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    Clinical Trial Results:
    A randomized, double-blind, multicenter, 2-period single-dose cross-over study to assess the early bronchodilation of glycopyrronium bromide (44 µg o.d.) compared to tiotropium (18 µg. o.d.) in patients with moderate to severe COPD Due to EudraCT system limitations, which EMA is aware of, results of crossover studies are not accurately represented in this record. Please go to https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.

    Summary
    EudraCT number
    		 2013-001445-13
    Trial protocol
    		 DE  
    Global end of trial date
    09 Jan 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Jul 2018
    First version publication date
    25 Jul 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CNVA237ADE02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01922271
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111 ,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111 ,
    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
    09 Jan 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jan 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that glycopyrronium bromide 44 µg q.d has superior efficacy compared to tiotropium 18 µg q. d. on early bronchodilation, determined by forced expiratory volume in 1 second (FEV1) area under the curve at 0 to 2 hours (AUC 0-2h), in moderate to severe chronic obstructive pulmonary disease (COPD) patients.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial. In addition, patients who experienced a moderate to severe COPD exacerbation had to be discontinued from study medication and the trial immediately. At the start of screening (Visit 1), all patients were provided with a short acting β2-agonist (salbutamol 100 μg) which they were instructed to use throughout the trial (when required) as rescue medication only. Nebulized salbutamol was not allowed as rescue medication. No other rescue treatment was permitted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Aug 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 152
    Worldwide total number of subjects
    152
    EEA total number of subjects
    152
    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)
    98
    From 65 to 84 years
    54
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 It was anticipated that at least 180 patients would be need to be screened to randomize 150 patients. Dropouts were not replaced. At the end of the study, 197 patients were screened and 152 patients randomized at 14 centers in Germany, with 76 patients per sequence.

    Period 1
    Period 1 title
    Period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Data analyst, Assessor, Subject
    Blinding implementation details
    A double-dummy design was used because the identity of the study drugs could not be disguised due to their different forms.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 NVA237 Followed by Tiotropium
    Arm description
    		 NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via HandiHaler® on Day 1 and Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) on Day 8.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Glycopyrronium Bromide
    Investigational medicinal product code
    NVA237 44 μg
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    NVA237 44 μg inhalation capsules o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via HandiHaler® at Visit 3 and Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 4.

    Investigational medicinal product name
    Placebo to Tiotropium 18 μg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, pre-dispensed
    Routes of administration
    Inhalation use
    Dosage and administration details
    NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via HandiHaler® at Visit 3 and Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 4.

    Investigational medicinal product name
    Tiotropium 18 μg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, pre-dispensed
    Routes of administration
    Inhalation use
    Dosage and administration details
    NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via HandiHaler® at Visit 3 and Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 4.

    Investigational medicinal product name
    Placebo to NVA237 44 μg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via HandiHaler® at Visit 3 and Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 4.

    Arm title
    		 Tiotropium Followed by NVA237
    Arm description
    		 Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) on Day 1 and NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via Handihaler® on Day 8.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, pre-dispensed
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 3 and NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via Handihaler® at Visit 4.

    Investigational medicinal product name
    Placebo to NVA237 44 μg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 3 and NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via Handihaler® at Visit 4.

    Investigational medicinal product name
    Glycopyrronium Bromide
    Investigational medicinal product code
    NVA237 44 μg
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 3 and NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via Handihaler® at Visit 4.

    Investigational medicinal product name
    Placebo to Tiotropium 18 μg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, pre-dispensed
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 3 and NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via Handihaler® at Visit 4.

    Number of subjects in period 1
    		NVA237 Followed by Tiotropium Tiotropium Followed by NVA237
    Started
    76
    76
    Completed
    76
    76
    Period 2
    Period 2 title
    Washout Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    A double-dummy design was used because the identity of the study drugs could not be disguised due to their different forms.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 NVA237 Followed by Tiotropium
    Arm description
    		 NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via HandiHaler® at Visit 3 and Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 4.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Glycopyrronium Bromide
    Investigational medicinal product code
    NVA237 44 μg
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    NVA237 44 μg inhalation capsules o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via HandiHaler® at Visit 3 and Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 4.

    Investigational medicinal product name
    Placebo to Tiotropium 18 μg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, pre-dispensed
    Routes of administration
    Inhalation use
    Dosage and administration details
    NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via HandiHaler® at Visit 3 and Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 4.

