Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43871   clinical trials with a EudraCT protocol, of which   7290   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Phase II Randomised, Double-blind, Placebo-controlled, Incomplete Crossover Trial With 4-week Treatment Periods to Evaluate Efficacy and Safety of Tiotropium Inhalation Solution (Doses of 1.25 µg, 2.5 µg and 5 µg) Delivered Via Respimat® Inhaler Once Daily in the Evening in Adolescents (12 to 17 Yrs Old) With Moderate Persistent Asthma

    Summary
    EudraCT number
    		 2009-017745-55
    Trial protocol
    		 DE   SI   LT   LV  
    Global end of trial date
    11 Apr 2011

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Jun 2016
    First version publication date
    17 May 2015
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    205.424
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01122680
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim Pharma GmbH & Co. KG
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim Pharma GmbH & Co. KG, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim Pharma GmbH & Co. KG, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000035-PIP02-09
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 May 2011
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Mar 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Apr 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial is to evaluate the efficacy and safety of tiotropium 1.25 μg (2 actuations of 0.625 μg), tiotropium 2.5 μg (2 actuations of 1.25 μg) and tiotropium 5 μg (2 actuations of 2.5 μg) once daily in the evening delivered by the Respimat inhaler in adolescents (12 to 17 years) with moderate persistent asthma, compared to placebo and on top of maintenance therapy with an inhaled corticosteroid controller medication. It is a randomised, double-blind, placebo-controlled Phase II trial with incomplete cross-over design. Patients need to be still symptomatic, i. e. not fully controlled with their maintenance treatment.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be randomised to trial treatment. 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. Salbutamol, short-acting β2-adrenergic agonist (SABA), was provided as rescue medication for use as necessary during the trial.
    Background therapy
    		 Patients maintained their background therapy , including inhaled corticosteroids (ICS).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Jun 2010
    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
    Lithuania: 43
    Country: Number of subjects enrolled
    Slovenia: 6
    Country: Number of subjects enrolled
    United States: 25
    Country: Number of subjects enrolled
    Latvia: 49
    Country: Number of subjects enrolled
    Germany: 16
    Worldwide total number of subjects
    139
    EEA total number of subjects
    114
    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)
    139
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 In this incomplete crossover design, 105 patients were randomised to one of four sequences (in general terms, ABC, BDA, CAD or DCB). Whilst there were 4 possible treatments, A, B, C and D, each patient would receive a maximum of 3 different treatments. Hence, approximately 75 patients would receive each of A, B, C and D at any time point.

    Pre-assignment
    Screening details
    		 All subjects were screened for eligibility to participate in the trial. Subjects attended specialist sites which would then ensure that they (the subjects) met all strictly implemented inclusion/exclusion criteria. Subjects were not to be randomised to trial treatment if any one of the specific entry criteria were violated.

    Period 1
    Period 1 title
    Period 1 (4 weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tio R5/Placebo/Tio R1.25
    Arm description
    		 Patients treated with Tiotropium 5 μg in period I, with a matching Placebo in period II and with Tiotropium 1.25 μg in period III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Tiotropium bromide/Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tio R5 - 2 puffs once daily for a total dose of 5 μg (evening dosing) Placebo - 2 puffs once daily (evening dosing) Tio R1.25 - 2 puffs once daily for a total dose of 1.25 μg (evening dosing)

    Arm title
    		 Tio R1.25/Tio R5/Tio R2.5
    Arm description
    		 Patients treated with Tiotropium 1.25 μg in period I, with Tiotropium 5 μg in period II and with Tiotropium 2.5 μg in period III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Tiotropium bromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tio R1.25 - 2 puffs once daily for a total dose of 1.25 μg (evening dosing) Tio R5 - 2 puffs once daily for a total dose of 5 μg (evening dosing) Tio R2.5 -2 puffs once daily for a total dose of 2.5 μg (evening dosing)

    Arm title
    		 Placebo/Tio R2.5/Tio R5
    Arm description
    		 Patients treated with a matching Placebo in period I, with Tiotropium 2.5 μg in period II and with Tiotropium 5 μg in period III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Placebo/Tiotropium bromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo - 2 puffs once daily (evening dosing) Tio R2.5 - 2 puffs once daily for a total dose of 2.5 μg (evening dosing) Tio R5 - 2 puffs once daily for a total dose of 5 μg (evening dosing)

    Arm title
    		 Tio R2.5/Tio R1.25/Placebo
    Arm description
    		 Patients treated with Tiotropium 2.5 μg in period I, with Tiotropium 1.25 μg in period II and with a matching Placebo in period III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Tiotropium bromide/Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tio R2.5 - 2 puffs once daily for a total dose of 2.5 μg (evening dosing) Tio R1.25 - 2 puffs once daily for a total dose of 1.25 μg (evening dosing) Placebo - 2 puffs once daily (evening dosing)

