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    Clinical Trial Results:
    A multicenter, 4-week crossover (total duration 12 weeks), placebo-controlled, double-blind study to determine the impact of QVA149 (indacaterol/glycopyrronium) 85/43 μg on nocturnal oxygen levels in Chronic Obstructive Pulmonary Disease (COPD)

    Summary
    EudraCT number
    		 2013-005573-51
    Trial protocol
    		 DK   SE  
    Global end of trial date
    22 Jun 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jul 2017
    First version publication date
    06 Jul 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CQVA149ANO01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02233543
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharmaceuticals
    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
    22 Jun 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the level of improvement in mean night time SpO2 following 4 weeks of administration of QVA149 compared to placebo.
    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
    24 Nov 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
    Norway: 14
    Country: Number of subjects enrolled
    Sweden: 13
    Country: Number of subjects enrolled
    Denmark: 11
    Worldwide total number of subjects
    38
    EEA total number of subjects
    38
    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)
    9
    From 65 to 84 years
    29
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants were randomized in a 1:1 ratio.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 First QVA149 (indacaterol/glycopyrronium), then Placebo
    Arm description
    		 Participants received 4 weeks of QVA149 85/43 μg delivered dose once daily in the morning between 08:00 and 11:00 AM at approximately the same time every day followed by 2 weeks washout. Then participants received 4 weeks of placebo once daily in the morning between 08:00 and 11:00 AM at approximately the same time every day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Indacaterol/glycpyrronium
    Investigational medicinal product code
    QVA149
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants received 4 weeks of QVA149 85/43 μg delivered dose once daily in the morning between 08:00 and 11:00 AM at approximately the same time every day.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants received 4 weeks of placebo once daily in the morning between 08:00 and 11:00 AM at approximately the same time every day.

    Arm title
    		 First Placebo, then QVA149 (indacaterol/glycopyrronium)
    Arm description
    		 Participants received 4 weeks of placebo once daily in the morning between 08:00 and 11:00 AM at approximately the same time every day followed by 2 weeks washout. Then participants received 4 weeks of QVA149 85/43 μg delivered dose once daily in the morning between 08:00 and 11:00 AM at approximately the same time every day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants received 4 weeks of placebo once daily in the morning between 08:00 and 11:00 AM at approximately the same time every day.

    Investigational medicinal product name
    Indacaterol/glycopyrronium
    Investigational medicinal product code
    QVA149
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants received 4 weeks of QVA149 85/43 μg delivered dose once daily in the morning between 08:00 and 11:00 AM at approximately the same time every day.

    Number of subjects in period 1
    		First QVA149 (indacaterol/glycopyrronium), then Placebo First Placebo, then QVA149 (indacaterol/glycopyrronium)
    Started
    22
    16
    Completed
    19
    13
    Not completed
    3
    3
         Consent withdrawn by subject
    1
    -
         Participants required other treatment.
    2
    3
    Period 2
    Period 2 title
    Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 First QVA149 (indacaterol/glycopyrronium), then Placebo
    Arm description
    		 Participants received 4 weeks of QVA149 85/43 μg delivered dose once daily in the morning between 08:00 and 11:00 AM at approximately the same time every day followed by 2 weeks washout. Then participants received 4 weeks of placebo once daily in the morning between 08:00 and 11:00 AM at approximately the same time every day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Indacaterol/glycopyrronium
    Investigational medicinal product code
    QVA149
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants received 4 weeks of QVA149 85/43 μg delivered dose once daily in the morning between 08:00 and 11:00 AM at approximately the same time every day

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants received 4 weeks of placebo once daily in the morning between 08:00 and 11:00 AM at approximately the same time every day.