    Investigational medicinal product name
    Tiotropium 18 μg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, pre-dispensed
    Routes of administration
    Inhalation use
    Dosage and administration details
    NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via HandiHaler® at Visit 3 and Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 4.

    Investigational medicinal product name
    Placebo to NVA237 44 μg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via HandiHaler® at Visit 3 and Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 4.

    Arm title
    		 Tiotropium Followed by NVA237
    Arm description
    		 Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 3 and NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via Handihaler® at Visit 4.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, pre-dispensed
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 3 and NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via Handihaler® at Visit 4.

    Investigational medicinal product name
    Placebo to NVA237 44 μg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 3 and NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via Handihaler® at Visit 4.

    Investigational medicinal product name
    Glycopyrronium Bromide
    Investigational medicinal product code
    NVA237 44 μg
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 3 and NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via Handihaler® at Visit 4.

    Investigational medicinal product name
    Placebo to Tiotropium 18 μg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, pre-dispensed
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 3 and NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via Handihaler® at Visit 4.

    Number of subjects in period 2
    		NVA237 Followed by Tiotropium Tiotropium Followed by NVA237
    Started
    76
    76
    Completed
    75
    76
    Not completed
    1
    0
         Consent withdrawn by subject
    1
    -
    Period 3
    Period 3 title
    Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    A double-dummy design was used because the identity of the study drugs could not be disguised due to their different forms.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 NVA237 Followed by Tiotropium
    Arm description
    		 NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via HandiHaler® at Visit 3 and Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 4.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Glycopyrronium Bromide
    Investigational medicinal product code
    NVA237 44 μg
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    NVA237 44 μg inhalation capsules o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via HandiHaler® at Visit 3 and Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 4.

    Investigational medicinal product name
    Placebo to Tiotropium 18 μg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, pre-dispensed
    Routes of administration
    Inhalation use
    Dosage and administration details
    NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via HandiHaler® at Visit 3 and Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 4.

    Investigational medicinal product name
    Tiotropium 18 μg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, pre-dispensed
    Routes of administration
    Inhalation use
    Dosage and administration details
    NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via HandiHaler® at Visit 3 and Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 4.

    Investigational medicinal product name
    Placebo to NVA237 44 μg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via HandiHaler® at Visit 3 and Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 4.

    Arm title
    		 Tiotropium Followed by NVA237
    Arm description
    		 Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 3 and NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via Handihaler® at Visit 4.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, pre-dispensed
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 3 and NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via Handihaler® at Visit 4.

    Investigational medicinal product name
    Placebo to NVA237 44 μg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 3 and NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via Handihaler® at Visit 4.

    Investigational medicinal product name
    Glycopyrronium Bromide
    Investigational medicinal product code
    NVA237 44 μg
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 3 and NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via Handihaler® at Visit 4.

    Investigational medicinal product name
    Placebo to Tiotropium 18 μg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, pre-dispensed
    Routes of administration
    Inhalation use
    Dosage and administration details
    Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 3 and NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via Handihaler® at Visit 4.

    Number of subjects in period 3
    		NVA237 Followed by Tiotropium Tiotropium Followed by NVA237
    Started
    75
    76
    Completed
    75
    76

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    NVA237 Followed by Tiotropium
    Reporting group description
    		 NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via HandiHaler® on Day 1 and Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) on Day 8.

    Reporting group title
    Tiotropium Followed by NVA237
    Reporting group description
    		 Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) on Day 1 and NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via Handihaler® on Day 8.

    Reporting group values
    		 NVA237 Followed by Tiotropium Tiotropium Followed by NVA237 Total
    Number of subjects
    		 76 76 152
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.9 ( 7.2 ) 61.7 ( 8.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 28 26 54
        Male
    		 48 50 98

    End points

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    End points reporting groups
    Reporting group title
    NVA237 Followed by Tiotropium
    Reporting group description
    		 NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via HandiHaler® on Day 1 and Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) on Day 8.

    Reporting group title
    Tiotropium Followed by NVA237
    Reporting group description
    		 Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) on Day 1 and NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via Handihaler® on Day 8.
    Reporting group title
    NVA237 Followed by Tiotropium
    Reporting group description
    		 NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via HandiHaler® at Visit 3 and Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 4.

    Reporting group title
    Tiotropium Followed by NVA237
    Reporting group description
    		 Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 3 and NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via Handihaler® at Visit 4.
    Reporting group title
    NVA237 Followed by Tiotropium
    Reporting group description
    		 NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via HandiHaler® at Visit 3 and Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 4.

