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    Clinical Trial Results:
    A multiple dose, randomised, double-blind, placebo controlled, parallel clinical trial to assess the effect of aclidinium bromide/formoterol fumarate fixed-dose combination on lung hyperinflation, exercise capacity and physical activity in patients with moderate to severe chronic obstructive pulmonary disease (COPD)

    Summary
    EudraCT number
    		 2014-005318-50
    Trial protocol
    		 HU   DE   ES  
    Global end of trial date
    25 Jul 2016

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

    Trial information

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    Trial identification
    Sponsor protocol code
    M-40464-33
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02424344
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    Karlebyhus, Astraallén, Södertälje, Sweden, SE-151 85
    Public contact
    Study Director, AstraZeneca, ClinicalTrialTransparency@astrazeneca.com
    Scientific contact
    Study Director, AstraZeneca, ClinicalTrialTransparency@astrazeneca.com
    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
    25 Jul 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Jul 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objectives of this study were to assess the effect of the aclidinium bromide/formoterol fumarate 400/12 μg BID on lung hyperinflation, exercise endurance and physical activity in patients with moderate to severe COPD. Additionally, the effect of a behavioural intervention on top of aclidinium bromide/formoterol fumarate 400/12 μg were assessed both on the exercise endurance and the physical activity.
    Protection of trial subjects
    This study was conducted in accordance with the recommendations guiding physicians in biomedical research involving human subjects adopted by the 18th World Medical Assembly of Helsinki (1964), revised at Tokyo (1975), Venice (1983), Hong-Kong (1989), Somerset West (1996) and Edinburgh (2000), including the Notes of clarification made by the World Medical Assembly of Washington (2002) and Tokyo (2004), 59th World Medical Association (WMA) General Assembly, Seoul (2008) and 64th WMA General Assembly, Fortaleza, Brazil (2013) as well as in compliance with ICH GCP guidelines and local regulations. Patients were provided with relief medication, salbutamol pressurised metered dose inhaler (pMDI), 100 μg/puff, which could be used from the time of signing the informed consent until the end of the treatment period.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Apr 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
    Canada: 9
    Country: Number of subjects enrolled
    Germany: 223
    Country: Number of subjects enrolled
    Hungary: 16
    Country: Number of subjects enrolled
    Spain: 19
    Worldwide total number of subjects
    267
    EEA total number of subjects
    258
    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)
    158
    From 65 to 84 years
    109
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 26 study centers, 15 in Germany, 4 in Hungary, 3 in Spain and 4 in Canada. The first patient was enrolled in April 2015 and the last patient visit was in July 2016.

    Pre-assignment
    Screening details
    		 This was a randomised, double-blind, parallel-group, placebo-controlled study. 335 patients were screened; 267 were assessed as eligible and were randomized into the study. 68 patients failed screening. The main reason for screening failure was non-fulfilment of inclusion or exclusion criteria (n=56; 16.7%).

    Period 1
    Period 1 title
    Overall Study (overall period)
    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
    		 AB/FF 400/12 μg
    Arm description
    		 Aclidinium Bromide/Formoterol Fumarate 400/12μg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aclidinium bromide/formoterol fumarate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    400/12 μg twice daily (BID)

    Arm title
    		 Placebo
    Arm description
    		 Placebo to Aclidinium Bromide/Formoterol Fumarate 400/12μg
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to Aclidinium/Formoterol 400/12 μg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Twice-daily (BID)

    Number of subjects in period 1
    		AB/FF 400/12 μg Placebo
    Started
    134
    133
    Completed
    127
    123
    Not completed
    7
    10
         Consent withdrawn by subject
    2
    1
         Adverse event, non-fatal
    4
    8
         Lost to follow-up
    1
    -
         Lack of efficacy
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AB/FF 400/12 μg
    Reporting group description
    		 Aclidinium Bromide/Formoterol Fumarate 400/12μg

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo to Aclidinium Bromide/Formoterol Fumarate 400/12μg

    Reporting group values
    		 AB/FF 400/12 μg Placebo Total
    Number of subjects
    		 134 133 267
    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)
    		 79 79 158
        From 65-84 years
    		 55 54 109
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 62.6 ( 7.9 ) 62.1 ( 7.7 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 53 54 107
        Male
    		 81 79 160

