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    Clinical Trial Results:
    Multicenter, randomized, blinded, two-period cross-over study to assess the effect of glycopyrronium (44 micrograms QD) versus tiotropium (18 micrograms QD) on morning symptoms and pulmonary function 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
    2013-002483-84
    Trial protocol
    DE   GB   IT   ES  
    Global end of trial date
    27 Oct 2014

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

    Trial information

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    Trial identification
    Sponsor protocol code
    CNVA237A3401
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01959516
    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
    27 Oct 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Oct 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to demonstrate that glycopyrronium QD is superior to tiotropium QD in terms of FEV1 AUC0-4h after first dose of treatment.
    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.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    13 Feb 2014
    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
    Spain: 11
    Country: Number of subjects enrolled
    United Kingdom: 38
    Country: Number of subjects enrolled
    Germany: 69
    Country: Number of subjects enrolled
    Italy: 8
    Worldwide total number of subjects
    126
    EEA total number of subjects
    126
    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)
    55
    From 65 to 84 years
    71
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 126 patients were randomized to one of the two treatment sequences in a ratio of 1:1. Due to misrandomization, two patients did not receive at least one dose of the study treatment. Both, safety and ITT population included 124 patients.

    Period 1
    Period 1 title
    Epoch 1
    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
    Glycopyrronium first, then Tiotropium
    Arm description
    Sequence A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto) to B (Tiotropium 18 μg QD + placebo of glycopyrronium) Sequence B (Tiotropium 18 μg QD + placebo of glycopyrronium) to A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto)
    Arm type
    Experimental

    Investigational medicinal product name
    Seebri® SDDPI / Glycopyrronium bromide
    Investigational medicinal product code
    CNVA237A
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    capsule for inhalation

    Arm title
    Tiotropium first, then Glycopyrronium
    Arm description
    Sequence B (Tiotropium 18 μg QD + placebo of glycopyrronium) to A (Glycopyrronium 44 μg QD + placebo of tiotropiumto) Sequence A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto) to B (Tiotropium 18 μg QD + placebo of glycopyrronium)
    Arm type
    Experimental

    Investigational medicinal product name
    Seebri® SDDPI / Glycopyrronium bromide
    Investigational medicinal product code
    CNVA237A
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    capsule for inhalation

    Number of subjects in period 1
    Glycopyrronium first, then Tiotropium Tiotropium first, then Glycopyrronium
    Started
    63
    63
    Safety population
    62
    62
    ITT population
    62
    62
    Completed
    53
    58
    Not completed
    10
    5
         Moderate or severe COPD exacerbation
    -
    1
         Use of prohibited treatment
    1
    -
         Subject withdrew consent
    3
    2
         unsatisfactory therapeutic effect
    1
    -
         Administrative problems
    1
    -
         Adverse event, non-fatal
    4
    1
         Protocol deviation
    -
    1
    Period 2
    Period 2 title
    Epoch 2
    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
    Glycopyrronium first, then Tiotropium\"
    Arm description
    Sequence A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto) to B (Tiotropium 18 μg QD + placebo of glycopyrronium) Sequence B (Tiotropium 18 μg QD + placebo of glycopyrronium) to A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto)
    Arm type
    Experimental

    Investigational medicinal product name
    Seebri® SDDPI / Glycopyrronium bromide
    Investigational medicinal product code
    CNVA237A
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    capsule for inhalation

    Arm title
    Tiotropium first, then Glycopyrronium
    Arm description
    Sequence B (Tiotropium 18 μg QD + placebo of glycopyrronium) to A (Glycopyrronium 44 μg QD + placebo of tiotropiumto) Sequence A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto) to B (Tiotropium 18 μg QD + placebo of glycopyrronium)
    Arm type
    Experimental

    Investigational medicinal product name
    Seebri® SDDPI / Glycopyrronium bromide
    Investigational medicinal product code
    CNVA237A
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    capsule for inhalation