    Reporting group title
    Tiotropium Followed by NVA237
    Reporting group description
    		 Tiotropium 18 μg o.d, delivered via the manufacturer’s proprietary inhalation device (HandiHaler®) plus placebo to NVA237 o.d., delivered via a single-dose dry powder inhaler (SDDPI) at Visit 3 and NVA237 44 μg o.d., delivered via a single-dose dry powder inhaler (SDDPI), plus placebo to tiotropium o.d. delivered via Handihaler® at Visit 4.

    Subject analysis set title
    NVA237
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients on NVA237 for Period 1 and Period 2. The Full Analysis Set (FAS) consisted of all randomized patients who applied at least one dose of study medication during at least one study period.

    Subject analysis set title
    Tiotropium
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients onTiotropium for Period 1 and Period 2. The Full Analysis Set (FAS) consisted of all randomized patients who applied at least one dose of study medication during at least one study period.

    Primary: Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve ( AUC) 0-2 Hours in Liters

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    End point title
    		 Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve ( AUC) 0-2 Hours in Liters
    End point description
    The AUC was calculated from the FEV1 measurements obtained at timepoints between 0 min and 2h using the trapezoidal rule and will be standardized (=divided) by the measurement time (i.e. 2h). FEV1 was collected during spriometric testing. Spirometric testing had to be performed in accordance with ATS standards. For all clinic spirometry assessments, three acceptable maneuvers (a maximum of 8 maneuvers) had to be performed for each time-point. The FEV1, FVC values recorded in the e-CRF were the highest values measured irrespective of whether or not they occurred on the same curve.
    End point type
    Primary
    End point timeframe
    Day 1
    End point values
    		 NVA237 Tiotropium
    Number of subjects analysed
    151
    150
    Units: liters
        arithmetic mean (standard deviation)
    1.49 ( 0.4232 )
    1.453 ( 0.4135 )
    Statistical analysis title
    		 Analysis of Primary Variable
    Statistical analysis description
    The primary endpoint is FEV1 AUC0-2h calculated at 0’, 5’, 15’, 45’, 75’ and 2h using the trapezoidal rule divided by actual measurement time. The null hypothesis was that there is no difference between treatments for AUC0-2h vs. glycopyrronium has a higher FEV1 AUC0-2h compared to tiotropium. Treatment comparisons were made using an analysis of variance model for center, period, patient-within-center and treatment. The null hypothesis was tested using a 2-sided significance level of 5%.
    Comparison groups
    NVA237 v Tiotropium
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0006
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.037
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.016
         upper limit
    		 0.059

    Secondary: Forced Expiratory Volume in 1 Second (FEV1) 15 Minutes Post-Dose

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    End point title
    		 Forced Expiratory Volume in 1 Second (FEV1) 15 Minutes Post-Dose
    End point description
    FEV1 was collected during spriometirci testing. Spirometric testing had to be performed in accordance with ATS standards . For all clinic spirometry assessments, three acceptable maneuvers (a maximum of 8 maneuvers) had to be performed for each time-point. The FEV1, FVC values recorded in the e-CRF were the highest values measured irrespective of whether or not they occurred on the same curve.
    End point type
    Secondary
    End point timeframe
    15 minutes post dose
    End point values
    		 NVA237 Tiotropium
    Number of subjects analysed
    152 [1]
    151 [2]
    Units: Liters
        arithmetic mean (standard deviation)
    1.433 ( 0.411 )
    1.398 ( 0.4092 )
    Notes
    [1] - Full analysis set
    [2] - Full analysis set
    No statistical analyses for this end point

