placebo
    Reporting group description
    		 Subjects were administered with Fixed dose combination (FDC) of Tiotropium 5 μg and Olodaterol 5 μg. Tiotropium+Olodaterol FDC inhalation solutions were administered via the Respimat® inhaler once daily. Fluticasone propionate+Salmeterol placebo inhalation powders were inhaled orally twice daily via Accuhaler® in accordance with predefined treatment administration times. Treatments were taken for 6 weeks and each treatment period was separated by a washout period of at least 21 days.

    Serious adverse events
    		 T+O 2.5/5 / F+S placebo F+S 250/50 / T+O placebo F+S 500/50 / T+O placebo T+O 5/5 / F+S placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 215 (2.79%)
    4 / 212 (1.89%)
    9 / 219 (4.11%)
    7 / 221 (3.17%)
         number of deaths (all causes)
    0
    0
    0
    2
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Fibula fracture
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 212 (0.00%)
    0 / 219 (0.00%)
    0 / 221 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 212 (0.00%)
    0 / 219 (0.00%)
    0 / 221 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 212 (0.47%)
    0 / 219 (0.00%)
    0 / 221 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular graft occlusion
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 212 (0.00%)
    1 / 219 (0.46%)
    0 / 221 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 215 (0.00%)
    0 / 212 (0.00%)
    1 / 219 (0.46%)
    0 / 221 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 212 (0.00%)
    0 / 219 (0.00%)
    0 / 221 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 212 (0.00%)
    0 / 219 (0.00%)
    0 / 221 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 215 (0.00%)
    0 / 212 (0.00%)
    1 / 219 (0.46%)
    0 / 221 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 215 (0.00%)
    0 / 212 (0.00%)
    0 / 219 (0.00%)
    1 / 221 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 215 (0.00%)
    0 / 212 (0.00%)
    0 / 219 (0.00%)
    1 / 221 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Transient ischaemic attack
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 212 (0.47%)
    0 / 219 (0.00%)
    0 / 221 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 215 (0.00%)
    0 / 212 (0.00%)
    0 / 219 (0.00%)
    1 / 221 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 215 (0.00%)
    0 / 212 (0.00%)
    1 / 219 (0.46%)
    0 / 221 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 215 (0.00%)
    0 / 212 (0.00%)
    0 / 219 (0.00%)
    1 / 221 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 212 (0.47%)
    0 / 219 (0.00%)
    0 / 221 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 215 (0.93%)
    2 / 212 (0.94%)
    4 / 219 (1.83%)
    2 / 221 (0.90%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 215 (0.00%)
    0 / 212 (0.00%)
    0 / 219 (0.00%)
    1 / 221 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 215 (0.00%)
    0 / 212 (0.00%)
    0 / 219 (0.00%)
    1 / 221 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteonecrosis
         subjects affected / exposed
    0 / 215 (0.00%)
    0 / 212 (0.00%)
    1 / 219 (0.46%)
    0 / 221 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 215 (0.00%)
    0 / 212 (0.00%)
    0 / 219 (0.00%)
    1 / 221 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 212 (0.47%)
    0 / 219 (0.00%)
    0 / 221 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 212 (0.00%)
    0 / 219 (0.00%)
    0 / 221 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 215 (0.00%)
    1 / 212 (0.47%)
    1 / 219 (0.46%)
    0 / 221 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sialoadenitis
         subjects affected / exposed
    1 / 215 (0.47%)
    0 / 212 (0.00%)
    0 / 219 (0.00%)
    0 / 221 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 215 (0.00%)
    0 / 212 (0.00%)
    0 / 219 (0.00%)
    1 / 221 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 T+O 2.5/5 / F+S placebo F+S 250/50 / T+O placebo F+S 500/50 / T+O placebo T+O 5/5 / F+S placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 215 (9.77%)
    19 / 212 (8.96%)
    24 / 219 (10.96%)
    28 / 221 (12.67%)
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    10 / 215 (4.65%)
    7 / 212 (3.30%)
    15 / 219 (6.85%)
    18 / 221 (8.14%)
         occurrences all number
    10
    8
    15
    20
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    12 / 215 (5.58%)
    13 / 212 (6.13%)
    11 / 219 (5.02%)
    12 / 221 (5.43%)
         occurrences all number
    12
    13
    11
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Apr 2014
    Global Amendment 1 included clarifications and administrative changes that did not require IRB/IEC/CA approval prior to implementation. Weather station, Accuhaler training and visit 10 for pregnancy testing was added. “patients taking Tiotropium prior to study entry” was changed to ”patients taking a LAMA prior to study entry”. Update with data from Phase III studies and Tiospir results. Further clarification of medication restrictions, dosing times and “rescheduling prior to randomisation” was provided. All hypotheses were changed to two-sided hypotheses with alpha=0.05. Handling of missing data and provided more details in the TSAP. Definition of period baseline was updated, correction to listedness section and comparator SPC was added.
    04 Feb 2015
    Amendment 2 was a change in the hierarchical testing strategy. The testing hierarchy was modified such that the primary and key secondary endpoints were first tested on the Tio+Olo 5/5 μg dose followed by the Tio+Olo 2.5/5 μg dose because Tio+Olo 5/5 μg was the dose planned for marketing. Global Amendment 2 did not require IRB/IEC/CA approval prior to implementation.

    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.
    1 subject with missing information for number of enrolled subjects has been included in age range Elderly (From 65-84 years) as the missing category is not available. Update initiated unnecessarily; Results in version 1 and version 2 are same.
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    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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