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    Clinical Trial Results:
    A 4-week, randomised, double-blind, parallel group study to evaluate the efficacy and safety of Tiotropium+Olodaterol fixeddose combination [5/5 μg] delivered by the RESPIMAT® inhaler versus the free combination of tiotropium 5 μg and olodaterol 5 μg delivered by separate RESPIMAT® inhalers in patients with Chronic Obstructive Pulmonary Disease [COPD]

    Summary
    EudraCT number
    		 2015-003879-29
    Trial protocol
    		 FI   AT   SI   DK   FR  
    Global end of trial date
    30 Jan 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Dec 2017
    First version publication date
    27 Dec 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1237.49
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02683109
    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, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 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
    13 Mar 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Jan 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this study was to show that the fixed-dose combination of Tiotropium+Olodaterol [5/5 μg] [Tio+Olo Fixed Dose Combination (FDC)] is non-inferior to the free combination of its individual components Tiotropium 5μg and Olodaterol 5 μg [Tio/Olo free combination], all delivered by the RESPIMAT® inhaler, in patients with moderate to severe COPD.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be 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
    		 Tiotropium/Olodaterol free combination solution for inhalation was the comparator in this study.
    Actual start date of recruitment
    01 Apr 2016
    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
    Austria: 30
    Country: Number of subjects enrolled
    Denmark: 39
    Country: Number of subjects enrolled
    France: 48
    Country: Number of subjects enrolled
    Finland: 46
    Country: Number of subjects enrolled
    Slovenia: 58
    Worldwide total number of subjects
    221
    EEA total number of subjects
    221
    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)
    75
    From 65 to 84 years
    146
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Definition: Open-Label Treated Set [OLTS]: This patient set includes all patients who signed the informed consent and were dispensed open-label study medication during the run-in period prior to randomisation and were documented to have taken any dose of this medication.

    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 was violated.

    Period 1
    Period 1 title
    Overall Study (Treatment period) (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 T+O 5/5
    Arm description
    		 The subjects were administered Tiotropium [T] + Olodaterol [O] Fixed Dose Combination [FDC] solution for inhalation 2.5 μg/2.5 μg per actuation, 2 inhalations orally once daily via RESPIMAT® inhaler. Placebo matching Tiotropium solution was administered 2 inhalations once daily via RESPIMAT® inhaler.
    Arm type
    		 Experimental

    Investigational medicinal product name
    T+O [FDC]
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Oral use
    Dosage and administration details
    Tiotropium+Olodaterol FDC was administered 2.5 μg/2.5 μg per actuation, 2 inhalations once daily via RESPIMAT® inhaler.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was administered 2 inhalations once daily.

    Arm title
    		 T 5/O 5
    Arm description
    		 The subjects were administered Tiotropium solution for inhalation, 2.5 μg per actuation + Olodaterol solution for inhalation, 2.5 μg per actuation as a free combination. Two inhalations were administered once daily [a.m. dosing] via RESPIMAT® inhaler for both Tiotropium and Olodaterol.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Oral use
    Dosage and administration details
    Tiotropium was administered 2.5 μg per actuation, 2 inhalations once daily via RESPIMAT® inhaler.

    Investigational medicinal product name
    Olodaterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Oral use
    Dosage and administration details
    Olodaterol was administered 2.5 μg per actuation, 2 inhalations once daily via RESPIMAT® inhaler.

    Number of subjects in period 1
    		T+O 5/5 T 5/O 5
    Started
    110
    111
    Completed
    109
    111
    Not completed
    1
    0
         Adverse event, non-fatal
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    T+O 5/5
    Reporting group description
    		 The subjects were administered Tiotropium [T] + Olodaterol [O] Fixed Dose Combination [FDC] solution for inhalation 2.5 μg/2.5 μg per actuation, 2 inhalations orally once daily via RESPIMAT® inhaler. Placebo matching Tiotropium solution was administered 2 inhalations once daily via RESPIMAT® inhaler.