    Secondary: Specific Airway Resistance (sRaw) Over Time

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    End point title
    		 Specific Airway Resistance (sRaw) Over Time
    End point description
    Constant-volume body plethysmography was used to assess sRaw. After having the maneuver explained to the subject, resting tidal breathing commenced during which a stable end-expiratory lung volume level and a stable tidal volume should be achieved. After approximately 5 normal tidal breaths at a breathing frequency not exceeding 0.5 – 1 per second the pressure-flow curves were collected to determine the specific airway resistance (sRaw).
    End point type
    Secondary
    End point timeframe
    Specific airway resistance (sRaw) was measured at -45 minutes prior to dosing and at 30 minutes, 1 hour, 1 hour 30 minutes, 2 hours 30 minutes, and 3 hours 30 minutes post dosing.
    End point values
    		 NVA237 Tiotropium
    Number of subjects analysed
    152 [3]
    150 [4]
    Units: SR tot (kPa*s)
    arithmetic mean (standard deviation)
        -45 minutes (n = 152, 150)
    4.203 ( 1.8102 )
    4.105 ( 1.8338 )
        30 min (n=150, 151)
    2.904 ( 1.4759 )
    3.089 ( 1.4555 )
        1 hr (n=151, 149)
    2.656 ( 1.3062 )
    2.877 ( 1.413 )
        1 hr 30 min (n=151, 150)
    2.632 ( 1.3152 )
    2.811 ( 1.4065 )
        2 hr 30 min (n=150, 149)
    2.643 ( 1.3146 )
    2.756 ( 1.4091 )
        3 hr 30 min (n=150, 149)
    2.779 ( 1.4496 )
    2.828 ( 1.4534 )
    Notes
    [3] - Full analysis set
    [4] - Full analysis set
    No statistical analyses for this end point

    Secondary: Functional Residual Capacity (FRCpleth)

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    End point title
    		 Functional Residual Capacity (FRCpleth)
    End point description
    FRC was collected during body plethysmography. After having the maneuver explained to the subject, resting tidal breathing commenced during which a stable end-expiratory lung volume level and a stable tidal volume should be achieved. After a few breaths, the shutter of the body plethysmograph was closed and the subject continued to breathe against the closed shutter for an additional few breaths during which the pressure-volume loops were collected and FRC obtained. After four to five breaths the shutter was opened and the measurement was completed. The subject should not hold their cheeks during the maneuver. Three acceptable measurements were done and the mean entered onto the eCRF.
    End point type
    Secondary
    End point timeframe
    Functional resistance capacity (FRC) in liters was measured at -45 minutes, 30 minutes, 1 hour, 1 hour 30 minutes, 2 hours 30 minutes, and 3 hours 30 minutes post dosing.
    End point values
    		 NVA237 Tiotropium
    Number of subjects analysed
    152 [5]
    151 [6]
    Units: Liters
    arithmetic mean (standard deviation)
        -45 min (n=152, 150)
    5.211 ( 1.3086 )
    5.142 ( 1.2656 )
        30 min (n=150, 151)
    4.823 ( 1.2517 )
    4.852 ( 1.1812 )
        1 hr (n=151, 149)
    4.769 ( 1.2571 )
    4.725 ( 1.1496 )
        1 hr 30 min (n=151, 149)
    4.756 ( 1.2366 )
    4.714 ( 1.1523 )
        2 h 30 min (n= 150, 149)
    4.736 ( 1.1545 )
    4.676 ( 1.2243 )
        3 h 30 min (n= 150, 148)
    4.761 ( 1.2286 )
    4.704 ( 1.1911 )
    Notes
    [5] - Full analysis set
    [6] - Full analysis set
    No statistical analyses for this end point

    Secondary: Residual Volume (RV)

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    End point title
    		 Residual Volume (RV)
    End point description
    This was collected during body plethysmography. After the inspiratory capacity maneuver the patient exhaled fully and slowly to the level of RV with verbal encouragement. The exhaled volume is the slow vital capacity (SVC). The exhalation had to be no longer than 15 s long or to fulfill the end-of-test criterion, which was less than 20 mL volume change in two consecutive seconds. The highest of the three measurements was reported and considered in RV calculation (RV = TLC – SVChighest). All volumes were reported in liters (L) under BTPS conditions (body temperature (37° C), ambient pressure, saturated with water vapor.
    End point type
    Secondary
    End point timeframe
    Residual volume in liters was measured at -45 minutes, 30 minutes, 1 hour, 1 hour 30 minutes, 2 hou
    End point values
    		 NVA237 Tiotropium
    Number of subjects analysed
    152 [7]
    151 [8]
    Units: liters
    arithmetic mean (standard deviation)
        -45 min (n=152, 150)
    4.433 ( 1.2596 )
    4.344 ( 1.1707 )
        30 min (n=150, 151)
    3.996 ( 1.1862 )
    4.035 ( 1.0689 )
        1 hr (n=151, 149)
    3.891 ( 1.1997 )
    3.913 ( 1.0281 )
        1 hr 30 min (n=151, 149)
    3.91 ( 1.1534 )
    3.903 ( 1.0281 )
        2 h 30 min (n= 150, 149)
    3.893 ( 1.0486 )
    3.861 ( 1.1058 )
        3 h 30 min (n= 150, 148)
    3.97 ( 1.1576 )
    3.895 ( 1.074 )
    Notes
    [7] - Full analysis set
    [8] - Full analysis set
    No statistical analyses for this end point