    Number of subjects in period 1
    		Tio R5/Placebo/Tio R1.25 Tio R1.25/Tio R5/Tio R2.5 Placebo/Tio R2.5/Tio R5 Tio R2.5/Tio R1.25/Placebo
    Started
    29
    26
    26
    24
    Completed
    26
    25
    26
    24
    Not completed
    3
    1
    0
    0
         Adverse event, non-fatal
    1
    -
    -
    -
         Non-compliant
    1
    -
    -
    -
         Other
    1
    1
    -
    -
    Period 2
    Period 2 title
    Period 2 (4 weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Tio R5/Placebo/Tio R1.25
    Arm description
    		 Patients treated with Tiotropium 5 μg in period I, with a matching Placebo in period II and with Tiotropium 1.25 μg in period III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Tiotropium bromide/Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tio R5 - 2 puffs once daily for a total dose of 5 μg (evening dosing) Placebo - 2 puffs once daily (evening dosing) Tio R1.25 - 2 puffs once daily for a total dose of 1.25 μg (evening dosing)

    Arm title
    		 Tio R1.25/Tio R5/Tio R2.5
    Arm description
    		 Patients treated with Tiotropium 1.25 μg in period I, with Tiotropium 5 μg in period II and with Tiotropium 2.5 μg in period III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Tiotropium bromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tio R1.25 - 2 puffs once daily for a total dose of 1.25 μg (evening dosing) Tio R5 - 2 puffs once daily for a total dose of 5 μg (evening dosing) Tio R2.5 - 2 puffs once daily for a total dose of 2.5 μg (evening dosing)

    Arm title
    		 Placebo/Tio R2.5/Tio R5
    Arm description
    		 Patients treated with a matching Placebo in period I, with Tiotropium 2.5 μg in period II and with Tiotropium 5 μg in period III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Placebo/Tiotropium bromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo - 2 puffs once daily (evening dosing) Tio R2.5 - 2 puffs once daily for a total dose of 2.5 μg (evening dosing) Tio R5 - 2 puffs once daily for a total dose of 5 μg (evening dosing)

    Arm title
    		 Tio R2.5/Tio R1.25/Placebo
    Arm description
    		 Patients treated with Tiotropium 2.5 μg in period I, with Tiotropium 1.25 μg in period II and with a matching Placebo in period III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Tiotropium bromide/Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tio R2.5 - 2 puffs once daily for a total dose of 2.5 μg (evening dosing) Tio R1.25 - 2 puffs once daily for a total dose of 1.25 μg (evening dosing) Placebo - 2 puffs once daily (evening dosing)

    Number of subjects in period 2
    		Tio R5/Placebo/Tio R1.25 Tio R1.25/Tio R5/Tio R2.5 Placebo/Tio R2.5/Tio R5 Tio R2.5/Tio R1.25/Placebo
    Started
    26
    25
    26
    24
    Completed
    25
    25
    26
    23
    Not completed
    1
    0
    0
    1
         Other
    1
    -
    -
    -
         Non-compliant
    -
    -
    -
    1
    Period 3
    Period 3 title
    Period 3 (4 weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Tio R5/Placebo/Tio R1.25
    Arm description
    		 Patients treated with Tiotropium 5 μg in period I, with a matching Placebo in period II and with Tiotropium 1.25 μg in period III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Tiotropium bromide/Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tio R5 - 2 puffs once daily for a total dose of 5 μg (evening dosing) Placebo - 2 puffs once daily (evening dosing) Tio R1.25 - 2 puffs once daily for a total dose of 1.25 μg (evening dosing)

    Arm title
    		 Tio R1.25/Tio R5/Tio R2.5
    Arm description
    		 Patients treated with Tiotropium 1.25 μg in period I, with Tiotropium 5 μg in period II and with Tiotropium 2.5 μg in period III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Tiotropium bromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tio R1.25 - 2 puffs once daily for a total dose of 1.25 μg (evening dosing) Tio R5 - 2 puffs once daily for a total dose of 5 μg (evening dosing) Tio R2.5 - 2 puffs once daily for a total dose of 2.5 μg (evening dosing)

    Arm title
    		 Placebo/Tio R2.5/Tio R5
    Arm description
    		 Patients treated with a matching Placebo in period I, with Tiotropium 2.5 μg in period II and with Tiotropium 5 μg in period III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Placebo/Tiotropium bromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo - 2 puffs once daily (evening dosing) Tio R2.5 - 2 puffs once daily for a total dose of 2.5 μg (evening dosing) Tio R5 - 2 puffs once daily for a total dose of 5 μg (evening dosing)