    Arm title
    		 First Placebo, then QVA149 (indacaterol/glycopyrronium)
    Arm description
    		 Participants received 4 weeks of placebo once daily in the morning between 08:00 and 11:00 AM at approximately the same time every day followed by 2 weeks washout. Then participants received 4 weeks of QVA149 85/43 μg delivered dose once daily in the morning between 08:00 and 11:00 AM at approximately the same time every day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Indacaterol/glycopyrronium
    Investigational medicinal product code
    QVA149
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants received 4 weeks of QVA149 85/43 μg delivered dose once daily in the morning between 08:00 and 11:00 AM at approximately the same time every day.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants received 4 weeks of placebo once daily in the morning between 08:00 and 11:00 AM at approximately the same time every day

    Number of subjects in period 2
    		First QVA149 (indacaterol/glycopyrronium), then Placebo First Placebo, then QVA149 (indacaterol/glycopyrronium)
    Started
    19
    13
    Completed
    17
    12
    Not completed
    2
    1
         Adverse event, non-fatal
    1
    -
         COPD exacerbation
    1
    -
         Participant required other treatment.
    -
    1

    Baseline characteristics

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

    Reporting group values
    		 Period 1 Total
    Number of subjects
    		 38 38
    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)
    		 9 9
        From 65-84 years
    		 29 29
        85 years and over
    		 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 68.4 ± 6.2 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 14 14
        Male
    		 24 24
    Subject analysis sets

    Subject analysis set title
    All participants (QVA149/Placebo)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received 4 weeks of QVA149 and 4 weeks of placebo according to either of the following sequences: QVA149 first and then placebo, or placebo first and then QVA149.

    Subject analysis set title
    QVA149 (indacaterol/glycopyrronium)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received 4 weeks of QVA149 85/43 μg delivered dose once daily in the morning between 08:00 and 11:00 AM at approximately the same time every day.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received 4 weeks of QVA149 85/43 μg delivered dose once daily in the morning between 08:00 and 11:00 AM at approximately the same time every day.

    Subject analysis sets values
    		 All participants (QVA149/Placebo) QVA149 (indacaterol/glycopyrronium) Placebo
    Number of subjects
    38
    35
    34
    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
        arithmetic mean (standard deviation)
    68.4 ± 6.2
    ±
    ±
    Gender, Male/Female
    Units: Subjects
        Female
    14
        Male
    24

    End points

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    End points reporting groups
    Reporting group title
    First QVA149 (indacaterol/glycopyrronium), then Placebo
    Reporting group description
    		 Participants received 4 weeks of QVA149 85/43 μg delivered dose once daily in the morning between 08:00 and 11:00 AM at approximately the same time every day followed by 2 weeks washout. Then participants received 4 weeks of placebo once daily in the morning between 08:00 and 11:00 AM at approximately the same time every day.

    Reporting group title
    First Placebo, then QVA149 (indacaterol/glycopyrronium)
    Reporting group description
    		 Participants received 4 weeks of placebo once daily in the morning between 08:00 and 11:00 AM at approximately the same time every day followed by 2 weeks washout. Then participants received 4 weeks of QVA149 85/43 μg delivered dose once daily in the morning between 08:00 and 11:00 AM at approximately the same time every day.
    Reporting group title
    First QVA149 (indacaterol/glycopyrronium), then Placebo
    Reporting group description
    		 Participants received 4 weeks of QVA149 85/43 μg delivered dose once daily in the morning between 08:00 and 11:00 AM at approximately the same time every day followed by 2 weeks washout. Then participants received 4 weeks of placebo once daily in the morning between 08:00 and 11:00 AM at approximately the same time every day.

    Reporting group title
    First Placebo, then QVA149 (indacaterol/glycopyrronium)
    Reporting group description
    		 Participants received 4 weeks of placebo once daily in the morning between 08:00 and 11:00 AM at approximately the same time every day followed by 2 weeks washout. Then participants received 4 weeks of QVA149 85/43 μg delivered dose once daily in the morning between 08:00 and 11:00 AM at approximately the same time every day.

    Subject analysis set title
    All participants (QVA149/Placebo)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received 4 weeks of QVA149 and 4 weeks of placebo according to either of the following sequences: QVA149 first and then placebo, or placebo first and then QVA149.

