Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   42771   clinical trials with a EudraCT protocol, of which   7044   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).


    Phase 1 trials conducted solely in adults and that are not part of an agreed PIP are not public in the EU CTR (refer to European Guidance 2008/C 168/02   Art. 3 par. 2 and   Commission Guideline 2012/C 302/03,   Art. 5) .

    Clinical Trials marked as "Trial now transitioned" were transitioned to the Clinical Trial Regulation 536/2014 and can be further followed in the Clinical Trial Information System  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A 12-Week, Double-Blind, Placebo-Controlled, Efficacy and Safety Study of Fluticasone Propionate Multidose Dry Powder Inhaler Compared with Fluticasone/Salmeterol Multidose Dry Powder Inhaler in Adolescent and Adult Patients with Persistent Asthma Symptomatic Despite Low-dose or Mid-dose Inhaled Corticosteroid Therapy

    Summary
    EudraCT number
    2014-001149-25
    Trial protocol
    CZ   PL   HU  
    Global end of trial date
    21 Sep 2015

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

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    FSS-AS-301
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02139644
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Teva Branded Pharmaceutical Products R&D, Inc
    Sponsor organisation address
    41 Moores Road, Frazer, Pennsylvania, United States, 19355
    Public contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 215-591-3000, ustevatrials@tevapharm.com
    Scientific contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 215-591-3000, ustevatrials@tevapharm.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
    15 Feb 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the efficacy of fluticasone propionate multidose dry powder inhaler (Fp MDPI) and fluticasone propionate/salmeterol xinafoate multidose dry powder inhaler (FS MDPI) when administered over 12 weeks in patients 12 years of age and older with persistent asthma.
    Protection of trial subjects
    This study was conducted in full accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any applicable national and local laws and regulations (eg, Code of Federal Regulations [CFR] Title 21, Parts 50, 54, 56, 312, and 314; European Union [EU] Directive 2001/20/EC on the approximation of the laws, regulations, and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use). Information regarding any investigational centers participating in this study that could not comply with these standards was documented. Written and/or oral information about the study was provided to all patients (or, in the case of minor patients [age 12 to 17 years or per local regulations], to patients and their parents/legally authorized representatives) in a language understandable by the patients (to the extent practical for minor patients) and/or representatives. The information included an adequate explanation of the aims, methods, anticipated benefits, potential hazards, and insurance arrangements in force. Written informed consent was obtained before any study procedures or assessments were done. It was explained that patients were free to refuse entry into the study and free to withdraw from the study at any time without prejudice to future treatment. Each patient’s willingness to participate in the study was documented in writing in an informed consent form (ICF) that was signed by the patient (or legally acceptable representative) with the date of that signature indicated. Each investigator kept the original ICFs, and copies were given to the patients. Analogous procedures applied to assent forms.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    25 Jun 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
    Poland: 107
    Country: Number of subjects enrolled
    Hungary: 68
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Russian Federation: 94
    Country: Number of subjects enrolled
    Ukraine: 43
    Country: Number of subjects enrolled
    United States: 456
    Country: Number of subjects enrolled
    South Africa: 16
    Worldwide total number of subjects
    787
    EEA total number of subjects
    175
    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)
    112
    Adults (18-64 years)
    595
    From 65 to 84 years
    79
    85 years and over
    1

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    A total of 1363 patients with persistent asthma were screened for enrollment into this study. Of the 787 patients enrolled, 140 were not randomized, most commonly (70 patients) because of not meeting randomization criteria.

    Pre-assignment
    Screening details
    787 patients at 129 investigational centers in the US and elsewhere internationally met entry criteria and were considered eligible for enrollment into the study.

    Period 1
    Period 1 title
    Run-In Period
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Single blind
    Roles blinded
    Subject
    Blinding implementation details
    Patients discontinued their current inhaled corticosteroid and instead took 1 inhalation twice a day of a single-blinded placebo multidose dry powder inhaler (MDPI) device and 1 puff twice a day of an open-label QVAR® (beclomethasone dipropionate 40 mcg metered-dose inhaler, or equivalent). Placebo, manufactured by Teva, was supplied in a MDPI device that was identical to the devices used to deliver active drug, and indistinguishable from the active treatments.

    Arms
    Arm title
    Enrolled Patients
    Arm description
    During the run-in period (from the screening visit to the randomization visit), all patients replaced their current rescue medication with study-specific rescue medication (albuterol/salbutamol HFA MDI) for use on an as-needed basis for the immediate relief of asthma symptoms throughout the period. All patients discontinued their current ICS or ICS/LABA, and took 1 inhalation twice a day from a single-blinded placebo MDPI device and 1 puff twice a day from open-label QVAR 40 mcg HFA MDI (or equivalent).
    Arm type
    Active comparator

    Investigational medicinal product name
    Albuterol/Salbutamol
    Investigational medicinal product code
    Other name
    ProAir
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    Albuterol/salbutamol hydrofluoroalkane (specifically, HFA 134a) metered dose inhaler (MDI), for use on an as-needed basis for the immediate relief of asthma symptoms. Albuterol/salmeterol HFA MDI was supplied to all patients for use as rescue medication throughout the run-in and treatment periods.

    Investigational medicinal product name
    Placebo MDPI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo administered via a multidose dry powder inhaler (MDPI) one puff in the morning and one puff in the evening for the duration of the Run-in Period (14-21 days).

    Investigational medicinal product name
    Beclomethasone dipropionate
    Investigational medicinal product code
    Other name
    QVAR
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    QVAR (beclomethasone dipropionate) 40 mcg Inhalation Aerosol is a pressurized MDI that contains a Food and Drug Administration (FDA)-approved formulation of beclomethasone dipropionate. Patients took 1 puff twice a day from open-label QVAR 40 mcg hydrofluoroalkane (specifically, HFA-134a) metered-dose inhaler (MDI). A clinically equivalent dose of inhaled corticosteroid (ICS) was substituted in countries where QVAR 40 mcg was not available.

    Number of subjects in period 1
    Enrolled Patients
    Started
    787
    Completed
    647
    Not completed
    140
         Inclusion criteria not met
    30
         Exclusion criteria met
    11
         Randomization criteria not met
    70
         Adverse event, non-fatal
    3
         not specified
    6
         Consent withdrawn by subject
    12
         Lost to follow-up
    8
    Period 2
    Period 2 title
    Treatment Period
    Is this the baseline period?
    Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor
    Blinding implementation details
    Patients were randomized 1:1:1:1:1 to receive Fp MDPI 50 mcg, Fp MDPI 100 mcg, FS MDPI 50/12.5 mcg, FS MDPI 100/12.5 mcg, or placebo MDPI for the entire treatment period. Patients and investigators remained blinded to treatment assignment during the study. The sponsor’s clinical personnel involved in the study were also blinded to the study drug identity until the database was locked for analysis and the treatment assignment revealed.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    FS MDPI 100 / 12.5 mcg
    Arm description
    Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 100 mcg (for a total daily dose of 200 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks.
    Arm type
    Active comparator

    Investigational medicinal product name
    Fluticasone propionate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone propionate (combined with salmeterol) multidose dry powder inhaler 100 mcg in the morning and evening for a total daily dose of 200 mcg.

    Investigational medicinal product name
    Salmeterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Salmeterol (combined with fluticasone propionate) multidose dry powder inhaler 12.5 mcg in the morning and evening for a total daily dose of 25 mcg.