    Reporting group title
    T 5/O 5
    Reporting group description
    		 The subjects were administered Tiotropium solution for inhalation, 2.5 μg per actuation + Olodaterol solution for inhalation, 2.5 μg per actuation as a free combination. Two inhalations were administered once daily [a.m. dosing] via RESPIMAT® inhaler for both Tiotropium and Olodaterol.

    Reporting group values
    		 T+O 5/5 T 5/O 5 Total
    Number of subjects
    		 110 111 221
    Age categorical
    Units: Subjects
    Age Continuous
    Treated set [TS]: This patient set is nested within the RS and includes all patients who were dispensed study medication and were documented to have taken any dose of study medication. Definition: [RS]: This patient set is nested within the OLTS and includes all patients who signed the informed consent form and were also randomised, regardless of whether the patient was treated with study medication or not.
    Units: years
        arithmetic mean (standard deviation)
    		 66.5 ± 7.1 66.5 ± 6.4 -
    Gender, Male/Female
    TS.
    Units: Subjects
        Female
    		 33 30 63
        Male
    		 77 81 158

    End points

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    End points reporting groups
    Reporting group title
    T+O 5/5
    Reporting group description
    		 The subjects were administered Tiotropium [T] + Olodaterol [O] Fixed Dose Combination [FDC] solution for inhalation 2.5 μg/2.5 μg per actuation, 2 inhalations orally once daily via RESPIMAT® inhaler. Placebo matching Tiotropium solution was administered 2 inhalations once daily via RESPIMAT® inhaler.

    Reporting group title
    T 5/O 5
    Reporting group description
    		 The subjects were administered Tiotropium solution for inhalation, 2.5 μg per actuation + Olodaterol solution for inhalation, 2.5 μg per actuation as a free combination. Two inhalations were administered once daily [a.m. dosing] via RESPIMAT® inhaler for both Tiotropium and Olodaterol.

    Primary: Trough Forced Expiratory Volume in 1 second [FEV1][in Liter] after 28 days of treatment

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    End point title
    		 Trough Forced Expiratory Volume in 1 second [FEV1][in Liter] after 28 days of treatment
    End point description
    This outcome measure presents FEV1 after 28 days of treatment [measurement on Day 29]. Trough FEV1 was defined as the FEV1 value at the end of the dosing interval [24 hours], and was measured at 24 hours [+/- 10 minutes] after trial medication administration at Visit 5. Full Analysis Set [FAS]: This patient set is nested within the TS and includes patients who had a baseline measurement and at least one post-baseline measurement for the primary endpoint. The FEV1 measurement at Visit 4, which was 24 hours after the last open-label run-in treatment intake and 15 minutes before the first double-blind study drug intake was the baseline measurement.
    End point type
    Primary
    End point timeframe
    Day 29
    End point values
    		 T+O 5/5 T 5/O 5
    Number of subjects analysed
    108 [1]
    108 [2]
    Units: Liter
        arithmetic mean (standard error)
    1.422 ± 0.016
    1.399 ± 0.016
    Notes
    [1] - FAS.
    [2] - FAS.
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The primary analysis was conducted using an Analysis of Covariance [ANCOVA] model including treatment as fixed categorical effect and baseline as continuous covariate.
    Comparison groups
    T+O 5/5 v T 5/O 5
    Number of subjects included in analysis
    216
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean
    Point estimate
    0.024
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.067
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.022
    Notes
    [3] - Non-inferiority of the Tio+Olo FDC versus the Tio/Olo free combination was tested at the one-sided α-level of 0.025 using a non-inferiority margin of 0.1 L.

