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    Clinical Trial Results:
    A Randomised, Double-Blind, Placebo-Controlled, Cross-Over, Single-Centre Study to Investigate the Acute Lung Deflation Effects of Fluticasone Furoate/Vilanterol Inhalation Powder 100/25mcg Once Daily on Cardiac Biventricular Function and Arterial Stiffness in Adults with Chronic Obstructive Pulmonary Disease (COPD)

    Summary
    EudraCT number
    		 2012-000927-42
    Trial protocol
    		 GB  
    Global end of trial date
    08 Aug 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Apr 2016
    First version publication date
    18 Apr 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HZC116601
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01691885
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343,
    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
    23 Oct 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Aug 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to test the hypothesis that lung hyperinflation contributes to cardiac dysfunction in COPD and that treatment of lung deflation with Fluticasone Furoate/Vilanterol (FF/VI) Inhalation Powder 100/25 mcg administered once daily (QD) will result in the reversal of this cardiac dysfunction compared with placebo. This will be assessed by measures of right and left global and regional systolic and diastolic cardiac function as assessed using a 30 minute CMR.
    Protection of trial subjects
    There were no specific measures other than using the baseline scan as the comparator against which treatment response were compared for both treatment periods, rather than adding another MRI scan at Contact/Visit 4. This reduced the number of visits to the hospital and reduced the number of MRI scans required, also limiting inconvenience to the participants. Subjects who were unable to tolerate the confined conditions of the scanner without claustrophobia were excluded from participating. Routine blood test were performed at screening and randomisation. Spirometry and plethysmography was supervised by a trained respiratory technician.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Nov 2012
    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
    United Kingdom: 96
    Worldwide total number of subjects
    96
    EEA total number of subjects
    96
    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)
    36
    From 65 to 84 years
    60
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 At Visit 1a, participants who met the eligibility criteria stopped their respiratory medication in preparation for their lung volume assessment at screening Visit 1b. At Visit 1b, participants entered a 7(plus or minus 3) day Run-in Period. Overall study duration, following Screening to Follow-up, was 36 days up to a maximum of 54 days.

    Period 1
    Period 1 title
    Treatment Period 1(7-14 days)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo then FF/VI
    Arm description
    		 Participants entering Treatment Period 1 received matching placebo once daily (QD), each morning via a dry powder inhaler (DPI) for a period of 7 days, up to a maximum of 14 days. Following Treatment Period 1, participants entered a washout period for 7 days, up to a maximum of 9 days. Following the washout period participants entered Treatment Period 2 and received Fluticasone Furoate/Vilanterol (FF/VI) 100/25 micrograms (µg), QD, each morning via a DPI for 7 days, up to a maximum of 14 days.
    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
    one inhalation each morning via dry powder inhaler

    Investigational medicinal product name
    FF/VI
    Investigational medicinal product code
    Other name
    Relvar (A combination product)
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Once a day – AM only. 100mcg/25mcg (FF/VI- combination product)

    Arm title
    		 FF/VI then Placebo
    Arm description
    		 Participants entering Treatment Period 1 received FF/VI 100/25 µg QD, each morning via a DPI for a period of 7 days, up to a maximum of 14 days. Following Treatment Period 1, participants entered a washout period for 7 days, up to a maximum of 9 days. Following the washout period, participants entered Treatment Period 2 and received matching placebo QD, each morning via a DPI for 7 days, up to a maximum of 14 days.
    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
    one inhalation each morning via dry powder inhaler

    Investigational medicinal product name
    FF/VI
    Investigational medicinal product code
    Other name
    Relvar (A combination product)
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Once a day – AM only. 100mcg/25mcg (FF/VI- combination product)

    Number of subjects in period 1 [1]
    		Placebo then FF/VI FF/VI then Placebo
    Started
    22
    23
    Completed
    21
    22
    Not completed
    1
    1
         Adverse event, non-fatal
    1
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Of the 96 total enrolled participants, only 45 were randomized to study treatment. These 45 participants comprised the Modified Intent to Treat and per Protocol populations for analysis.
    Period 2
    Period 2 title
    Washout Period (7-9 days)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo then FF/VI
    Arm description
    		 Following Treatment Period 1, participants entered a washout period for 7 days, up to a maximum of 9 days.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 FF/VI then Placebo
    Arm description
    		 Following Treatment Period 1, participants entered a washout period for 7 days, up to a maximum of 9 days.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Placebo then FF/VI FF/VI then Placebo
    Started
    21
    22
    Completed
    21
    21
    Not completed
    0
    1
         Adverse event, non-fatal
    -
    1
    Period 3
    Period 3 title
    Treatment Period 2 (7-14 days)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo then FF/VI
    Arm description
    		 Participants entering Treatment Period 1 received matching placebo once daily (QD), each morning via a dry powder inhaler (DPI) for a period of 7 days, up to a maximum of 14 days. Following Treatment Period 1, participants entered a washout period for 7 days, up to a maximum of 9 days. Following the washout period participants entered Treatment Period 2 and received FF/VI 100/25 micrograms (µg), QD, each morning via a DPI for 7 days, up to a maximum of 14 days.
    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
    one inhalation each morning via dry powder inhaler