    Arm title
    FS MDPI 50 / 12.5 mcg
    Arm description
    Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 50 mcg (for a total daily dose of 100 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks.
    Arm type
    Active comparator

    Investigational medicinal product name
    Fluticasone propionate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone propionate (combined with salmeterol) multidose dry powder inhaler 50 mcg in the morning and evening for a total daily dose of 100 mcg.

    Investigational medicinal product name
    Salmeterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Salmeterol (combined with fluticasone propionate) multidose dry powder inhaler 12.5 mcg in the morning and evening for a total daily dose of 25 mcg.

    Arm title
    Fp MDPI 100 mcg
    Arm description
    Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 200 mcg for 12 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Fluticasone propionate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone propionate multidose dry powder inhaler 100 mcg in the morning and evening for a total daily dose of 200 mcg.

    Arm title
    Fp MDPI 50 mcg
    Arm description
    Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 100 mcg for 12 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Fluticasone propionate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone propionate multidose dry powder inhaler 50 mcg in the morning and evening for a total daily dose of 100 mcg.

    Arm title
    Placebo MDPI
    Arm description
    The placebo multidose dry powder inhaler was identical to the devices used to deliver active drug, and indistinguishable from the active treatments. Patients took one inhalation twice a day (approximately 12 hours apart).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo MDPI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo administered via a multidose dry powder inhaler (MDPI) one puff in the morning and one puff in the evening for12 weeks.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 is the Run-In Period in which all patients were given the same medications and qualifying tests. Patients who successfully met study criteria were randomized and treated in the Treatment Period. Hence baseline information is offered for those patients who entered the Treatment Period.
    Number of subjects in period 2 [2]
    FS MDPI 100 / 12.5 mcg FS MDPI 50 / 12.5 mcg Fp MDPI 100 mcg Fp MDPI 50 mcg Placebo MDPI
    Started
    129
    129
    130
    129
    130
    Intent to treat population
    129
    129
    130
    129
    130
    Safety population
    126
    128
    129
    129
    129
    Full analysis set
    126
    128
    129
    128
    129
    Completed
    126
    121
    121
    121
    113
    Not completed
    3
    8
    9
    8
    17
         Protocol deviation
    -
    -
    1
    1
    1
         Randomized but not treated
    3
    1
    1
    -
    1
         Non-compliance
    -
    -
    1
    -
    -
         Lack of efficacy
    -
    1
    -
    1
    4
         Adverse event, non-fatal
    -
    3
    2
    1
    6
         Consent withdrawn by subject
    -
    2
    2
    3
    2
         Disease progression
    -
    -
    1
    1
    2
         Lost to follow-up
    -
    1
    1
    1
    1
    Notes
    [2] - 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: The number of subjects enrolled matches the number of subjects in the Run-In Period.

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    FS MDPI 100 / 12.5 mcg
    Reporting group description
    Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 100 mcg (for a total daily dose of 200 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks.

    Reporting group title
    FS MDPI 50 / 12.5 mcg
    Reporting group description
    Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 50 mcg (for a total daily dose of 100 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks.

    Reporting group title
    Fp MDPI 100 mcg
    Reporting group description
    Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 200 mcg for 12 weeks.

    Reporting group title
    Fp MDPI 50 mcg
    Reporting group description
    Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 100 mcg for 12 weeks.

    Reporting group title
    Placebo MDPI
    Reporting group description
    The placebo multidose dry powder inhaler was identical to the devices used to deliver active drug, and indistinguishable from the active treatments. Patients took one inhalation twice a day (approximately 12 hours apart).

    Reporting group values
    FS MDPI 100 / 12.5 mcg FS MDPI 50 / 12.5 mcg Fp MDPI 100 mcg Fp MDPI 50 mcg Placebo MDPI Total
    Number of subjects
    129 129 130 129 130 647
    Age categorical
    ITT population
    Units: Subjects
        Adolescents (12-17 years)
    19 19 18 13 17 86
        Adults (18-64 years)
    100 97 102 93 102 494
        65+ years
    10 13 10 23 11 67
    Age continuous
    ITT population
    Units: years
        arithmetic mean (standard deviation)
    41 ± 17 41.4 ± 18.61 40.6 ± 17.16 43.3 ± 17.96 40.9 ± 17.35 -
    Gender categorical
    ITT population
    Units: Subjects
        Female
    72 71 76 75 70 364
        Male
    57 58 54 54 60 283
    Race
    ITT population
    Units: Subjects
        White
    105 109 93 107 101 515
        Black or African American
    20 19 30 18 26 113
        Asian
    4 1 4 1 1 11
        American Indian or Alaska Native
    0 0 1 0 0 1
        Native Hawaiian or other Pacific Islander
    0 0 0 1 0 1
        Other
    0 0 2 2 2 6
    Ethnicity
    ITT population
    Units: Subjects
        Not Hispanic or Latino
    119 121 114 121 122 597
        Hispanic or Latino
    10 8 16 8 7 49
        Unknown
    0 0 0 0 1 1
    History of smoking
    ITT population
    Units: Subjects
        Prior smoker
    18 13 15 14 12 72
        No tobacco use
    111 116 115 115 118 575
    Previous Asthma Therapy
    ITT population
    Units: Subjects
        Inhaled corticosteroid
    97 90 83 89 102 461
        Inhaled corticosteroid/long-acting beta2-agonist
    32 39 47 40 28 186
    Body Mass Index
    ITT population
    Units: kg/m^2
        arithmetic mean (standard deviation)
    27.94 ± 6.686 28 ± 7.166 27.63 ± 6.603 27.94 ± 7.259 27.99 ± 6.849 -
    Forced Expiratory Volume in 1 second (FEV1)
    ITT population (n=126, 128, 129, 129, 129)
    Units: liters
        arithmetic mean (standard deviation)
    2.162 ± 0.5522 2.302 ± 0.6526 2.166 ± 0.5725 2.132 ± 0.6341 2.188 ± 0.5628 -

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Enrolled Patients
    Reporting group description
    During the run-in period (from the screening visit to the randomization visit), all patients replaced their current rescue medication with study-specific rescue medication (albuterol/salbutamol HFA MDI) for use on an as-needed basis for the immediate relief of asthma symptoms throughout the period. All patients discontinued their current ICS or ICS/LABA, and took 1 inhalation twice a day from a single-blinded placebo MDPI device and 1 puff twice a day from open-label QVAR 40 mcg HFA MDI (or equivalent).
    Reporting group title
    FS MDPI 100 / 12.5 mcg
    Reporting group description
    Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 100 mcg (for a total daily dose of 200 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks.

    Reporting group title
    FS MDPI 50 / 12.5 mcg
    Reporting group description
    Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 50 mcg (for a total daily dose of 100 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks.

    Reporting group title
    Fp MDPI 100 mcg
    Reporting group description
    Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 200 mcg for 12 weeks.

    Reporting group title
    Fp MDPI 50 mcg
    Reporting group description
    Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 100 mcg for 12 weeks.

    Reporting group title
    Placebo MDPI
    Reporting group description
    The placebo multidose dry powder inhaler was identical to the devices used to deliver active drug, and indistinguishable from the active treatments. Patients took one inhalation twice a day (approximately 12 hours apart).

    Subject analysis set title
    Serial Spirometry Subset:FS MDPI 100 / 12.5 mcg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    A subset of patients who performed postdose serial spirometry at the baseline visit and week 12, and were randomized to the fluticasone propionate 100 mcg and salmeterol 12.5 mcg/dose BID treatment group.