    Arm title
    		 Tio R2.5/Tio R1.25/Placebo
    Arm description
    		 Patients treated with Tiotropium 2.5 μg in period I, with Tiotropium 1.25 μg in period II and with a matching Placebo in period III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.
    Arm type
    		 Treatment sequence

    Investigational medicinal product name
    Tiotropium bromide/Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tio R2.5 - 2 puffs once daily for a total dose of 2.5 μg (evening dosing) Tio R1.25 - 2 puffs once daily for a total dose of 1.25 μg (evening dosing) Placebo - 2 puffs once daily (evening dosing)

    Number of subjects in period 3
    		Tio R5/Placebo/Tio R1.25 Tio R1.25/Tio R5/Tio R2.5 Placebo/Tio R2.5/Tio R5 Tio R2.5/Tio R1.25/Placebo
    Started
    25
    25
    26
    23
    Completed
    24
    24
    26
    23
    Not completed
    1
    1
    0
    0
         Adverse event, non-fatal
    1
    -
    -
    -
         Consent withdrawn
    -
    1
    -
    -
    Period 4
    Period 4 title
    Overall trial (Treatment period)
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Placebo
    Arm description
    		 Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 puffs once daily (evening dosing)

    Arm title
    		 Tio R1.25
    Arm description
    		 Tiotropium 1.25 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium bromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 puffs once daily for a total dose of 1.25 μg (evening dosing)

    Arm title
    		 Tio R2.5
    Arm description
    		 Tiotropium 2.5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium bromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 puffs once daily for a total dose of 2.5 μg (evening dosing)

    Arm title
    		 Tio R5
    Arm description
    		 Tiotropium 5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tiotropium bromide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    2 puffs once daily for a total dose of 5 μg (evening dosing)

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Since the baseline characteristics are presented for the overall trial and at least one defined period had to be selected as a baseline period, overall trial (treatment period) was used to report the baseline characteristics.
    Number of subjects in period 4
    		Placebo Tio R1.25 Tio R2.5 Tio R5
    Started
    75
    75
    75
    80
    Completed
    74
    72
    74
    77
    Not completed
    1
    3
    1
    3
         Adverse event, non-fatal
    -
    1
    -
    1
         Other
    1
    1
    -
    1
         Non-compliant
    -
    1
    -
    1
         Consent withdrawn
    -
    -
    1
    -

    Baseline characteristics

    		 Close Top of page
    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 of the trial medication.
    Reporting group values
    		 Overall trial (Treatment period) Total
    Number of subjects
    		 105 105
    Age categorical
    Units: Subjects
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    		 14 ( 1.5 ) -
    Gender, Male/Female
    Units: Number
        Female
    		 38 38
        Male
    		 67 67
    Forced expiratory volume in 1s (FEV1)
    Units: Litre
        arithmetic mean (standard deviation)
    		 2.742 ( 0.697 ) -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Tio R5/Placebo/Tio R1.25
    Reporting group description
    		 Patients treated with Tiotropium 5 μg in period I, with a matching Placebo in period II and with Tiotropium 1.25 μg in period III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.

    Reporting group title
    Tio R1.25/Tio R5/Tio R2.5
    Reporting group description
    		 Patients treated with Tiotropium 1.25 μg in period I, with Tiotropium 5 μg in period II and with Tiotropium 2.5 μg in period III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.

    Reporting group title
    Placebo/Tio R2.5/Tio R5
    Reporting group description
    		 Patients treated with a matching Placebo in period I, with Tiotropium 2.5 μg in period II and with Tiotropium 5 μg in period III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.

    Reporting group title
    Tio R2.5/Tio R1.25/Placebo
    Reporting group description
    		 Patients treated with Tiotropium 2.5 μg in period I, with Tiotropium 1.25 μg in period II and with a matching Placebo in period III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.
    Reporting group title
    Tio R5/Placebo/Tio R1.25
    Reporting group description
    		 Patients treated with Tiotropium 5 μg in period I, with a matching Placebo in period II and with Tiotropium 1.25 μg in period III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.

    Reporting group title
    Tio R1.25/Tio R5/Tio R2.5
    Reporting group description
    		 Patients treated with Tiotropium 1.25 μg in period I, with Tiotropium 5 μg in period II and with Tiotropium 2.5 μg in period III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.

    Reporting group title
    Placebo/Tio R2.5/Tio R5
    Reporting group description
    		 Patients treated with a matching Placebo in period I, with Tiotropium 2.5 μg in period II and with Tiotropium 5 μg in period III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.

    Reporting group title
    Tio R2.5/Tio R1.25/Placebo
    Reporting group description
    		 Patients treated with Tiotropium 2.5 μg in period I, with Tiotropium 1.25 μg in period II and with a matching Placebo in period III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.
    Reporting group title
    Tio R5/Placebo/Tio R1.25
    Reporting group description
    		 Patients treated with Tiotropium 5 μg in period I, with a matching Placebo in period II and with Tiotropium 1.25 μg in period III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.