    Investigational medicinal product name
    FF/VI
    Investigational medicinal product code
    Other name
    Relvar (A combination product)
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Once a day – AM only. 100mcg/25mcg (FF/VI- combination product)

    Arm title
    		 FF/VI then Placebo
    Arm description
    		 Participants entering Treatment Period 1 received FF/VI 100/25 µg QD, each morning via a DPI for a period of 7 days, up to a maximum of 14 days. Following Treatment Period 1, participants entered a washout period for 7 days, up to a maximum of 9 days. Following the washout period, participants entered Treatment Period 2 and received matching placebo QD, each morning via a DPI for 7 days, up to a maximum of 14 days.
    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
    one inhalation each morning via dry powder inhaler

    Investigational medicinal product name
    FF/VI
    Investigational medicinal product code
    Other name
    Relvar (A combination product)
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Once a day – AM only. 100mcg/25mcg (FF/VI- combination product)

    Number of subjects in period 3
    		Placebo then FF/VI FF/VI then Placebo
    Started
    21
    21
    Completed
    21
    21

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Period 1(7-14 days)
    Reporting group description
    		 All participants received placebo or FF/VI 100/25 µg in either of the two treatment periods QD, each morning from a DPI. Treatment periods lasted 7 days up to a maximum of 14 days for each period. The two treatments were separated by a wash out period of 7 days, up to a maximum of 9 days. Participants were provided salbutamol/ ipratropium bromide (administered via a MDI or nebules) to be used as needed throughout the study.

    Reporting group values
    		 Treatment Period 1(7-14 days) Total
    Number of subjects
    		 45 45
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.4 ± 8.95 -
    Gender categorical
    Units: Subjects
        Female
    		 17 17
        Male
    		 28 28
    Race, Customized
    Units: Subjects
        African American/African Heritage
    		 6 6
        White - White/Caucasian/European Heritage
    		 39 39

    End points

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    End points reporting groups
    Reporting group title
    Placebo then FF/VI
    Reporting group description
    		 Participants entering Treatment Period 1 received matching placebo once daily (QD), each morning via a dry powder inhaler (DPI) for a period of 7 days, up to a maximum of 14 days. Following Treatment Period 1, participants entered a washout period for 7 days, up to a maximum of 9 days. Following the washout period participants entered Treatment Period 2 and received Fluticasone Furoate/Vilanterol (FF/VI) 100/25 micrograms (µg), QD, each morning via a DPI for 7 days, up to a maximum of 14 days.

    Reporting group title
    FF/VI then Placebo
    Reporting group description
    		 Participants entering Treatment Period 1 received FF/VI 100/25 µg QD, each morning via a DPI for a period of 7 days, up to a maximum of 14 days. Following Treatment Period 1, participants entered a washout period for 7 days, up to a maximum of 9 days. Following the washout period, participants entered Treatment Period 2 and received matching placebo QD, each morning via a DPI for 7 days, up to a maximum of 14 days.
    Reporting group title
    Placebo then FF/VI
    Reporting group description
    		 Following Treatment Period 1, participants entered a washout period for 7 days, up to a maximum of 9 days.

    Reporting group title
    FF/VI then Placebo
    Reporting group description
    		 Following Treatment Period 1, participants entered a washout period for 7 days, up to a maximum of 9 days.
    Reporting group title
    Placebo then FF/VI
    Reporting group description
    		 Participants entering Treatment Period 1 received matching placebo once daily (QD), each morning via a dry powder inhaler (DPI) for a period of 7 days, up to a maximum of 14 days. Following Treatment Period 1, participants entered a washout period for 7 days, up to a maximum of 9 days. Following the washout period participants entered Treatment Period 2 and received FF/VI 100/25 micrograms (µg), QD, each morning via a DPI for 7 days, up to a maximum of 14 days.

    Reporting group title
    FF/VI then Placebo
    Reporting group description
    		 Participants entering Treatment Period 1 received FF/VI 100/25 µg QD, each morning via a DPI for a period of 7 days, up to a maximum of 14 days. Following Treatment Period 1, participants entered a washout period for 7 days, up to a maximum of 9 days. Following the washout period, participants entered Treatment Period 2 and received matching placebo QD, each morning via a DPI for 7 days, up to a maximum of 14 days.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received matching placebo once daily (QD), each morning via a dry powder inhaler (DPI) for a period of 7 days, up to a maximum of 14 days during one of the two Treatment Periods. Participants that received placebo in Treatment Period 1, crossed over after the washout period to receive FF/VI 100/25 μg during Treatment Period 2. Participants that received FF/VI 100/25 μg during Treatment Period 1, crossed over after the washout period to receive placebo during Treatment Period 2.