    Subject analysis set title
    Serial Spirometry Subset:FS MDPI 50 / 12.5 mcg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    A subset of patients who performed postdose serial spirometry at the baseline visit and week 12, and were randomized to the fluticasone propionate 50 mcg and salmeterol 12.5 mcg/dose BID treatment group.

    Subject analysis set title
    Serial Spirometry Subset: Fp MDPI 100 mcg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    A subset of patients who performed postdose serial spirometry at the baseline visit and week 12, and were randomized to the fluticasone propionate 100 mcg/dose BID treatment group.

    Subject analysis set title
    Serial Spirometry Subset: Fp MDPI 50 mcg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    A subset of patients who performed postdose serial spirometry at the baseline visit and week 12, and were randomized to the fluticasone propionate 50 mcg/dose BID treatment group.

    Subject analysis set title
    Serial Spirometry Subset: Placebo MDPI
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    A subset of patients who performed postdose serial spirometry at the baseline visit and week 12, and were randomized to the placebo treatment group.

    Primary: Standardized Baseline-Adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Effect Curve from Time Zero to 12 Hours Postdose (FEV1 AUEC0-12h) at Week 12

    Close Top of page
    End point title
    Standardized Baseline-Adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Effect Curve from Time Zero to 12 Hours Postdose (FEV1 AUEC0-12h) at Week 12
    End point description
    A subset of approximately 300 patients who performed postdose serial spirometry is based on sample size calculation. Data from these assessments were used to analyze the primary endpoint of baseline-adjusted FEV1 AUEC0-12h at week 12 using the trapezoidal rule based on actual time of measurement. It was standardized by dividing it by the number of hours between the start time of dose administration and the end time of the last nonmissing FEV1 measurement. The baseline FEV1 was the average of the 2 predose FEV1 measurements (30 and 10 minutes predose). If 1 of these was missing, the nonmissing value was used; if both were missing, baseline was treated as missing. Baseline-adjusted FEV1 was calculated as postdose FEV1 after subtracting the baseline FEV1 value.
    End point type
    Primary
    End point timeframe
    Day 1 (predose, baseline), Week 12 and was performed at the following times relative to the administration of study drug (±5 minutes): 15 and 30 minutes and 1, 2, 3, 4, 6, 8, 10, and 12 hours.
    End point values
    Serial Spirometry Subset:FS MDPI 100 / 12.5 mcg Serial Spirometry Subset:FS MDPI 50 / 12.5 mcg Serial Spirometry Subset: Fp MDPI 100 mcg Serial Spirometry Subset: Fp MDPI 50 mcg Serial Spirometry Subset: Placebo MDPI
    Number of subjects analysed
    61 [1]
    56 [2]
    72 [3]
    63 [4]
    60 [5]
    Units: liters
        least squares mean (standard error)
    0.408 ± 0.0465
    0.399 ± 0.0479
    0.254 ± 0.0434
    0.268 ± 0.0457
    0.074 ± 0.0487
    Notes
    [1] - FAS
    [2] - FAS
    [3] - FAS
    [4] - FAS
    [5] - FAS
    Statistical analysis title
    AUEC0-12h: FS 100/12.5 vs Fp 100 mcg
    Statistical analysis description
    A fixed-sequence multiple testing procedure was used to control the overall Type I error rate at the 0.05 level (2-sided) for the primary endpoints analyses. Analyses appear in the defined sequence. This is the first in the sequence.
    Comparison groups
    Serial Spirometry Subset:FS MDPI 100 / 12.5 mcg v Serial Spirometry Subset: Fp MDPI 100 mcg
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0076 [6]
    Method
    ANCOVA
    Parameter type
    LSM difference
    Point estimate
    0.154
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.041
         upper limit
    0.267
    Notes
    [6] - Fixed effects of treatment, sex, (pooled) center, previous therapy (ICS or ICS/LABA), and covariates of age and baseline FEV1.
    Statistical analysis title
    AUEC0-12h: FS 50/12.5 vs Fp 50 mcg
    Statistical analysis description
    A fixed-sequence multiple testing procedure was used to control the overall Type I error rate at the 0.05 level (2-sided) for the primary endpoints analyses. Analyses appear in the defined sequence. This is the second in the sequence.
    Comparison groups
    Serial Spirometry Subset:FS MDPI 50 / 12.5 mcg v Serial Spirometry Subset: Fp MDPI 50 mcg
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0322 [7]
    Method
    ANCOVA
    Parameter type
    LSM difference
    Point estimate
    0.131
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.011
         upper limit
    0.25
    Notes
    [7] - Fixed effects of treatment, sex, (pooled) center, previous therapy (ICS or ICS/LABA), and covariates of age and baseline FEV1.
    Statistical analysis title
    AUEC0-12h: FS 100/12.5 vs Placebo
    Statistical analysis description
    A fixed-sequence multiple testing procedure was used to control the overall Type I error rate at the 0.05 level (2-sided) for the primary endpoints analyses. Analyses appear in the defined sequence. This is the third in the sequence.
    Comparison groups
    Serial Spirometry Subset:FS MDPI 100 / 12.5 mcg v Serial Spirometry Subset: Placebo MDPI
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0 [8]
    Method
    ANCOVA
    Parameter type
    LSM difference
    Point estimate
    0.335
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.216
         upper limit
    0.453
    Notes
    [8] - Fixed effects of treatment, sex, (pooled) center, previous therapy (ICS or ICS/LABA), and covariates of age and baseline FEV1.
    Statistical analysis title
    AUEC0-12h: FS 50/12.5 vs Placebo
    Statistical analysis description
    A fixed-sequence multiple testing procedure was used to control the overall Type I error rate at the 0.05 level (2-sided) for the primary endpoints analyses. Analyses appear in the defined sequence. This is the fourth in the sequence.
    Comparison groups
    Serial Spirometry Subset:FS MDPI 50 / 12.5 mcg v Serial Spirometry Subset: Placebo MDPI
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0 [9]
    Method
    ANCOVA
    Parameter type
    LSM difference
    Point estimate
    0.325
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.203
         upper limit
    0.447
    Notes
    [9] - Fixed effects of treatment, sex, (pooled) center, previous therapy (ICS or ICS/LABA), and covariates of age and baseline FEV1.

    Primary: Change from Baseline in Morning Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12