    Reporting group title
    Tio R1.25/Tio R5/Tio R2.5
    Reporting group description
    		 Patients treated with Tiotropium 1.25 μg in period I, with Tiotropium 5 μg in period II and with Tiotropium 2.5 μg in period III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.

    Reporting group title
    Placebo/Tio R2.5/Tio R5
    Reporting group description
    		 Patients treated with a matching Placebo in period I, with Tiotropium 2.5 μg in period II and with Tiotropium 5 μg in period III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.

    Reporting group title
    Tio R2.5/Tio R1.25/Placebo
    Reporting group description
    		 Patients treated with Tiotropium 2.5 μg in period I, with Tiotropium 1.25 μg in period II and with a matching Placebo in period III. All products were administered once daily (QD) in the evening, delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication. No washouts (off-treatment periods) between treatments.
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.

    Reporting group title
    Tio R1.25
    Reporting group description
    		 Tiotropium 1.25 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.

    Reporting group title
    Tio R2.5
    Reporting group description
    		 Tiotropium 2.5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.

    Reporting group title
    Tio R5
    Reporting group description
    		 Tiotropium 5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.

    Primary: Forced Expiratory Volume (FEV1) peak (0-3h) response

    		 Close Top of page
    End point title
    		 Forced Expiratory Volume (FEV1) peak (0-3h) response
    End point description
    The FEV1 peak (0-3h) response is determined at the end of the 4 week treatment period. This is the difference between the maximum FEV1 measured within the first 3 hours post dosing and the FEV1 baseline measurement. Analysis adjusted for treatment, period, patient and baseline using a mixed model. The analysis set used for this analysis was full analysis set (FAS) reduced to patients with non-missing FEV1 data. The FAS is defined as patients randomised, treated, with baseline data and at least one on-treatment efficacy measurement after 4 weeks on treatment within a period.
    End point type
    Primary
    End point timeframe
    Baseline and 4 weeks
    End point values
    		 Placebo Tio R1.25 Tio R2.5 Tio R5
    Number of subjects analysed
    74 [1]
    73 [2]
    74 [3]
    77 [4]
    Units: Litre
        least squares mean (standard error)
    0.489 ( 0.047 )
    0.556 ( 0.047 )
    0.546 ( 0.047 )
    0.602 ( 0.046 )
    Notes
    [1] - Full Analysis Set (FAS) reduced to patients with non-missing FEV1 data.
    [2] - Full Analysis Set (FAS) reduced to patients with non-missing FEV1 data.
    [3] - Full Analysis Set (FAS) reduced to patients with non-missing FEV1 data.
    [4] - Full Analysis Set (FAS) reduced to patients with non-missing FEV1 data.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Mixed model repeated measures (MMRM) was used. This MMRM model includes treatment, period and baseline as fixed effects, and patient as a random effect. Difference was calculated as Tio R5 minus Placebo. The actual number of subjects analyzed is 104. As this is an incomplete cross over study and arms are not mutually exclusive, the pre-specified, by the system automatically calculated number that is provided in the statistical analysis below (151) does not reflect the actual number.
    Comparison groups
    Placebo v Tio R5
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0043 [5]
    Method
    		 Mixed model repeated measures (MMRM)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.113
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.036
         upper limit
    		 0.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.039
    Notes
    [5] - First step of closed testing procedure, where the active treatments are compared to placebo. If this statisical test is significant at the 0.05 alpha level then proceed to comparison of the next lower dose to placebo.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Mixed model repeated measures (MMRM) was used. This MMRM model includes treatment, period and baseline as fixed effects, and patient as a random effect. Difference was calculated as Tio R2.5 minus Placebo. The actual number of subjects analyzed is 104. As this is an incomplete cross over study and arms are not mutually exclusive, the pre-specified, by the system automatically calculated number that is provided in the statistical analysis below (148) does not reflect the actual number.
    Comparison groups
    Placebo v Tio R2.5
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1484 [6]
    Method
    		 Mixed effect repeated measures (MMRM)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.057
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.021
         upper limit
    		 0.135
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.039
    Notes
    [6] - Second step of closed testing procedure. If this statisical test significant at the 0.05 alpha level then proceed to comparison of the next lower dose to placebo.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Mixed model repeated measures (MMRM) was used. This MMRM model includes treatment, period and baseline as fixed effects, and patient as a random effect. Difference was calculated as Tio R1.25 minus Placebo. The actual number of subjects analyzed is 104. As this is an incomplete cross over study and arms are not mutually exclusive, the pre-specified, by the system automatically calculated number that is provided in the statistical analysis below (147) does not reflect the actual number.
    Comparison groups
    Tio R1.25 v Placebo
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0664 [7]
    Method
    		 Mixed effect repeated measures (MMRM)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.067
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.005
         upper limit
    		 0.138
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.036
    Notes
    [7] - This test is considered as descriptive.
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Mixed model repeated measures (MMRM) was used. This MMRM model includes treatment, period and baseline as fixed effects, and patient as a random effect. Difference was calculated as Tio R5 minus Tio R1.25. The actual number of subjects analyzed is 104. As this is an incomplete cross over study and arms are not mutually exclusive, the pre-specified, by the system automatically calculated number that is provided in the statistical analysis below (150) does not reflect the actual number.
    Comparison groups
    Tio R1.25 v Tio R5
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    		 Mixed effect repeated measures (MMRM)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.046
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.031
         upper limit
    		 0.124
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.039
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Mixed model repeated measures (MMRM) was used. This MMRM model includes treatment, period and baseline as fixed effects, and patient as a random effect. Difference was calculated as Tio R5 minus Tio R2.5. The actual number of subjects analyzed is 104. As this is an incomplete cross over study and arms are not mutually exclusive, the pre-specified, by the system automatically calculated number that is provided in the statistical analysis below (151) does not reflect the actual number.
    Comparison groups
    Tio R2.5 v Tio R5
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    		 Mixed effect repeated measures (MMRM)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.056
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.014
         upper limit
    		 0.126
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.036
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Mixed model repeated measures (MMRM) was used. This MMRM model includes treatment, period and baseline as fixed effects, and patient as a random effect. Difference was calculated as Tio R2.5 minus Tio R1.25. The actual number of subjects analyzed is 104. As this is an incomplete cross over study and arms are not mutually exclusive, the pre-specified, by the system automatically calculated number that is provided in the statistical analysis below (147) does not reflect the actual number.
    Comparison groups
    Tio R2.5 v Tio R1.25
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    		 Mixed effect repeated measures (MMRM)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.088
         upper limit
    		 0.069
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.04