    End points

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    End points reporting groups
    Reporting group title
    AB/FF 400/12 μg
    Reporting group description
    		 Aclidinium Bromide/Formoterol Fumarate 400/12μg

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo to Aclidinium Bromide/Formoterol Fumarate 400/12μg

    Primary: Change from baseline in trough Functional Residual capacity (FRC) after 4 weeks of treatment

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    End point title
    		 Change from baseline in trough Functional Residual capacity (FRC) after 4 weeks of treatment
    End point description
    Baseline values in FRC were defined as the corresponding values just before randomization on Day 1 of treatment (Week 0). Trough values were obtained prior to study drug administration.
    End point type
    Primary
    End point timeframe
    Baseline and Week 4
    End point values
    		 AB/FF 400/12 μg Placebo
    Number of subjects analysed
    124
    125
    Units: Liters
        least squares mean (standard error)
    -0.162 ( 0.05 )
    -0.037 ( 0.05 )
    Statistical analysis title
    		 AB/FF 400/12μg v Placebo
    Statistical analysis description
    Adjusted by baseline and age as covariates, and treatment group, sex and smoking-status as fixed effect factors
    Comparison groups
    AB/FF 400/12 μg v Placebo
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.069
    Method
    		 ANCOVA
    Parameter type
    		 Least Square mean difference
    Point estimate
    -0.125
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.259
         upper limit
    		 0.01

    Secondary: Change from baseline in Endurance Time (ET) during constant work rate cycle ergometry at Week 8

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    End point title
    		 Change from baseline in Endurance Time (ET) during constant work rate cycle ergometry at Week 8
    End point description
    The ET was the time from the increase in work rate to 75% Wmax to the point of symptom limitation. Baseline measurements were taken prior to the IP dose on Day 1. Measurements at Week 8 were taken at 3 hours post-dose. Participants underwent a behavioural intervention (consisting of a telecoaching programme to enhance physical activity) between Week 4 and Week 8.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 8
    End point values
    		 AB/FF 400/12 μg Placebo
    Number of subjects analysed
    124
    121
    Units: Seconds
        least squares mean (standard error)
    50.7 ( 18.1 )
    -4.6 ( 18.2 )
    No statistical analyses for this end point

    Secondary: Percentage of inactive patients (mean of <6000 steps per day) at Week 8

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    End point title
    		 Percentage of inactive patients (mean of <6000 steps per day) at Week 8
    End point description
    Physical activity was assessed by means of measurement of activity paramenters (e.g. number of steps) through a Dynaport MoveMonitor and completion of the Daily ProActive Physical Activity in COPD questionnaire. Compliant criterion based on at least 8 hours per day, and at least 3 days per week. Participants underwent a behavioural intervention (consisting of a telecoaching programme to enhance physical activity) between Week 4 and Week 8. Baseline was defined as mean of steps/day assessed during the week before the randomisation visit.
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    		 AB/FF 400/12 μg Placebo
    Number of subjects analysed
    118
    117
    Units: Percent
        number (not applicable)
    41.53
    50.43
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    70+3
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Aclidinium Bromide/Formoterol Fumarate FDC 400/12μg
    Reporting group description
    		 8 weeks, double blind treatment period

    Reporting group title
    Placebo to Aclidinium/Formoterol
    Reporting group description
    		 8 weeks, double blind treatment period

    Serious adverse events
    		 Aclidinium Bromide/Formoterol Fumarate FDC 400/12μg Placebo to Aclidinium/Formoterol
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 134 (1.49%)
    3 / 133 (2.26%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Pubis fracture
         subjects affected / exposed
    1 / 134 (0.75%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 134 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 134 (0.75%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 134 (0.75%)
    0 / 133 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Lens dislocation
         subjects affected / exposed
    0 / 134 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    0 / 134 (0.00%)
    1 / 133 (0.75%)
         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
    		 Aclidinium Bromide/Formoterol Fumarate FDC 400/12μg Placebo to Aclidinium/Formoterol
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 134 (10.45%)
    24 / 133 (18.05%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 134 (2.99%)
    12 / 133 (9.02%)
         occurrences all number
    4
    24
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    14 / 134 (10.45%)
    13 / 133 (9.77%)
         occurrences all number
    14
    13

    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
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    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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