    Close Top of page
    End point title
    Change from Baseline in Morning Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12
    End point description
    Trough FEV1 was a morning spirometry taken predose and pre-rescue bronchodilator. If the patient inadvertently administered asthma medication/study drug at home on the AM of the visit, or if the patient took rescue medication within 6 hours of testing, the visit was rescheduled. The baseline for predose FEV1 was defined as the average of the 30-minute and 10-minute predose measurements obtained at the randomization visit (Day 1).
    End point type
    Primary
    End point timeframe
    Day 1 (predose, baseline), Week 12
    End point values
    FS MDPI 100 / 12.5 mcg FS MDPI 50 / 12.5 mcg Fp MDPI 100 mcg Fp MDPI 50 mcg Placebo MDPI
    Number of subjects analysed
    126 [10]
    128 [11]
    129 [12]
    128 [13]
    129 [14]
    Units: liters
        least squares mean (standard error)
    0.315 ± 0.0352
    0.319 ± 0.035
    0.204 ± 0.034
    0.172 ± 0.0347
    0.053 ± 0.035
    Notes
    [10] - FAS
    [11] - FAS
    [12] - FAS
    [13] - FAS
    [14] - FAS
    Statistical analysis title
    FEV1: FS 100/12.5 mcg vs Placebo
    Statistical analysis description
    A fixed-sequence multiple testing procedure was used to control the overall Type I error rate at the 0.05 level (2-sided) for the primary endpoints analyses. Analyses appear in the defined sequence. This is the fifth in the sequence.
    Comparison groups
    FS MDPI 100 / 12.5 mcg v Placebo MDPI
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0 [15]
    Method
    ANCOVA
    Parameter type
    LSM difference
    Point estimate
    0.262
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.168
         upper limit
    0.356
    Notes
    [15] - Effects due to baseline trough AM FEV1, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment.
    Statistical analysis title
    FEV1: FS 50/12.5 mcg vs Placebo
    Statistical analysis description
    A fixed-sequence multiple testing procedure was used to control the overall Type I error rate at the 0.05 level (2-sided) for the primary endpoints analyses. Analyses appear in the defined sequence. This is the sixth in the sequence.
    Comparison groups
    FS MDPI 50 / 12.5 mcg v Placebo MDPI
    Number of subjects included in analysis
    257
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0 [16]
    Method
    ANCOVA
    Parameter type
    LSM difference
    Point estimate
    0.266
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.172
         upper limit
    0.36
    Notes
    [16] - Effects due to baseline trough AM FEV1, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment.
    Statistical analysis title
    FEV1: Fp 100 mcg vs Placebo
    Statistical analysis description
    A fixed-sequence multiple testing procedure was used to control the overall Type I error rate at the 0.05 level (2-sided) for the primary endpoints analyses. Analyses appear in the defined sequence. This is the seventh in the sequence.
    Comparison groups
    Fp MDPI 100 mcg v Placebo MDPI
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0017 [17]
    Method
    ANCOVA
    Parameter type
    LSM difference
    Point estimate
    0.151
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.057
         upper limit
    0.244
    Notes
    [17] - Effects due to baseline trough AM FEV1, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment.
    Statistical analysis title
    FEV1: Fp 50 mcg vs Placebo
    Statistical analysis description
    A fixed-sequence multiple testing procedure was used to control the overall Type I error rate at the 0.05 level (2-sided) for the primary endpoints analyses. Analyses appear in the defined sequence. This is the eighth in the sequence.
    Comparison groups
    Fp MDPI 50 mcg v Placebo MDPI
    Number of subjects included in analysis
    257
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0132 [18]
    Method
    ANCOVA
    Parameter type
    LSM difference
    Point estimate
    0.119
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.025
         upper limit
    0.212
    Notes
    [18] - Effects due to baseline trough AM FEV1, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment.

    Secondary: Change from Baseline in the Weekly Average of the Daily Morning Trough Peak Expiratory Flow (PEF) Over the 12 Week Treatment

    Close Top of page
    End point title
    Change from Baseline in the Weekly Average of the Daily Morning Trough Peak Expiratory Flow (PEF) Over the 12 Week Treatment
    End point description
    Morning PEF tests were performed before administration of study drug or rescue medications (data were excluded if the time of PEF measurement was more than 5 minutes after the dose time). The patient recorded the highest value of 3 measurements obtained in the patient diary. The baseline PEF was the average value of recorded (nonmissing) morning assessments over the 7 days prior to randomization on Day 1. For efficacy analyses of weekly average morning PEF measurements, values were the averages based on available data for that week.
    End point type
    Secondary
    End point timeframe
    Days -6 to Day 1 (predose), Day 1 (postdose) daily until Week 12
    End point values
    FS MDPI 100 / 12.5 mcg FS MDPI 50 / 12.5 mcg Fp MDPI 100 mcg Fp MDPI 50 mcg Placebo MDPI
    Number of subjects analysed
    125 [19]
    128 [20]
    129 [21]
    128 [22]
    128 [23]
    Units: liters / minute
        least squares mean (standard error)
    24.415 ± 3.153
    24.864 ± 3.1182
    14.517 ± 3.0778
    10.609 ± 3.1176
    3.591 ± 3.1474
    Notes
    [19] - FAS
    [20] - FAS
    [21] - FAS
    [22] - FAS
    [23] - FAS
    Statistical analysis title
    AM PEF: Fp 100 mcg vs Placebo
    Statistical analysis description
    The analysis of change from baseline in weekly average of daily (AM predose and pre-rescue bronchodilator) PEF over the 12-week treatment period was performed using an mixed model for repeated measures (MMRM) with an unstructured covariance matrix and with effects due to baseline weekly average of daily AM PEF, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.
    Comparison groups
    Fp MDPI 100 mcg v Placebo MDPI
    Number of subjects included in analysis
    257
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0123 [24]
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    10.926
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.38
         upper limit
    19.471
    Notes
    [24] - Significance level of 0.05.
    Statistical analysis title
    AM PEF: Fp 50 mcg vs Placebo
    Statistical analysis description
    The analysis of change from baseline in weekly average of daily (AM predose and pre-rescue bronchodilator) PEF over the 12-week treatment period was performed using an mixed model for repeated measures (MMRM) with an unstructured covariance matrix and with effects due to baseline weekly average of daily AM PEF, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.
    Comparison groups
    Fp MDPI 50 mcg v Placebo MDPI
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1074 [25]
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    7.018
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.531
         upper limit
    15.567
    Notes
    [25] - Significance level of 0.05.
    Statistical analysis title
    AM PEF: FS 100/12.5 mcg vs Placebo
    Statistical analysis description
    The analysis of change from baseline in weekly average of daily (AM predose and pre-rescue bronchodilator) PEF over the 12-week treatment period was performed using an mixed model for repeated measures (MMRM) with an unstructured covariance matrix and with effects due to baseline weekly average of daily AM PEF, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.
    Comparison groups
    FS MDPI 100 / 12.5 mcg v Placebo MDPI
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0 [26]
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    20.824
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    12.253
         upper limit
    29.395
    Notes
    [26] - Significance level of 0.05.
    Statistical analysis title
    AM PEF: FS 50/12.5 mcg vs Placebo
    Statistical analysis description
    The analysis of change from baseline in weekly average of daily (AM predose and pre-rescue bronchodilator) PEF over the 12-week treatment period was performed using an mixed model for repeated measures (MMRM) with an unstructured covariance matrix and with effects due to baseline weekly average of daily AM PEF, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.
    Comparison groups
    FS MDPI 50 / 12.5 mcg v Placebo MDPI
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0 [27]
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    21.273
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    12.728
         upper limit
    29.818
    Notes
    [27] - Significance level of 0.05.
    Statistical analysis title
    AM PEF: FS 100/12.5 mcg vs FP 100 mcg
    Statistical analysis description
    The analysis of change from baseline in weekly average of daily (AM predose and pre-rescue bronchodilator) PEF over the 12-week treatment period was performed using an mixed model for repeated measures (MMRM) with an unstructured covariance matrix and with effects due to baseline weekly average of daily AM PEF, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.
    Comparison groups
    FS MDPI 100 / 12.5 mcg v Fp MDPI 100 mcg
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0233 [28]
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    9.898
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.349
         upper limit
    18.447
    Notes
    [28] - Significance level of 0.05.
    Statistical analysis title
    AM PEF: FS 50/12.5 mcg vs FP 50 mcg
    Statistical analysis description
    The analysis of change from baseline in weekly average of daily (AM predose and pre-rescue bronchodilator) PEF over the 12-week treatment period was performed using an mixed model for repeated measures (MMRM) with an unstructured covariance matrix and with effects due to baseline weekly average of daily AM PEF, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.
    Comparison groups
    FS MDPI 50 / 12.5 mcg v Fp MDPI 50 mcg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0011 [29]
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    14.255
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    5.732
         upper limit
    22.778
    Notes
    [29] - Significance level of 0.05.
    Statistical analysis title
    AM PEF: FS 50/12.5 mcg vs FP 100 mcg
    Statistical analysis description
    The analysis of change from baseline in weekly average of daily (AM predose and pre-rescue bronchodilator) PEF over the 12-week treatment period was performed using an mixed model for repeated measures (MMRM) with an unstructured covariance matrix and with effects due to baseline weekly average of daily AM PEF, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.
    Comparison groups
    FS MDPI 50 / 12.5 mcg v Fp MDPI 100 mcg
    Number of subjects included in analysis
    257
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0175 [30]
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    10.347
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.822
         upper limit
    18.872
    Notes
    [30] - Significance level of 0.05.