    Secondary: Trough FEV1 response

    		 Close Top of page
    End point title
    		 Trough FEV1 response
    End point description
    The trough FEV1 is defined as the pre-dose FEV1 measured just prior to the last administration of randomised treatment. Response was defined as the change from baseline at the end of the 4-week treatment period. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 weeks
    End point values
    		 Placebo Tio R1.25 Tio R2.5 Tio R5
    Number of subjects analysed
    74 [8]
    73 [9]
    74 [10]
    77 [11]
    Units: Litre
        least squares mean (standard error)
    0.292 ( 0.045 )
    0.384 ( 0.045 )
    0.353 ( 0.045 )
    0.442 ( 0.045 )
    Notes
    [8] - FAS with non-missing FEV1 data.
    [9] - FAS with non-missing FEV1 data.
    [10] - FAS with non-missing FEV1 data.
    [11] - FAS with non-missing FEV1 data.
    No statistical analyses for this end point

    Secondary: FEV1 Area under the curve from 0 to 3 h (AUC0-3h) response

    		 Close Top of page
    End point title
    		 FEV1 Area under the curve from 0 to 3 h (AUC0-3h) response
    End point description
    FEV1 (AUC0-3h) will be calculated as the area under the curve from 0 to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. Response was defined as the change from baseline at the end of the 4-week treatment period. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 weeks
    End point values
    		 Placebo Tio R1.25 Tio R2.5 Tio R5
    Number of subjects analysed
    74 [12]
    73 [13]
    74 [14]
    77 [15]
    Units: Litre
        least squares mean (standard error)
    0.363 ( 0.045 )
    0.455 ( 0.045 )
    0.434 ( 0.045 )
    0.497 ( 0.045 )
    Notes
    [12] - FAS with non-missing FEV1 data.
    [13] - FAS with non-missing FEV1 data.
    [14] - FAS with non-missing FEV1 data.
    [15] - FAS with non-missing FEV1 data.
    No statistical analyses for this end point