    Subject analysis set title
    FF/VI
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received FF/VI 100/25 μg QD, each morning via a DPI for a period of 7 days, up to a maximum of 14 days during one of the two Treatment Periods. Participants that received FF/VI 100/25 μg in Treatment Period 1, crossed over after the washout period to receive placebo during Treatment Period 2. Participants that received placebo during Treatment Period 1, crossed over after the washout period to receive FF/VI 100/25 μg during Treatment Period 2.

    Primary: Mean change from Baseline in right ventricular end diastolic volume index (RVEDVI) at the end of the Overall Treatment Period

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    End point title
    		 Mean change from Baseline in right ventricular end diastolic volume index (RVEDVI) at the end of the Overall Treatment Period
    End point description
    RVEDVI is a measure of the volume of blood in the right ventricle at the end of diastole, normalized over body surface area and was measured using Cardiac Magnetic Resonance (CMR) imaging. RVEDVI is calculated as the right ventricular end diastolic volume (RDEDV) divided by the body surface area (BSA). The change from Baseline in RVEDVI was analyzed using a mixed model analysis with period, treatment group, and Baseline RVEDVI fitted as fixed effects and participants fitted as a random effect. The Baseline is defined as the assessment performed pre-dose at Day 1 of Treatment Period 1. The change from Baseline is calculated as the RVEDVI value at the end of each treatment period minus the Baseline value. The Per Protocol (PP) Population was comprised of all participants in the modified intent-to-treat (mITT) Population not identified as having deviations considered to impact the primary efficacy analysis.
    End point type
    Primary
    End point timeframe
    Baseline and end of Treatment Period
    End point values
    		 Placebo FF/VI
    Number of subjects analysed
    41 [1]
    43 [2]
    Units: Milliliter per meter square (mL/m^2)
        least squares mean (standard error)
    -0.47 ± 1.393
    5.35 ± 1.365
    Notes
    [1] - PP Population. Only those participants available at the specified time points were analyzed
    [2] - PP Population. Only those participants available at the specified time points were analyzed
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The statistical analysis shows that 41 participants received placebo (in either treatment period 1 or treatment period 2) and 43 participants received FF/VI (in either treatment period 1 or treatment period 2). In a cross over study each participant acts as their own control and therefore appear in both treatment groups, unless withdrawn. Therefore, the comparison groups total should be 45, not 84 as automatically totalled by the database.
    Comparison groups
    Placebo v FF/VI
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [3]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.74
         upper limit
    		 8.91
    Notes
    [3] - Analysis was performed using an ANCOVA model with covariates of treatment, baseline, period and subject as a random effect.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On treatment serious adverse events (SAEs) were collected from the signing of informed consent and non-serious adverse events (AEs) were collected from the start of study treatment (randomization) and up to the end of treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo once daily (QD), each morning via a dry powder inhaler (DPI) for a period of 7 days, up to a maximum of 14 days during one of the two Treatment Periods. Participants that received placebo in Treatment Period 1, crossed over after the washout period to receive FF/VI 100/25 μg during Treatment Period 2. Participants that received FF/VI 100/25 μg during Treatment Period 1, crossed over after the washout period to receive placebo during Treatment Period 2. Participants were provided salbutamol/ ipratropium bromide (administered via a MDI or nebules) to be used as needed throughout the study.

    Reporting group title
    FF/VI
    Reporting group description
    		 Participants received FF/VI 100/25 μg QD, each morning via a DPI for a period of 7 days, up to a maximum of 14 days during one of the two Treatment Periods. Participants that received FF/VI 100/25 μg in Treatment Period 1, crossed over after the washout period to receive placebo during Treatment Period 2. Participants that received placebo during Treatment Period 1, crossed over after the washout period to receive FF/VI 100/25 μg during Treatment Period 2. Participants were provided salbutamol/ ipratropium bromide (administered via a MDI or nebules) to be used as needed throughout the study.

    Serious adverse events
    		 Placebo FF/VI
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 44 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Placebo FF/VI
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 43 (4.65%)
    2 / 44 (4.55%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 43 (4.65%)
    2 / 44 (4.55%)
         occurrences all number
    2
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Jun 2013
    Allow subject screening to occur over two separate screening visits Allow an extension of the screening period window to permit subjects to be included following an exacerbation Change to medication inclusion criteria Clarification to the time related to washout of medications Addition of lung function endpoints Correction of minor typographical errors

    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
    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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