    Secondary: Change from Baseline in the Weekly Average of the Total Daily Asthma Symptom Score Over the 12-Week Treatment Period

    Close Top of page
    End point title
    Change from Baseline in the Weekly Average of the Total Daily Asthma Symptom Score Over the 12-Week Treatment Period
    End point description
    The total daily asthma symptom score is the average of the daytime and nighttime scores as recorded in the patient diary. Daytime Symptom Score: 0=No symptoms 1=Symptoms for 1 short period 2=Symptoms for 2+ short periods 3=Symptoms for most of the day - did not affect normal daily activities 4=Symptoms for most of the day - did affect normal daily activities 5=Symptoms so severe that I could not go to work or perform normal daily activities Nighttime Symptom Score (determined in the AM): 0=No symptoms 1=Symptoms causing me to wake once (or wake early) 2=Symptoms causing me to wake twice or more (including waking early) 3=Symptoms causing me to be awake for most of the night 4=Symptoms so severe that I did not sleep Baseline was the average of recorded scores over the 7 days before randomization. The change from baseline in the weekly average over weeks 1 to 12 was analyzed using an mixed model for repeated measures (MMRM).
    End point type
    Secondary
    End point timeframe
    Days -6 to Day 1 (predose, baseline) to Week 12
    End point values
    FS MDPI 100 / 12.5 mcg FS MDPI 50 / 12.5 mcg Fp MDPI 100 mcg Fp MDPI 50 mcg Placebo MDPI
    Number of subjects analysed
    125 [31]
    128 [32]
    129 [33]
    128 [34]
    128 [35]
    Units: units on a scale
        least squares mean (standard error)
    -0.364 ± 0.0318
    -0.329 ± 0.0314
    -0.3 ± 0.0308
    -0.278 ± 0.0314
    -0.135 ± 0.0318
    Notes
    [31] - FAS
    [32] - FAS
    [33] - FAS
    [34] - FAS
    [35] - FAS
    Statistical analysis title
    Asthma Symptoms: Fp 100 mcg vs Placebo
    Statistical analysis description
    The change from baseline in the weekly average of the total daily asthma symptom scores over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.
    Comparison groups
    Fp MDPI 100 mcg v Placebo MDPI
    Number of subjects included in analysis
    257
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002 [36]
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    -0.165
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.251
         upper limit
    -0.08
    Notes
    [36] - Significance level of 0.05.
    Statistical analysis title
    Asthma Symptoms: Fp 50 mcg vs Placebo
    Statistical analysis description
    The change from baseline in the weekly average of the total daily asthma symptom scores over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.
    Comparison groups
    Fp MDPI 50 mcg v Placebo MDPI
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001 [37]
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    -0.143
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.229
         upper limit
    -0.058
    Notes
    [37] - Significance level of 0.05.
    Statistical analysis title
    Asthma Symptoms: FS 100/12.5 vs Placebo
    Statistical analysis description
    The change from baseline in the weekly average of the total daily asthma symptom scores over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.
    Comparison groups
    FS MDPI 100 / 12.5 mcg v Placebo MDPI
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0 [38]
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    -0.23
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.315
         upper limit
    -0.144
    Notes
    [38] - Significance level of 0.05.
    Statistical analysis title
    Asthma Symptoms: FS 50/12.5 vs Placebo
    Statistical analysis description
    The change from baseline in the weekly average of the total daily asthma symptom scores over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.
    Comparison groups
    FS MDPI 50 / 12.5 mcg v Placebo MDPI
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0 [39]
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    -0.194
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.279
         upper limit
    -0.109
    Notes
    [39] - Significance level of 0.05.
    Statistical analysis title
    Asthma Symptoms: FS 100/12.5 mcg vs Fp 100 mcg
    Statistical analysis description
    The change from baseline in the weekly average of the total daily asthma symptom scores over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.
    Comparison groups
    FS MDPI 100 / 12.5 mcg v Fp MDPI 100 mcg
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1381 [40]
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    -0.064
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.15
         upper limit
    0.021
    Notes
    [40] - Significance level of 0.05.
    Statistical analysis title
    Asthma Symptoms: FS 50/12.5 mcg vs Fp 50 mcg
    Statistical analysis description
    The change from baseline in the weekly average of the total daily asthma symptom scores over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.
    Comparison groups
    FS MDPI 50 / 12.5 mcg v Fp MDPI 50 mcg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2438 [41]
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    -0.051
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.136
         upper limit
    0.035
    Notes
    [41] - Significance level of 0.05.
    Statistical analysis title
    Asthma Symptoms: FS 50/12.5 mcg vs Fp 100 mcg
    Statistical analysis description
    The change from baseline in the weekly average of the total daily asthma symptom scores over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.
    Comparison groups
    FS MDPI 50 / 12.5 mcg v Fp MDPI 100 mcg
    Number of subjects included in analysis
    257
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5095 [42]
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    -0.029
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.114
         upper limit
    0.057
    Notes
    [42] - Significance level of 0.05.

    Secondary: Change from Baseline in the Weekly Average of the Total Daily (24-hour) Use of Albuterol/Salbutamol Inhalation Aerosol Over the 12-Week Treatment Period