    Secondary: FEV1 individual measurements response at each time-point

    		 Close Top of page
    End point title
    		 FEV1 individual measurements response at each time-point
    End point description
    Individual FEV1 measurements at each time-point ("personal best"). Response was defined as the change from baseline at the end of the 4-week treatment period. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 weeks (10 min pre-dose, 30 min, 1,2,3 hours (hr) post-dose)
    End point values
    		 Placebo Tio R1.25 Tio R2.5 Tio R5
    Number of subjects analysed
    74 [16]
    73 [17]
    74 [18]
    77 [19]
    Units: Litre
    least squares mean (standard error)
        Timepoint -0:10 hr response
    0.292 ( 0.045 )
    0.384 ( 0.045 )
    0.353 ( 0.045 )
    0.442 ( 0.045 )
        Timepoint 0:30 hr response
    0.337 ( 0.047 )
    0.456 ( 0.047 )
    0.407 ( 0.047 )
    0.486 ( 0.047 )
        Timepoint 1:00 hr response
    0.353 ( 0.048 )
    0.456 ( 0.048 )
    0.416 ( 0.048 )
    0.505 ( 0.047 )
        Timepoint 2:00 hr response
    0.394 ( 0.047 )
    0.467 ( 0.048 )
    0.453 ( 0.047 )
    0.501 ( 0.047 )
        Timepoint 3:00 hr response
    0.396 ( 0.048 )
    0.467 ( 0.048 )
    0.489 ( 0.048 )
    0.497 ( 0.047 )
    Notes
    [16] - FAS with non-missing FEV1 data.
    [17] - FAS with non-missing FEV1 data.
    [18] - FAS with non-missing FEV1 data.
    [19] - FAS with non-missing FEV1 data.
    No statistical analyses for this end point

    Secondary: Forced Vital Capacity (FVC) peak (0-3h) response

    		 Close Top of page
    End point title
    		 Forced Vital Capacity (FVC) peak (0-3h) response
    End point description
    The FVC peak (0-3h) response is determined at the end of the 4 week treatment period. This is the difference between the maximum FVC measured within the first 3 hours post dosing and the FVC baseline measurement. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 weeks
    End point values
    		 Placebo Tio R1.25 Tio R2.5 Tio R5
    Number of subjects analysed
    74 [20]
    73 [21]
    74 [22]
    77 [23]
    Units: Litre
        least squares mean (standard error)
    0.546 ( 0.049 )
    0.554 ( 0.049 )
    0.554 ( 0.048 )
    0.548 ( 0.048 )
    Notes
    [20] - FAS with non-missing FVC data.
    [21] - FAS with non-missing FVC data.
    [22] - FAS with non-missing FVC data.
    [23] - FAS with non-missing FVC data.
    No statistical analyses for this end point

    Secondary: FVC Trough response

    		 Close Top of page
    End point title
    		 FVC Trough response
    End point description
    The trough FVC response is defined as the pre-dose FVC measured just prior to the last administration of randomised treatment. Response was defined as the change from baseline at the end of the 4-week treatment period. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 weeks
    End point values
    		 Placebo Tio R1.25 Tio R2.5 Tio R5
    Number of subjects analysed
    74 [24]
    73 [25]
    74 [26]
    77 [27]
    Units: Litre
        least squares mean (standard error)
    0.357 ( 0.047 )
    0.375 ( 0.047 )
    0.381 ( 0.047 )
    0.4 ( 0.047 )
    Notes
    [24] - FAS with non-missing FVC data.
    [25] - FAS with non-missing FVC data.
    [26] - FAS with non-missing FVC data.
    [27] - FAS with non-missing FVC data.
    No statistical analyses for this end point

    Secondary: FVC Area under the curve from 0 to 3 h (AUC0-3h) response

    		 Close Top of page
    End point title
    		 FVC Area under the curve from 0 to 3 h (AUC0-3h) response
    End point description
    FVC (AUC0-3h) will be calculated as the area under the curve from 0 to 3 hours using the trapezoidal rule divided by the observation time (3 hours) to report in litres. Response was defined as the change from baseline at the end of the 4-week treatment period. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 weeks
    End point values
    		 Placebo Tio R1.25 Tio R2.5 Tio R5
    Number of subjects analysed
    74 [28]
    73 [29]
    74 [30]
    77 [31]
    Units: Litre
        least squares mean (standard error)
    0.413 ( 0.046 )
    0.441 ( 0.046 )
    0.417 ( 0.045 )
    0.429 ( 0.045 )
    Notes
    [28] - FAS with non-missing FVC data.
    [29] - FAS with non-missing FVC data.
    [30] - FAS with non-missing FVC data.
    [31] - FAS with non-missing FVC data.
    No statistical analyses for this end point