    Secondary: Trough Forced Vital Capacity [FVC] [in Liter] after 28 days of treatment

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    End point title
    		 Trough Forced Vital Capacity [FVC] [in Liter] after 28 days of treatment
    End point description
    This outcome measure presents trough FVC after 28 days of treatment [measurement on Day 29]. The FVC measurement at Visit 4, which was 24 hours after the last open-label run-in treatment intake and 15 minutes before the first double-blind study drug intake was the baseline measurement for FVC.
    End point type
    Secondary
    End point timeframe
    Day 29
    End point values
    		 T+O 5/5 T 5/O 5
    Number of subjects analysed
    108 [4]
    108 [5]
    Units: Liter
        arithmetic mean (standard error)
    3.126 ± 0.024
    3.121 ± 0.024
    Notes
    [4] - FAS.
    [5] - FAS.
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The secondary analysis was conducted using an ANCOVA model including treatment as fixed categorical effect and baseline as continuous covariate.
    Comparison groups
    T+O 5/5 v T 5/O 5
    Number of subjects included in analysis
    216
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8648
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean
    Point estimate
    0.006
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.061
         upper limit
    		 0.073
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.034

    Secondary: Chronic Obstructive Pulmonary Disease [COPD] Assessment Test™ [CAT] score on Day 28

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    End point title
    		 Chronic Obstructive Pulmonary Disease [COPD] Assessment Test™ [CAT] score on Day 28
    End point description
    This outcome measure presents COPD assessment test score on Day 28. The COPD Assessment Test™ is a short 8-item questionnaire for assessment and monitoring of COPD health status in routine practice. Its scale is 0-40 [high score = poor health]. The CAT measurement on Visit 4 prior to the first dose of double-blind study drug was the baseline for CAT.
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 T+O 5/5 T 5/O 5
    Number of subjects analysed
    108 [6]
    107 [7]
    Units: Score on scale
        arithmetic mean (standard error)
    15.423 ± 0.377
    15.750 ± 0.379
    Notes
    [6] - FAS.
    [7] - FAS. One patient in the T 5/O 5 free combination group had missing data for the CAT questionnaire.
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The secondary analysis was conducted using an ANCOVA model including treatment as fixed categorical effect and baseline as continuous covariate.
    Comparison groups
    T+O 5/5 v T 5/O 5
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.542
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean
    Point estimate
    -0.327
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.384
         upper limit
    		 0.729
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.536

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first drug administration until 28 days after last drug administration, up to 49 days.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    T+O 5/5
    Reporting group description
    		 The subjects were administered Tiotropium [T] + Olodaterol [O] Fixed Dose Combination [FDC] solution for inhalation 2.5 μg/2.5 μg per actuation, 2 inhalations orally once daily via RESPIMAT® inhaler. Placebo matching Tiotropium solution was administered 2 inhalations once daily via RESPIMAT® inhaler.

    Reporting group title
    Total
    Reporting group description
    		 The total number of subjects who were administered T+O 5/5 or T 5/O 5.

    Reporting group title
    T 5/O 5
    Reporting group description
    		 The subjects were administered Tiotropium solution for inhalation, 2.5 μg per actuation + Olodaterol solution for inhalation, 2.5 μg per actuation as a free combination. Two inhalations were administered once daily [a.m. dosing] via RESPIMAT® inhaler for both Tiotropium and Olodaterol.

    Serious adverse events
    		 T+O 5/5 Total T 5/O 5
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 110 (0.91%)
    3 / 221 (1.36%)
    2 / 111 (1.80%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 221 (0.45%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 110 (0.91%)
    1 / 221 (0.45%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 110 (0.00%)
    1 / 221 (0.45%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 T+O 5/5 Total T 5/O 5
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 110 (8.18%)
    18 / 221 (8.14%)
    9 / 111 (8.11%)
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    9 / 110 (8.18%)
    18 / 221 (8.14%)
    9 / 111 (8.11%)
         occurrences all number
    10
    19
    9

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 May 2016
    The amendment changed the exclusion criterion 5 to exclude patients with a current diagnosis of asthma, not with a history of asthma, as the original Clinical Trial Protocol [CTP] stated. Clarifications concerning the Interactive Response Technology [IRT] call, dispensation of study medications, and collection of vital signs, COPD Assessment TestTM [CAT], and compliance data were added.

    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
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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
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