    Subject analysis set title
    QVA149 (indacaterol/glycopyrronium)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received 4 weeks of QVA149 85/43 μg delivered dose once daily in the morning between 08:00 and 11:00 AM at approximately the same time every day.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received 4 weeks of QVA149 85/43 μg delivered dose once daily in the morning between 08:00 and 11:00 AM at approximately the same time every day.

    Primary: Mean night-time blood oxygenation

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    End point title
    		 Mean night-time blood oxygenation
    End point description
    The mean night-time blood oxygenation following 4 weeks administration of QVA149 compared to placebo was assessed. Night time oxygenation (SpO2) was measured using polygraphy.
    End point type
    Primary
    End point timeframe
    Post 4 weeks administration of QVA149, post 4 weeks administration of placebo
    End point values
    		 QVA149 (indacaterol/glycopyrronium) Placebo
    Number of subjects analysed
    35
    34
    Units: Percent
        least squares mean (standard error)
    89.59 ± 0.3
    90.04 ± 0.28
    Statistical analysis title
    		 Mean night-time blood oxygenation
    Comparison groups
    QVA149 (indacaterol/glycopyrronium) v Placebo
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2419
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.21
         upper limit
    		 0.32

    Secondary: Time during the night spent below 90 % in blood oxygen saturation

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    End point title
    		 Time during the night spent below 90 % in blood oxygen saturation
    End point description
    The time during the night spent below 90 % in blood oxygen saturation following 4 weeks administration of QVA149 compared to placebo was assessed. Night time oxygenation (SpO2) was measured using polygraphy.
    End point type
    Secondary
    End point timeframe
    Post 4 weeks administration of QVA149, post 4 weeks administration of placebo
    End point values
    		 QVA149 (indacaterol/glycopyrronium) Placebo
    Number of subjects analysed
    35
    34
    Units: Percent
        least squares mean (standard error)
    44.37 ± 5.09
    36.58 ± 4.84
    Statistical analysis title
    		 Time during the night spent below 90% blood oxygen
    Comparison groups
    QVA149 (indacaterol/glycopyrronium) v Placebo
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2016
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    7.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.51
         upper limit
    		 20.08

    Adverse events

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    Adverse events information
    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
    17.0
    Reporting groups
    Reporting group title
    QVA149
    Reporting group description
    		 QVA149

    Reporting group title
    PLACEBO
    Reporting group description
    		 PLACEBO

    Serious adverse events
    		 QVA149 PLACEBO
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 34 (2.94%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 QVA149 PLACEBO
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 35 (40.00%)
    12 / 34 (35.29%)
    Investigations
    Blood glucose increased
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    2
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 35 (2.86%)
    1 / 34 (2.94%)
         occurrences all number
    1
    1
    Pyrexia
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Blindness transient
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 35 (5.71%)
    3 / 34 (8.82%)
         occurrences all number
    2
    3
    Cough
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    Dyspnoea
         subjects affected / exposed
    5 / 35 (14.29%)
    4 / 34 (11.76%)
         occurrences all number
    5
    4
    Laryngospasm
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    Productive cough
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    Pulmonary embolism
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthritis reactive
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 35 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    3 / 35 (8.57%)
    2 / 34 (5.88%)
         occurrences all number
    3
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Aug 2014
    The procedures for keeping the treatment codes blinded and the responsibilities of the unblinded pharmacist/trained site staff were clarified; The procedures for unblinding the study medication in case of emergency situations were clarified; Sponsor contact details in case of medical emergency situations were added; Inclusion criterion number 5 was modified to specify the criteria for COPD diagnosis; Exclusion criterion number 18 was modified to specify that hypersensitivity relates to the investigational therapy; Non-selective beta blockers (including eye drops) and anticholinergic medications (except for study treatment) were added to the list of prohibited medications. Two new exclusion criteria (number 20 and number 21) specifying this were added; The procedures for archiving of essential documents were clarified; Corrections of typos and some additional clarifications to the text were made.

    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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