    Secondary: FVC individual measurements at each time-point

    		 Close Top of page
    End point title
    		 FVC individual measurements at each time-point
    End point description
    Individual FVC measurements at each time-point ("personal best"). Response was defined as the change from baseline at the end of the 4-week treatment period. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 weeks (10 min pre-dose, 30 min, 1,2,3 hours post-dose)
    End point values
    		 Placebo Tio R1.25 Tio R2.5 Tio R5
    Number of subjects analysed
    74 [32]
    73 [33]
    74 [34]
    77 [35]
    Units: Litre
    least squares mean (standard error)
        Timepoint -0:10 hr response
    0.357 ( 0.047 )
    0.375 ( 0.047 )
    0.381 ( 0.047 )
    0.4 ( 0.047 )
        Timepoint 0:30 hr response
    0.397 ( 0.049 )
    0.434 ( 0.049 )
    0.394 ( 0.049 )
    0.409 ( 0.049 )
        Timepoint 1:00 hr response
    0.417 ( 0.049 )
    0.443 ( 0.05 )
    0.387 ( 0.049 )
    0.448 ( 0.049 )
        Timepoint 2:00 hr response
    0.429 ( 0.048 )
    0.438 ( 0.048 )
    0.444 ( 0.048 )
    0.423 ( 0.048 )
        Timepoint 3:00 hr response
    0.43 ( 0.048 )
    0.461 ( 0.048 )
    0.454 ( 0.048 )
    0.456 ( 0.048 )
    Notes
    [32] - FAS with non-missing FVC data.
    [33] - FAS with non-missing FVC data.
    [34] - FAS with non-missing FVC data.
    [35] - FAS with non-missing FVC data.
    No statistical analyses for this end point

    Secondary: Forced expiratory flow (FEF) 25-75% individual measurements response at each time point

    		 Close Top of page
    End point title
    		 Forced expiratory flow (FEF) 25-75% individual measurements response at each time point
    End point description
    FEF 25-75% is the mean forced expiratory flow between 25% and 75% of the FVC determined at the end of the 4-week treatment period. This is often referred to as the maximum midexpiratory flow. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 weeks (10 min pre-dose, 30 min, 1,2,3 hours post-dose)
    End point values
    		 Placebo Tio R1.25 Tio R2.5 Tio R5
    Number of subjects analysed
    49 [36]
    47 [37]
    47 [38]
    50 [39]
    Units: Litre
    least squares mean (standard error)
        Timepoint -0:10 hr response
    0.242 ( 0.081 )
    0.533 ( 0.082 )
    0.38 ( 0.082 )
    0.566 ( 0.08 )
        Timepoint 0:30 hr response
    0.268 ( 0.083 )
    0.643 ( 0.084 )
    0.513 ( 0.084 )
    0.647 ( 0.082 )
        Timepoint 1:00 hr response
    0.321 ( 0.087 )
    0.655 ( 0.087 )
    0.569 ( 0.087 )
    0.641 ( 0.086 )
        Timepoint 2:00 hr response
    0.357 ( 0.088 )
    0.678 ( 0.089 )
    0.607 ( 0.089 )
    0.622 ( 0.087 )
        Timepoint 3:00 hr response
    0.329 ( 0.083 )
    0.662 ( 0.084 )
    0.616 ( 0.084 )
    0.62 ( 0.083 )
    Notes
    [36] - FAS with non-missing FEF data
    [37] - FAS with non-missing FEF data
    [38] - FAS with non-missing FEF data
    [39] - FAS with non-missing FEF data
    No statistical analyses for this end point

    Secondary: Mean morning peak expiratory flow (PEF) response

    		 Close Top of page
    End point title
    		 Mean morning peak expiratory flow (PEF) response
    End point description
    Mean morning PEF assessed by patients at home. Response was defined as the change from baseline based on the weekly mean of the last week of treatment for each treatment period. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 weeks
    End point values
    		 Placebo Tio R1.25 Tio R2.5 Tio R5
    Number of subjects analysed
    73 [40]
    75 [41]
    73 [42]
    79 [43]
    Units: Litre/min
        least squares mean (standard error)
    7.267 ( 6.152 )
    18.613 ( 6.118 )
    23.185 ( 6.146 )
    20.491 ( 6.031 )
    Notes
    [40] - FAS with non-missing morning PEF data
    [41] - FAS with non-missing morning PEF data
    [42] - FAS with non-missing morning PEF data
    [43] - FAS with non-missing morning PEF data
    No statistical analyses for this end point

    Secondary: Mean evening PEF response

    		 Close Top of page
    End point title
    		 Mean evening PEF response
    End point description
    Mean evening PEF assessed by patients at home. Response was defined as the change from baseline based on the weekly mean of the last week of treatment for each treatment period. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 weeks
    End point values
    		 Placebo Tio R1.25 Tio R2.5 Tio R5
    Number of subjects analysed
    73 [44]
    74 [45]
    75 [46]
    79 [47]
    Units: Litre/min
        least squares mean (standard error)
    -0.552 ( 6.098 )
    5.985 ( 6.089 )
    18.971 ( 6.043 )
    16.565 ( 5.97 )
    Notes
    [44] - FAS with non-missing evening PEF data
    [45] - FAS with non-missing evening PEF data
    [46] - FAS with non-missing evening PEF data
    [47] - FAS with non-missing evening PEF data
    No statistical analyses for this end point

    Secondary: Change from baseline in the number of puffs of rescue medication per day