    Secondary: Inspiratory capacity (IC)

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    End point title
    		 Inspiratory capacity (IC)
    End point description
    Inspiratory capacity was measured during body plethysmography. After measuring sRaw and FRC in a linked maneuver, the patient had to follow the verbal command to fill up their lungs slowly and completely to reach a plateau at the total lung capacity level.
    End point type
    Secondary
    End point timeframe
    Inspiratory capacity in liters was measured at -45 minutes, 30 minutes, 1 hour, 1 hour 30 minutes, 2 hours 30 minutes, and 3 hours 30 minutes post dosing.
    End point values
    		 NVA237 Tiotropium
    Number of subjects analysed
    152 [9]
    151 [10]
    Units: liters
    arithmetic mean (standard deviation)
        -45 min (n=152, 150)
    2.169 ( 0.5548 )
    2.193 ( 0.5583 )
        30 min (n=150, 151)
    2.433 ( 0.5934 )
    2.422 ( 0.5996 )
        1hr (n=151, 149)
    2.455 ( 0.6001 )
    2.435 ( 0.5908 )
        1hr 30 min (n=151, 150)
    2.472 ( 0.62 )
    2.457 ( 0.5883 )
        2hr 30 min (n=150, 149)
    2.467 ( 0.5929 )
    2.474 ( 0.6051 )
        3hr 30 min (n=150, 149)
    2.479 ( 2.449 )
    2.449 ( 0.5907 )
    Notes
    [9] - Full analysis set
    [10] - Full analysis set
    No statistical analyses for this end point

    Secondary: Total Lung Capacity (TLC)

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    End point title
    		 Total Lung Capacity (TLC)
    End point description
    Total lung capacity was collected during body plethysmography.
    End point type
    Secondary
    End point timeframe
    Total lung capacity in liters was measured at -45 minutes, 30 minutes, 1 hour, 1 hour 30 minutes, 2 hours 30 minutes, and 3 hours 30 minutes post dosing.
    End point values
    		 NVA237 Tiotropium
    Number of subjects analysed
    Units: liters
    arithmetic mean (standard deviation)
        -45 min (n=152, 150)
    7.38 ( 1.4781 )
    7.335 ( 1.4328 )
        30 min (n=150, 151)
    7.255 ( 1.4628 )
    7.274 ( 1.4032 )
        1hr (n=151, 149)
    7.224 ( 1.4294 )
    7.161 ( 1.4015 )
        1hr 30 min (n=151, 149)
    7.227 ( 1.4383 )
    7.165 ( 1.369 )
        2hr 30 min (n=150, 149)
    7.203 ( 1.37 )
    7.149 ( 1.4476 )
        3hr 30 min (n=150, 148)
    7.24 ( 1.4297 )
    7.149 ( 1.3963 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    NVA237
    Reporting group description
    		 All patients on NVA237 for Period 1 and Period 2. The Full Analysis Set (FAS) consisted of all randomized patients who applied at least one dose of study medication during at least one study period.

    Reporting group title
    Tiotropium
    Reporting group description
    		 All patients onTiotropium for Period 1 and Period 2. The Full Analysis Set (FAS) consisted of all randomized patients who applied at least one dose of study medication during at least one study period.

    Serious adverse events
    		 NVA237 Tiotropium
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 152 (1.32%)
    2 / 151 (1.32%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 152 (0.66%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Nephrectomy
         subjects affected / exposed
    0 / 152 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 NVA237 Tiotropium
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 152 (1.97%)
    4 / 151 (2.65%)
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 152 (1.97%)
    4 / 151 (2.65%)
         occurrences all number
    3
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Aug 2013
    Amendment was issued after inclusion of 33% of patients. Spirometry decribed that patients with a decrease in post bronchodilator FEV1 compared to pre-bronchodilator FEV1 should be screen failed. This was now added to exclusion criterion.

    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.
    Due to EudraCT system limitations, which EMA is aware of, results of crossover studies are not accurately represented in this record. Please go to https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.
    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.

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