    Number of subjects in period 2
    Glycopyrronium first, then Tiotropium\" Tiotropium first, then Glycopyrronium
    Started
    53
    58
    Completed
    51
    57
    Not completed
    2
    1
         Moderate or severe COPD exacerbation
    -
    1
         Subject withdrew consent
    1
    -
         unsatisfactory therapeutic effect
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Epoch 1
    Reporting group description
    -

    Reporting group values
    Epoch 1 Total
    Number of subjects
    126 126
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    55 55
        From 65-84 years
    71 71
        85 years and over
    0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    65.7 ± 8.1 -
    Gender, Male/Female
    Units: Participants
        Female
    37 37
        Male
    89 89
    Subject analysis sets

    Subject analysis set title
    All participants (Intent To Treat analysis,ITT)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All participants who were randomized to one of the two treatment sequences in a ratio of 1:1. Participants will receive sequence A = glycopyrronium + placebo to tiotropium during 28 days, followed by a 14 day washout period, then sequence B= tiotropium + placebo to glycopyrronium for 28 days.

    Subject analysis set title
    Glycopyronium from sequence A to B and sequence B to A
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Sequence A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto) to B (Tiotropium 18 μg QD + placebo of glycopyrronium) Sequence B (Tiotropium 18 μg QD + placebo of glycopyrronium) to A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto)

    Subject analysis set title
    Tiotropium from sequence A to B and sequence B to A
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Sequence B (Tiotropium 18 μg QD + placebo of glycopyrronium) to A (Glycopyrronium 44 μg QD + placebo of tiotropiumto)Sequence A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto) to B (Tiotropium 18 μg QD + placebo of glycopyrronium)

    Subject analysis sets values
    All participants (Intent To Treat analysis,ITT) Glycopyronium from sequence A to B and sequence B to A Tiotropium from sequence A to B and sequence B to A
    Number of subjects
    126
    126
    126
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
        Adults (18-64 years)
    0
    0
    55
        From 65-84 years
    0
    0
    71
        85 years and over
    0
    0
    0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    65.7 ± 8.1
    ±
    ±
    Gender, Male/Female
    Units: Participants
        Female
    37
        Male
    89

    End points

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    End points reporting groups
    Reporting group title
    Glycopyrronium first, then Tiotropium
    Reporting group description
    Sequence A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto) to B (Tiotropium 18 μg QD + placebo of glycopyrronium) Sequence B (Tiotropium 18 μg QD + placebo of glycopyrronium) to A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto)

    Reporting group title
    Tiotropium first, then Glycopyrronium
    Reporting group description
    Sequence B (Tiotropium 18 μg QD + placebo of glycopyrronium) to A (Glycopyrronium 44 μg QD + placebo of tiotropiumto) Sequence A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto) to B (Tiotropium 18 μg QD + placebo of glycopyrronium)
    Reporting group title
    Glycopyrronium first, then Tiotropium\"
    Reporting group description
    Sequence A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto) to B (Tiotropium 18 μg QD + placebo of glycopyrronium) Sequence B (Tiotropium 18 μg QD + placebo of glycopyrronium) to A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto)

    Reporting group title
    Tiotropium first, then Glycopyrronium
    Reporting group description
    Sequence B (Tiotropium 18 μg QD + placebo of glycopyrronium) to A (Glycopyrronium 44 μg QD + placebo of tiotropiumto) Sequence A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto) to B (Tiotropium 18 μg QD + placebo of glycopyrronium)

    Subject analysis set title
    All participants (Intent To Treat analysis,ITT)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All participants who were randomized to one of the two treatment sequences in a ratio of 1:1. Participants will receive sequence A = glycopyrronium + placebo to tiotropium during 28 days, followed by a 14 day washout period, then sequence B= tiotropium + placebo to glycopyrronium for 28 days.