    		 Close Top of page
    End point title
    		 Change from baseline in the number of puffs of rescue medication per day
    End point description
    Mean number of inhalations (puffs) of unscheduled rescue salbutamol therapy during whole day. Response was defined as change from baseline based on the weekly mean of the last week of treatment for each treatment periodAnalysis adjusted for treatment, period, patient and baseline using a mixed model.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 weeks
    End point values
    		 Placebo Tio R1.25 Tio R2.5 Tio R5
    Number of subjects analysed
    73 [48]
    73 [49]
    73 [50]
    79 [51]
    Units: Puffs/day
        least squares mean (standard error)
    -0.412 ( 0.155 )
    -0.635 ( 0.156 )
    -0.521 ( 0.154 )
    -0.528 ( 0.151 )
    Notes
    [48] - FAS with non-missing data for rescue medication
    [49] - FAS with non-missing data for rescue medication
    [50] - FAS with non-missing data for rescue medication
    [51] - FAS with non-missing data for rescue medication
    No statistical analyses for this end point

    Secondary: Control of asthma as assessed by Asthma control questionnaire (ACQ)

    		 Close Top of page
    End point title
    		 Control of asthma as assessed by Asthma control questionnaire (ACQ)
    End point description
    ACQ is a questionnaire consisting of a seven point Likert scale ranging from 0 to 6, whereby 0 represents good control and 6 represents poor control of asthma. The scale describes the frequency and severity of asthma symptoms. This endpoint was determined at the end of each 4-week treatment period. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
    End point type
    Secondary
    End point timeframe
    4 weeks
    End point values
    		 Placebo Tio R1.25 Tio R2.5 Tio R5
    Number of subjects analysed
    74 [52]
    73 [53]
    74 [54]
    77 [55]
    Units: Units on a scale
        least squares mean (standard error)
    1.371 ( 0.078 )
    1.189 ( 0.079 )
    1.366 ( 0.078 )
    1.287 ( 0.078 )
    Notes
    [52] - FAS with non-missing ACQ data
    [53] - FAS with non-missing ACQ data
    [54] - FAS with non-missing ACQ data
    [55] - FAS with non-missing ACQ data
    No statistical analyses for this end point

    Secondary: Change from baseline in mean number of nighttime awakenings

    		 Close Top of page
    End point title
    		 Change from baseline in mean number of nighttime awakenings
    End point description
    Mean number of nighttime awakenings due to asthma symptoms as assessed by patients eDiary incorporated in the AM3® device. Response was defined as change from baseline based on the weekly mean of the last week of treatment for each treatment period. Analysis adjusted for treatment, period, patient and baseline using a mixed model.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 weeks
    End point values
    		 Placebo Tio R1.25 Tio R2.5 Tio R5
    Number of subjects analysed
    73 [56]
    75 [57]
    73 [58]
    79 [59]
    Units: Night awakenings per week
        least squares mean (standard error)
    -0.086 ( 0.03 )
    -0.027 ( 0.03 )
    -0.074 ( 0.03 )
    -0.066 ( 0.029 )
    Notes
    [56] - FAS with non-missing data for nighttime awakenings
    [57] - FAS with non-missing data for nighttime awakenings
    [58] - FAS with non-missing data for nighttime awakenings
    [59] - FAS with non-missing data for nighttime awakenings
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information [1]
    Timeframe for reporting adverse events
    4 weeks + 30 days if in last period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.

    Reporting group title
    Tio R1.25
    Reporting group description
    		 Tiotropium 1.25 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.

    Reporting group title
    Tio R2.5
    Reporting group description
    		 Tiotropium 2.5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.

    Reporting group title
    Tio R5
    Reporting group description
    		 Tiotropium 5 microgram once daily (QD) in the evening delivered by the Respimat® inhaler, on top on maintenance therapy with an inhaled corticosteroid controller medication.

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Although non-serious adverse events were reported, the 5% threshold wasn't reached on a preferred term level.
    Serious adverse events
    		 Placebo Tio R1.25 Tio R2.5 Tio R5
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    1 / 80 (1.25%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Nervous system disorders
    Presyncope
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 75 (0.00%)
    0 / 75 (0.00%)
    1 / 80 (1.25%)
         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
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    H1N1 influenza
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 80 (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
    Pneumonia mycoplasmal
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 80 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Tio R1.25 Tio R2.5 Tio R5
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 75 (0.00%)
    0 / 75 (0.00%)
    0 / 80 (0.00%)

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Aug 2010
    Flowcharts, inclusion criterion 4, instructions for use of the AM3® device and instructions for 24 h lung function testing was revised for consistency, practicality, and clarity.

    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
    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.

    European Medicines Agency © 1995-Thu May 02 21:36:50 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA