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    Clinical Trial Results:
    The effectiveness of single dose Ultibro Breezhaler (indacaterol/glycopyrronium) by sd-DPI versus ipratropium/salbutamol by nebulizer in improving FEV1 and dyspnea during stable state of COPD

    Summary
    EudraCT number
    		 2015-000473-12
    Trial protocol
    		 NL  
    Global end of trial date
    30 Sep 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Sep 2021
    First version publication date
    04 Sep 2021
    Other versions
    Summary report(s)
    		 results

    Trial information

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    Trial identification
    Sponsor protocol code
    ULT01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02576626
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UMCG
    Sponsor organisation address
    hanzeplein, Groningen, Netherlands,
    Public contact
    Afdeling Longziekten, UMCG, h.a.m.kerstjens@umcg.nl
    Scientific contact
    Afdeling Longziekten, UMCG, h.a.m.kerstjens@umcg.nl
    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
    30 Dec 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Sep 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To test our hypothesis that: The combination of the two long-acting bronchodilators indacaterol and glycopyrronium confers a superior improvement compared to nebulisation with ipratropium/salbutamol, as administered single dose in patients with stable state COPD. Primary objective: The combination of the two long-acting bronchodilators indacaterol and glycopyrronium once daily confers a superior improvement in FEV1 as compared to nebulisation with ipratropium/salbutamol, both administered single dose in patients with stable state COPD.
    Protection of trial subjects
    Rescue medication as needed open label fenoterol/ipratropium was provided in the wasout period.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 May 2015
    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
    Netherlands: 33
    Worldwide total number of subjects
    33
    EEA total number of subjects
    33
    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)
    8
    From 65 to 84 years
    25
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The main inclusion criteria were an age of at least 40 years with a diagnosis of COPD and a post-bronchodilator FEV1 below 80% predicted. COPD was defined as a physician diagnosis and an FEV1/FVC ratio of less than 0.70 after bronchodilation. Main exclusion criteria were asthma, chronic hypoxaemia, and the occurrence of a COPD exacerbation

    Pre-assignment
    Screening details
    		 The main inclusion criteria were an age of at least 40 years with a diagnosis of COPD and a post-bronchodilator FEV1 below 80% predicted. COPD was defined as a physician diagnosis and an FEV1/FVC ratio of less than 0.70 after bronchodilation. Main exclusion criteria were asthma, chronic hypoxaemia, and the occurrence of a COPD exacerbation

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 indacaterol/glycopyrronium
    Arm description
    		 indacaterol/glycopyrronium
    Arm type
    		 Crossover

    Investigational medicinal product name
    indacaterol/glycopyrronium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    indacaterol/glycopyrronium 110/50 μg as Ultibro® via Breezhaler®

    Arm title
    		 short-acting salbutamol plus ipratropium via nebulizer
    Arm description
    		 -
    Arm type
    		 Nebulizer

    Investigational medicinal product name
    salbutamol/ipratropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for nebuliser solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    salbutamol/ipratropium 2,5/0,5 mg via air driven nebulization (SAL/IPR)

    Number of subjects in period 1
    		indacaterol/glycopyrronium short-acting salbutamol plus ipratropium via nebulizer
    Started
    33
    33
    Completed
    33
    33

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 33 33
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        geometric mean (standard deviation)
    		 69 ( 6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 7 7
        Male
    		 26 26
    Subject analysis sets

    Subject analysis set title
    Primairy endpoint
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Between September 2015 and August 2017 53 patients were screened of whom 39 were included in the trial. Of those included, 33 completed the trial and were deemed evaluable

    Subject analysis sets values
    		 Primairy endpoint
    Number of subjects
    33
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        geometric mean (standard deviation)
    69 ( 6 )
    Gender categorical
    Units: Subjects
        Female
    7
        Male
    26

    End points

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    End points reporting groups
    Reporting group title
    indacaterol/glycopyrronium
    Reporting group description
    		 indacaterol/glycopyrronium

    Reporting group title
    short-acting salbutamol plus ipratropium via nebulizer
    Reporting group description
    		 -

    Subject analysis set title
    Primairy endpoint
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Between September 2015 and August 2017 53 patients were screened of whom 39 were included in the trial. Of those included, 33 completed the trial and were deemed evaluable

    Primary: FEV1

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    End point title
    		 FEV1
    End point description
    The primary endpoint, FEV1 AUC 0–6, showed a non-significant difference in favour of the SAL/IPR regimen: 2965 mL +/-1544 (mean +/- SD) for IND/GLY versus 3513 mL +/-1762 for SAL/IPR respectively (P= 0.08)
    End point type
    Primary
    End point timeframe
    2015-2017
    End point values
    		 indacaterol/glycopyrronium short-acting salbutamol plus ipratropium via nebulizer
    Number of subjects analysed
    33
    33
    Units: ML
        geometric mean (standard deviation)
    2965 ( 1544 )
    3513 ( 1762 )
    Statistical analysis title
    		 Stats
    Statistical analysis description
    power calculation was performed for both the area under the curve (AUC) of the FEV1 and the Borg score. We used an alpha of 0.05 and a power of 90%. The estimated difference was extrapolated based on the known MCID of FEV1 and BORG for one time point. In a cross-over study aiming at superiority, with a two-tailed test this required a total sample size of 34 evaluable patients for the AUC of the FEV 1 and for the Borg score 30 patients. Data was analysed with IBM SPSS 24. Differences between
    Comparison groups
    indacaterol/glycopyrronium v short-acting salbutamol plus ipratropium via nebulizer
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.08
    Method
    		 t-test, 2-sided
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    2015-2017
    Adverse event reporting additional description
    No serious adverse events were reported in this short running trial. Six patients did not complete the trial due to mild and moderate adverse events.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 UMCG
    Dictionary version
    2017
    Reporting groups
    Reporting group title
    Analysis
    Reporting group description
    		 -

    Serious adverse events
    		 Analysis
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 33 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Analysis
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 33 (3.03%)
    Respiratory, thoracic and mediastinal disorders
    2017
    Additional description: One patient reported coughing after inhalation of IND/GLY
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences all number
    1

    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.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32917359
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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