    Subject analysis set title
    Glycopyronium from sequence A to B and sequence B to A
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Sequence A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto) to B (Tiotropium 18 μg QD + placebo of glycopyrronium) Sequence B (Tiotropium 18 μg QD + placebo of glycopyrronium) to A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto)

    Subject analysis set title
    Tiotropium from sequence A to B and sequence B to A
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Sequence B (Tiotropium 18 μg QD + placebo of glycopyrronium) to A (Glycopyrronium 44 μg QD + placebo of tiotropiumto)Sequence A (Glycopyrronium 44 μg QD+ placebo of tiotropiumto) to B (Tiotropium 18 μg QD + placebo of glycopyrronium)

    Primary: Forced Expiratory Volume in 1 second (FEV1) AUC0-4h after first dose of treatment.

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    End point title
    Forced Expiratory Volume in 1 second (FEV1) AUC0-4h after first dose of treatment.
    End point description
    Forced Expiratory Volume in 1 second (FEV1) Area Under the Curve (AUC) will measured via spirometry and calculated from 0 to 4 hours post-dose on day 1 of study treatment.
    End point type
    Primary
    End point timeframe
    Day 1
    End point values
    Glycopyronium from sequence A to B and sequence B to A Tiotropium from sequence A to B and sequence B to A
    Number of subjects analysed
    124
    124
    Units: Liters*hours
        least squares mean (confidence interval 95%)
    1.7432 (1.7132 to 1.7732)
    1.7132 (1.683 to 1.7434)
    Statistical analysis title
    Forced Expiratory Volume in 1 second
    Comparison groups
    Glycopyronium from sequence A to B and sequence B to A v Tiotropium from sequence A to B and sequence B to A
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.025
    Method
    Mixed models analysis
    Confidence interval

    Secondary: Comparison of glycopyrronium QD versus tiotropium QD on symptoms outcome

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    End point title
    Comparison of glycopyrronium QD versus tiotropium QD on symptoms outcome
    End point description
    Comparison of symptoms outcome between glycopyrronium QD versus tiotropium QD will be conducted via the PROMorning COPD Symptoms questionnaire. This questionnaire will be completed by participants at waking-up, pre-inhalation of study treatment (at home), and they will complete Part 2 of PRO-Morning COPD Symptoms questionnaire at site, 3hours post-inhalation of study treatment. The PRO-Morning COPD Symptoms Questionnaire is a self-administered patient reported outcome (PRO) instrument developed by the sponsor to evaluate patients' experience of early morning symptoms of COPD. The questionnaire consists of two parts : predose and postdose. Each part has 6 questions and for each question a scale of 0 to 10 can be reached. For the predose and postdose part of the questionnaire you will have then each a total score of 0-60 by adding the sub-scores for each question, higher scores represent worse severity of COPD morning symptoms
    End point type
    Secondary
    End point timeframe
    day 1 (baseline) and week 4
    End point values
    Glycopyronium from sequence A to B and sequence B to A Tiotropium from sequence A to B and sequence B to A
    Number of subjects analysed
    124
    124
    Units: Scores on a scale
    least squares mean (confidence interval 95%)
        3h post-dose (Day 1)
    9.7068 (8.7294 to 10.6841)
    10.3974 (9.4036 to 11.3913)
        3h post-dose (Week 4)
    10.4641 (9.3786 to 11.5496)
    10.3193 (9.2286 to 11.41)
    Statistical analysis title
    Comparison of glycopyrronium versus tiotropium
    Comparison groups
    Glycopyronium from sequence A to B and sequence B to A v Tiotropium from sequence A to B and sequence B to A
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.1439
    Method
    Mixed models analysis
    Confidence interval

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Tiotropium
    Reporting group description
    Tiotropium

    Reporting group title
    Glycopyrronium
    Reporting group description
    Glycopyrronium

    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: AEs are validated
    Serious adverse events
    Tiotropium Glycopyrronium
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 124 (1.61%)
    2 / 124 (1.61%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 124 (0.81%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 124 (0.00%)
    1 / 124 (0.81%)
         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: 5%
    Non-serious adverse events
    Tiotropium Glycopyrronium
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 124 (0.00%)
    0 / 124 (0.00%)

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    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.
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