    Close Top of page
    End point title
    Change from Baseline in the Weekly Average of the Total Daily (24-hour) Use of Albuterol/Salbutamol Inhalation Aerosol Over the 12-Week Treatment Period
    End point description
    Patients recorded the number of inhalations of rescue medication (albuterol/salbutamol HFA MDI) each AM and PM in the diary. The average number of daily inhalations over the 7 days before the randomization visit was the baseline value. The weekly average was based on the available data for the 7 days before each analysis week. The change from baseline in the weekly average of total daily (24-hour) use of albuterol/ salbutamol inhalation aerosol (number of inhalations) over weeks 1 to 12 was analyzed using a mixed model for repeated measures.
    End point type
    Secondary
    End point timeframe
    Days -6 to Day 1 (predose, baseline), up to week 12
    End point values
    FS MDPI 100 / 12.5 mcg FS MDPI 50 / 12.5 mcg Fp MDPI 100 mcg Fp MDPI 50 mcg Placebo MDPI
    Number of subjects analysed
    126 [43]
    128 [44]
    129 [45]
    128 [46]
    129 [47]
    Units: puffs
        least squares mean (standard error)
    -0.677 ± 0.0937
    -0.706 ± 0.093
    -0.466 ± 0.0915
    -0.467 ± 0.0928
    -0.003 ± 0.0937
    Notes
    [43] - FAS
    [44] - FAS
    [45] - FAS
    [46] - FAS
    [47] - FAS
    Statistical analysis title
    Rescue Meds: Fp 100 mcg vs Placebo
    Statistical analysis description
    The change from baseline in the weekly average of total daily (24-hour) use of albuterol/ salbutamol inhalation aerosol (number of inhalations) over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline value, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.
    Comparison groups
    Fp MDPI 100 mcg v Placebo MDPI
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0004 [48]
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    -0.463
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.716
         upper limit
    -0.209
    Notes
    [48] - Significance level of 0.05.
    Statistical analysis title
    Rescue Meds: Fp 50 mcg vs Placebo
    Statistical analysis description
    The change from baseline in the weekly average of total daily (24-hour) use of albuterol/ salbutamol inhalation aerosol (number of inhalations) over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline value, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.
    Comparison groups
    Fp MDPI 50 mcg v Placebo MDPI
    Number of subjects included in analysis
    257
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0003 [49]
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    -0.464
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.718
         upper limit
    -0.211
    Notes
    [49] - Significance level of 0.05.
    Statistical analysis title
    Rescue Meds: FS 100/12.5 mcg vs Placebo
    Statistical analysis description
    The change from baseline in the weekly average of total daily (24-hour) use of albuterol/ salbutamol inhalation aerosol (number of inhalations) over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline value, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.
    Comparison groups
    FS MDPI 100 / 12.5 mcg v Placebo MDPI
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0 [50]
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    -0.675
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.928
         upper limit
    -0.421
    Notes
    [50] - Significance level of 0.05.
    Statistical analysis title
    Rescue Meds: FS 50/12.5 mcg vs Placebo
    Statistical analysis description
    The change from baseline in the weekly average of total daily (24-hour) use of albuterol/ salbutamol inhalation aerosol (number of inhalations) over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline value, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.
    Comparison groups
    FS MDPI 50 / 12.5 mcg v Placebo MDPI
    Number of subjects included in analysis
    257
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0 [51]
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    -0.704
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.957
         upper limit
    -0.45
    Notes
    [51] - Significance level of 0.05.
    Statistical analysis title
    Rescue Meds: FS 100/12.5 mcg vs Fp 100 mcg
    Statistical analysis description
    The change from baseline in the weekly average of total daily (24-hour) use of albuterol/ salbutamol inhalation aerosol (number of inhalations) over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline value, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.
    Comparison groups
    FS MDPI 100 / 12.5 mcg v Fp MDPI 100 mcg
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1014 [52]
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    -0.212
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.465
         upper limit
    0.042
    Notes
    [52] - Significance level of 0.05.
    Statistical analysis title
    Rescue Meds: FS 50/12.5 mcg vs Fp 50 mcg
    Statistical analysis description
    The change from baseline in the weekly average of total daily (24-hour) use of albuterol/ salbutamol inhalation aerosol (number of inhalations) over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline value, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.
    Comparison groups
    FS MDPI 50 / 12.5 mcg v Fp MDPI 50 mcg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.064 [53]
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    -0.239
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.492
         upper limit
    0.014
    Notes
    [53] - Significance level of 0.05.
    Statistical analysis title
    Rescue Meds: FS 50/12.5 mcg vs Fp 100 mcg
    Statistical analysis description
    The change from baseline in the weekly average of total daily (24-hour) use of albuterol/ salbutamol inhalation aerosol (number of inhalations) over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline value, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.
    Comparison groups
    FS MDPI 50 / 12.5 mcg v Fp MDPI 100 mcg
    Number of subjects included in analysis
    257
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0626 [54]
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    -0.241
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.494
         upper limit
    0.013
    Notes
    [54] - Significance level of 0.05.

    Secondary: Kaplan-Meier Estimate of Probability of Remaining in Study At Week 12

    Close Top of page
    End point title
    Kaplan-Meier Estimate of Probability of Remaining in Study At Week 12
    End point description
    The analysis of probability of remaining in the study at Week 12 used the time to patient withdrawal for worsening asthma, defined as the number of days elapsed from the date of randomization to the date of withdrawal due to worsening asthma. Patients who were lost to follow-up, who had not withdrawn due to worsening asthma by week 12, or who had withdrawn due to reasons other than worsening asthma were right-censored at the date of last assessment.
    End point type
    Secondary
    End point timeframe
    up to Week 12 of the Treatment Period
    End point values
    FS MDPI 100 / 12.5 mcg FS MDPI 50 / 12.5 mcg Fp MDPI 100 mcg Fp MDPI 50 mcg Placebo MDPI
    Number of subjects analysed
    126 [55]
    128 [56]
    129 [57]
    128 [58]
    129 [59]
    Units: probability
        number (confidence interval 95%)
    1 (1 to 1)
    0.9917 (0.942 to 0.999)
    0.9919 (0.944 to 0.999)
    0.9919 (0.944 to 0.999)
    0.9681 (0.917 to 0.988)
    Notes
    [55] - FAS
    [56] - FAS
    [57] - FAS
    [58] - FAS
    [59] - FAS
    Statistical analysis title
    Probability 12 Weeks: Fp 100 mcg vs Placebo
    Comparison groups
    Fp MDPI 100 mcg v Placebo MDPI
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1679 [60]
    Method
    Logrank
    Confidence interval
    Notes
    [60] - Significance level of 0.05.
    Statistical analysis title
    Probability 12 Weeks: Fp 50 mcg vs Placebo
    Comparison groups
    Fp MDPI 50 mcg v Placebo MDPI
    Number of subjects included in analysis
    257
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1701 [61]
    Method
    Logrank
    Confidence interval
    Notes
    [61] - Significance level of 0.05.
    Statistical analysis title
    Probability 12 Weeks: FS 100/12.5 mcg vs Placebo
    Comparison groups
    FS MDPI 100 / 12.5 mcg v Placebo MDPI
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0437 [62]
    Method
    Logrank
    Confidence interval
    Notes
    [62] - Significance level of 0.05.
    Statistical analysis title
    Probability 12 Weeks: FS 50/12.5 mcg vs Placebo
    Comparison groups
    FS MDPI 50 / 12.5 mcg v Placebo MDPI
    Number of subjects included in analysis
    257
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1718 [63]
    Method
    Logrank
    Confidence interval
    Notes
    [63] - Significance level of 0.05.
    Statistical analysis title
    Probability 12 Weeks: FS 100/12.5 mcg vs Fp100 mcg
    Comparison groups
    FS MDPI 100 / 12.5 mcg v Fp MDPI 100 mcg
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3134 [64]
    Method
    Logrank
    Confidence interval
    Notes
    [64] - Significance level of 0.05.
    Statistical analysis title
    Probability 12 Weeks: FS 50/12.5 mcg vs Fp 50 mcg
    Comparison groups
    FS MDPI 50 / 12.5 mcg v Fp MDPI 50 mcg
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.993 [65]
    Method
    Logrank
    Confidence interval
    Notes
    [65] - Significance level of 0.05.
    Statistical analysis title
    Probability 12 Weeks: FS 50/12.5 mcg vs Fp100 mcg
    Comparison groups
    FS MDPI 50 / 12.5 mcg v Fp MDPI 100 mcg
    Number of subjects included in analysis
    257
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9999 [66]
    Method
    Logrank
    Confidence interval
    Notes
    [66] - Significance level of 0.05.

    Secondary: Change from Baseline in the Asthma Quality of Life Questionnaire with Standardized Activities (AQLQ(S)) Score at Endpoint for Patients >=18 Years Old

    Close Top of page
    End point title
    Change from Baseline in the Asthma Quality of Life Questionnaire with Standardized Activities (AQLQ(S)) Score at Endpoint for Patients >=18 Years Old
    End point description
    The AQLQ(S) (September 2010 version; patients aged ≥18 years) was self-administered by the patients at the investigational center at the randomization visit and at Week 12 or end of trial. The questionnaire is a tool to measure the impact of asthma on a patient’s quality of life (physical, emotional, social, and occupational) with a recall period of 2 weeks. The AQLQ(S) was administered only to patients 18 years and older. The 32 individual questions in the AQLQ were equally weighted. The overall AQLQ score was the mean of the responses to each of the 32 questions, and ranged from 1 to 7. A score of 7.0 indicated that the patient had no impairments due to asthma and a score of 1.0 indicated severe impairment. Positive change from baseline scores indicate improved quality of life.
    End point type
    Secondary
    End point timeframe
    Day 1 (predose, baseline), end of trial (up to week 12)
    End point values
    FS MDPI 100 / 12.5 mcg FS MDPI 50 / 12.5 mcg Fp MDPI 100 mcg Fp MDPI 50 mcg Placebo MDPI
    Number of subjects analysed
    109 [67]
    102 [68]
    103 [69]
    108 [70]
    97 [71]
    Units: units on a scale
        least squares mean (standard error)
    0.808 ± 0.0728
    0.565 ± 0.0752
    0.636 ± 0.0736
    0.588 ± 0.0733
    0.335 ± 0.0777
    Notes
    [67] - FAS patients who contributed at least once to analysis and were >= 18 years old
    [68] - FAS patients who contributed at least once to analysis and were >= 18 years old
    [69] - FAS patients who contributed at least once to analysis and were >= 18 years old
    [70] - FAS patients who contributed at least once to analysis and were >= 18 years old
    [71] - FAS patients who contributed at least once to analysis and were >= 18 years old
    Statistical analysis title
    AQLQ(S): Fp 100 mcg vs Placebo
    Statistical analysis description
    The change from baseline in AQLQ(S) score (patients ≥18 years of age) at endpoint (ie, last postbaseline observation) was analyzed using an ANCOVA model with effects due to baseline AQLQ(S) score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment, imputing missing data via last observation carried forward (LOCF).
    Comparison groups
    Fp MDPI 100 mcg v Placebo MDPI
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0044 [72]
    Method
    ANCOVA
    Parameter type
    LSM difference
    Point estimate
    0.301
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.094
         upper limit
    0.508
    Notes
    [72] - Significance level of 0.05.
    Statistical analysis title
    AQLQ(S): Fp 50 mcg vs Placebo
    Statistical analysis description
    The change from baseline in AQLQ(S) score (patients ≥18 years of age) at endpoint (ie, last postbaseline observation) was analyzed using an ANCOVA model with effects due to baseline AQLQ(S) score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment, imputing missing data via last observation carried forward (LOCF).
    Comparison groups
    Fp MDPI 50 mcg v Placebo MDPI
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0155 [73]
    Method
    ANCOVA
    Parameter type
    LSM difference
    Point estimate
    0.253
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.048
         upper limit
    0.458
    Notes
    [73] - Significance level of 0.05.
    Statistical analysis title
    AQLQ(S): FS 100/12.5 mcg vs Placebo
    Statistical analysis description
    The change from baseline in AQLQ(S) score (patients ≥18 years of age) at endpoint (ie, last postbaseline observation) was analyzed using an ANCOVA model with effects due to baseline AQLQ(S) score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment, imputing missing data via last observation carried forward (LOCF).
    Comparison groups
    FS MDPI 100 / 12.5 mcg v Placebo MDPI
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0 [74]
    Method
    ANCOVA
    Parameter type
    LSM difference
    Point estimate
    0.473
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.27
         upper limit
    0.676
    Notes
    [74] - Significance level of 0.05.
    Statistical analysis title
    AQLQ(S): FS 50/12.5 mcg vs Placebo
    Statistical analysis description
    The change from baseline in AQLQ(S) score (patients ≥18 years of age) at endpoint (ie, last postbaseline observation) was analyzed using an ANCOVA model with effects due to baseline AQLQ(S) score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment, imputing missing data via last observation carried forward (LOCF).
    Comparison groups
    FS MDPI 50 / 12.5 mcg v Placebo MDPI
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0293 [75]
    Method
    ANCOVA
    Parameter type
    LSM difference
    Point estimate
    0.23
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.023
         upper limit
    0.437
    Notes
    [75] - Significance level of 0.05.
    Statistical analysis title
    AQLQ(S): FS 100/12.5 mcg vs Fp 100 mcg
    Statistical analysis description
    The change from baseline in AQLQ(S) score (patients ≥18 years of age) at endpoint (ie, last postbaseline observation) was analyzed using an ANCOVA model with effects due to baseline AQLQ(S) score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment, imputing missing data via last observation carried forward (LOCF).
    Comparison groups
    FS MDPI 100 / 12.5 mcg v Fp MDPI 100 mcg
    Number of subjects included in analysis
    212
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0913 [76]
    Method
    ANCOVA
    Parameter type
    LSM difference
    Point estimate
    0.172
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.028
         upper limit
    0.372
    Notes
    [76] - Significance level of 0.05.
    Statistical analysis title
    AQLQ(S): FS 50/12.5 mcg vs Fp 50 mcg
    Statistical analysis description
    The change from baseline in AQLQ(S) score (patients ≥18 years of age) at endpoint (ie, last postbaseline observation) was analyzed using an ANCOVA model with effects due to baseline AQLQ(S) score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment, imputing missing data via last observation carried forward (LOCF).
    Comparison groups
    FS MDPI 50 / 12.5 mcg v Fp MDPI 50 mcg
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8216 [77]
    Method
    ANCOVA
    Parameter type
    LSM difference
    Point estimate
    -0.023
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.223
         upper limit
    0.177
    Notes
    [77] - Significance level of 0.05.
    Statistical analysis title
    AQLQ(S): FS 50/12.5 mcg vs Fp 100 mcg
    Statistical analysis description
    The change from baseline in AQLQ(S) score (patients ≥18 years of age) at endpoint (ie, last postbaseline observation) was analyzed using an ANCOVA model with effects due to baseline AQLQ(S) score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment, imputing missing data via last observation carried forward (LOCF).
    Comparison groups
    FS MDPI 50 / 12.5 mcg v Fp MDPI 100 mcg
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4934 [78]
    Method
    ANCOVA
    Parameter type
    LSM difference
    Point estimate
    -0.071
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.275
         upper limit
    0.133
    Notes
    [78] - Significance level of 0.05.

    Secondary: Kaplan-Meier Estimates for Time to 15% and 12% Improvement from Baseline in FEV1 Postdose on Day 1

    Close Top of page
    End point title
    Kaplan-Meier Estimates for Time to 15% and 12% Improvement from Baseline in FEV1 Postdose on Day 1
    End point description
    A subset of approximately 300 patients who performed postdose serial spirometry is based on sample size calculation. Baseline FEV1 was the average of 2 FEV1 measurements (30 and 10 minutes predose) on Day 1. If one of these was missing, the other measurement was used as baseline value. If both were missing, baseline was treated as missing. Time to target improvement (15% or 12%) was defined as the time elapsed from the time of first dose to the first time the target improvement in FEV1 was achieved. If an exact target increase was not achieved at a measured timepoint, then the time was estimated by linear interpolation between the timepoint when target was reached and the timepoint immediately before. Patients who did not achieve the target improvement were censored at the time of last serial spirometry assessment. Values of 9999 indicate the values could not be estimated which happened when the estimated probability of not achieving target is more than 50%.
    End point type
    Secondary
    End point timeframe
    Day 1 of the Treatment Period (predose and postdose)
    End point values
    Serial Spirometry Subset:FS MDPI 100 / 12.5 mcg Serial Spirometry Subset:FS MDPI 50 / 12.5 mcg Serial Spirometry Subset: Fp MDPI 100 mcg Serial Spirometry Subset: Fp MDPI 50 mcg Serial Spirometry Subset: Placebo MDPI
    Number of subjects analysed
    61 [79]
    56 [80]
    72 [81]
    63 [82]
    60 [83]
    Units: hours
    median (confidence interval 95%)
        15% improvement
    4.3 (1.07 to 9999)
    1.3 (0.6 to 2.75)
    9999 (10.19 to 9999)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
        12% improvement
    1 (0.46 to 3.72)
    0.5 (0.3 to 1.55)
    9999 (7.36 to 9999)
    9999 (3.89 to 9999)
    9999 (7.27 to 9999)
    Notes
    [79] - FAS
    [80] - FAS
    [81] - FAS
    [82] - FAS
    [83] - FAS
    No statistical analyses for this end point

    Secondary: Patients with Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period

    Close Top of page
    End point title
    Patients with Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period
    End point description
    An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents normal daily activities. Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 12 of the Treatment Period
    End point values
    FS MDPI 100 / 12.5 mcg FS MDPI 50 / 12.5 mcg Fp MDPI 100 mcg Fp MDPI 50 mcg Placebo MDPI
    Number of subjects analysed
    126 [84]
    128 [85]
    129 [86]
    129 [87]
    129 [88]
    Units: patients
        >=1 TEAE
    37
    46
    40
    44
    47
        >=1 severe TEAE
    2
    0
    1
    1
    0
        >=1 treatment-related TEAE
    4
    4
    5
    7
    5
        >=1 severe treatment-related TEAE
    0
    0
    0
    0
    0
        >=1 serious TEAE
    1
    0
    1
    0
    2
        >=1 TEAE leading to withdrawal
    0
    3
    2
    1
    6
        >=1 nonserious TEAE
    36
    46
    39
    44
    45
        >=1 TEAE resulting in death
    0
    0
    0
    0
    0
    Notes
    [84] - Safety population
    [85] - Safety population
    [86] - Safety population
    [87] - Safety population
    [88] - Safety population
    No statistical analyses for this end point

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Day 1 up to Week 12
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    FS MDPI 100 / 12.5 mcg
    Reporting group description
    Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 100 mcg (for a total daily dose of 200 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks.

    Reporting group title
    FS MDPI 50 / 12.5 mcg
    Reporting group description
    Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 50 mcg (for a total daily dose of 100 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks.

    Reporting group title
    Fp MDPI 100 mcg
    Reporting group description
    Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 200 mcg for 12 weeks.

    Reporting group title
    Fp MDPI 50 mcg
    Reporting group description
    Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 100 mcg for 12 weeks.

    Reporting group title
    Placebo MDPI
    Reporting group description
    The placebo multidose dry powder inhaler was identical to the devices used to deliver active drug, and indistinguishable from the active treatments. Patients took one inhalation twice a day (approximately 12 hours apart).

    Serious adverse events
    FS MDPI 100 / 12.5 mcg FS MDPI 50 / 12.5 mcg Fp MDPI 100 mcg Fp MDPI 50 mcg Placebo MDPI
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 128 (0.00%)
    1 / 129 (0.78%)
    0 / 129 (0.00%)
    2 / 129 (1.55%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Plasma cell myeloma
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    1 / 129 (0.78%)
    0 / 129 (0.00%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 129 (0.00%)
    0 / 129 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 129 (0.00%)
    0 / 129 (0.00%)
    1 / 129 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 128 (0.00%)
    0 / 129 (0.00%)
    0 / 129 (0.00%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 128 (0.00%)
    0 / 129 (0.00%)
    0 / 129 (0.00%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 128 (0.00%)
    0 / 129 (0.00%)
    0 / 129 (0.00%)
    0 / 129 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    FS MDPI 100 / 12.5 mcg FS MDPI 50 / 12.5 mcg Fp MDPI 100 mcg Fp MDPI 50 mcg Placebo MDPI
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 126 (9.52%)
    22 / 128 (17.19%)
    21 / 129 (16.28%)
    15 / 129 (11.63%)
    15 / 129 (11.63%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 126 (5.56%)
    7 / 128 (5.47%)
    9 / 129 (6.98%)
    2 / 129 (1.55%)
    5 / 129 (3.88%)
         occurrences all number
    10
    8
    11
    4
    7
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 126 (1.59%)
    6 / 128 (4.69%)
    4 / 129 (3.10%)
    7 / 129 (5.43%)
    6 / 129 (4.65%)
         occurrences all number
    2
    6
    4
    8
    6
    Nasopharyngitis
         subjects affected / exposed
    3 / 126 (2.38%)
    11 / 128 (8.59%)
    9 / 129 (6.98%)
    7 / 129 (5.43%)
    4 / 129 (3.10%)
         occurrences all number
    3
    11
    10
    8
    5

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Nov 2014
    Amendment 1 (dated 17 November 2014) to the protocol was issued when 115 patients had been enrolled into the study. The following major procedural changes (not all-inclusive) were made to the protocol: • Based on discussions with the US FDA, the primary endpoint was changed from change from baseline in trough (AM predose and pre-rescue bronchodilator) FEV1 over the 12-week treatment period to standardized baseline-adjusted FEV1 AUEC0-12wk. Sample size, power, and statistical considerations were updated. • Rescreening and retesting procedures for spirometry and reversibility were clarified. • Spirometry procedures were updated from 5 to 8 permissible efforts per test. • Clarification was provided about when a severe asthma exacerbation would be considered a serious adverse event. • The number of anticipated sites was increased from 80 to 200.
    19 Feb 2015
    Amendment 2 (dated 19 February 2015) to the protocol was issued when 309 patients had been enrolled into the study. The following major procedural changes (not all-inclusive) were made to the protocol: • The inclusion criteria were modified to allow patients on mid-dose ICS therapy to participate in the study (in addition to those on low-dose ICS therapy already included in the study). • The determination of potentially exclusionary ECG findings was clarified.
    14 Jul 2015
    Amendment 3 (dated 14 July 2015) to the protocol was issued when 647 patients had been enrolled into the study. The following major procedural changes (not all-inclusive) were made to the protocol: • Based on discussions with the US FDA, the primary endpoint was changed from standardized change from baseline-adjusted trough (AM predose and pre-rescue bronchodilator) FEV1 AUEC0-12wk at week 12 to change from baseline in trough (AM predose and pre-rescue bronchodilator) FEV1 at week 12. • As recommended by the US FDA, the CPRA graph was added to examine all possible response levels of interest. • Related to the change in the primary endpoint, the method for its analysis was changed, the methods for handling missing data were modified, and the sequential order of comparisons was adjusted. • Statistical power considerations were recalculated based on the change in the primary endpoint and on newly available data from Teva studies. • Specific secondary efficacy endpoints were changed to other efficacy endpoints, and the sequential orders of secondary and other endpoints were changed. • The analyses of the AQLQ(S) and PAQLQ(S) were separated. • A subgroup analysis by region (US and non-US) was added.

    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
    For support, visit the EMA Service Desk , log in using your EMA account and open a ticket specifying "EU CTR" in your request.
    If you do not have an account, please visit the EMA Account management page page click on "Create an EMA account" and follow the instructions.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2022 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA