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    Clinical Trial Results:
    A 12-Week Dose-ranging Study to Evaluate the Efficacy and Safety of Fp Spiromax® (Fluticasone Propionate Inhalation Powder) Administered Orally Twice Daily compared with Placebo in Adolescent and Adult Subjects with Severe Persistent Asthma Uncontrolled on High dose Inhaled Corticosteroid Therapy

    Summary
    EudraCT number
    2010-023601-35
    Trial protocol
    ES   HU   BG   BE   GB   DE   PL   GR  
    Global end of trial date
    09 Oct 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    25 Sep 2016
    First version publication date
    25 Sep 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    FpS-AS-202
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01576718
    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,
    Scientific contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products R&D, Inc., 001 215-591-3000,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Sep 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the dose response, efficacy and safety of 4 different doses of fluticasone propionate (50, 100, 200, and 400mcg) delivered as Fluticasone Spiromax® Inhalation Powder (Fp Spiromax) when administered twice daily in subjects 12 years of age and older with severe persistent asthma who are uncontrolled on high dose ICS therapy.
    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 GCP in the conduct of clinical trials on medicinal products for human use). Written and/or oral information about the study was provided to all subjects in a language understandable by the subjects. The information included an adequate explanation of the aims, methods, anticipated benefits, potential hazards, and insurance arrangements in force. Written informed consent was obtained from each subject before any study procedures or assessments were done. It was explained to the subjects that they were free to refuse entry into the study and free to withdraw from the study at any time without prejudice to future treatment. Each subject’s willingness to participate in the study was documented in writing in a consent form that was signed by the subject with the date of that signature indicated. Each investigator kept the original consent forms, and copies were given to the subjects.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    30 Apr 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 64
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    United Kingdom: 150
    Country: Number of subjects enrolled
    Bulgaria: 49
    Country: Number of subjects enrolled
    Germany: 57
    Country: Number of subjects enrolled
    Greece: 12
    Country: Number of subjects enrolled
    Hungary: 72
    Country: Number of subjects enrolled
    Israel: 6
    Country: Number of subjects enrolled
    New Zealand: 1
    Country: Number of subjects enrolled
    United States: 444
    Country: Number of subjects enrolled
    Romania: 29
    Country: Number of subjects enrolled
    Serbia: 2
    Worldwide total number of subjects
    889
    EEA total number of subjects
    436
    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)
    25
    Adults (18-64 years)
    756
    From 65 to 84 years
    108
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    1238 subjects with asthma at 180 centers were screened for enrollment. 889 subjects met entry criteria and were enrolled into the run-in period of the study. Of the 349 subjects who were not enrolled, 337 were excluded on the basis of inclusion/exclusion criteria, 5 subjects withdrew consent, and for 6 the reason given was “other”.

    Pre-assignment period milestones
    Number of subjects started
    889
    Number of subjects completed
    640

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Consent withdrawn by subject: 17
    Reason: Number of subjects
    Inclusion criteria not met/Exclusion criteria met: 49
    Reason: Number of subjects
    Randomization criteria not met: 166
    Reason: Number of subjects
    Lost to follow-up: 2
    Reason: Number of subjects
    Not specified: 15
    Period 1
    Period 1 title
    Treatment Period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    The run-in period of this study was conducted in a single-blind manner (subject blinded) with respect to the placebo MDPI treatment. The treatment period of this study was conducted in a double-blind manner (investigator and subject blinded) with respect to Fp MDPI and placebo MDPI. FLOVENT DISKUS was administered in an open-label manner.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Fp MDPI 50 mcg
    Arm description
    Fluticasone propionate (Fp) 50 mcg per dose twice a day (for a total daily dose of 100 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner (investigator and subject blinded). During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.
    Arm type
    Experimental

    Investigational medicinal product name
    Fluticasone propionate
    Investigational medicinal product code
    Other name
    Fp SPIROMAX® Inhalation Powder
    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. This medication was part of the double-blind study.

    Investigational medicinal product name
    albuterol/salbutamol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    A short-acting β2-adrenergic agonists (SABA), albuterol/salbutamol HFA MDI, was provided to be used as needed for the relief of asthma symptoms during both the run-in and treatment periods (to replace the subject’s current rescue medication).

    Arm title
    Fp MDPI 100 mcg
    Arm description
    Fluticasone propionate (Fp) 100 mcg per dose twice a day (for a total daily dose of 200 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner (investigator and subject blinded). During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.
    Arm type
    Experimental

    Investigational medicinal product name
    Fluticasone propionate
    Investigational medicinal product code
    Other name
    Fp SPIROMAX® Inhalation Powder
    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. This medication was part of the double-blind study.

    Investigational medicinal product name
    albuterol/salbutamol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    A short-acting β2-adrenergic agonists (SABA), albuterol/salbutamol HFA MDI, was provided to be used as needed for the relief of asthma symptoms during both the run-in and treatment periods (to replace the subject’s current rescue medication).

    Arm title
    Fp MDPI 200 mcg
    Arm description
    Fluticasone propionate (Fp) 200 mcg per dose twice a day (for a total daily dose of 400 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner (investigator and subject blinded). During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.
    Arm type
    Experimental

    Investigational medicinal product name
    Fluticasone propionate
    Investigational medicinal product code
    Other name
    Fp SPIROMAX® Inhalation Powder
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone propionate multidose dry powder inhaler 200 mcg in the morning and evening for a total daily dose of 400 mcg. This medication was part of the double-blind study.

    Investigational medicinal product name
    albuterol/salbutamol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    A short-acting β2-adrenergic agonists (SABA), albuterol/salbutamol HFA MDI, was provided to be used as needed for the relief of asthma symptoms during both the run-in and treatment periods (to replace the subject’s current rescue medication).

    Arm title
    Fp MDPI 400 mcg
    Arm description
    Fluticasone propionate (Fp) 400 mcg per dose twice a day (for a total daily dose of 800 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner (investigator and subject blinded). During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.
    Arm type
    Experimental

    Investigational medicinal product name
    Fluticasone propionate
    Investigational medicinal product code
    Other name
    Fp SPIROMAX® Inhalation Powder
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone propionate multidose dry powder inhaler 400 mcg in the morning and evening for a total daily dose of 800 mcg. This medication was part of the double-blind study.

    Investigational medicinal product name
    albuterol/salbutamol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    A short-acting β2-adrenergic agonists (SABA), albuterol/salbutamol HFA MDI, was provided to be used as needed for the relief of asthma symptoms during both the run-in and treatment periods (to replace the subject’s current rescue medication).

    Arm title
    Placebo MDPI
    Arm description
    Placebo twice a day using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner (investigator and subject blinded). During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo multidose dry powder inhaler in the morning and evening. Placebo MDPI was provided in devices identical in appearance to Fp MDPI and was part of the double-blind study.

    Investigational medicinal product name
    albuterol/salbutamol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    A short-acting β2-adrenergic agonists (SABA), albuterol/salbutamol HFA MDI, was provided to be used as needed for the relief of asthma symptoms during both the run-in and treatment periods (to replace the subject’s current rescue medication).

    Arm title
    Flovent Diskus
    Arm description
    Fluticasone propionate (Fp) 250 mcg per dose twice a day (for a total daily dose of 500 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in an open-label manner. During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.
    Arm type
    Active comparator

    Investigational medicinal product name
    Fluticasone propionate
    Investigational medicinal product code
    Other name
    Flovent Diskus
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    250 mcg

    Investigational medicinal product name
    albuterol/salbutamol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    A short-acting β2-adrenergic agonists (SABA), albuterol/salbutamol HFA MDI, was provided to be used as needed for the relief of asthma symptoms during both the run-in and treatment periods (to replace the subject’s current rescue medication).

    Number of subjects in period 1 [1]
    Fp MDPI 50 mcg Fp MDPI 100 mcg Fp MDPI 200 mcg Fp MDPI 400 mcg Placebo MDPI Flovent Diskus
    Started
    107
    107
    106
    107
    106
    107
    Safety population
    107
    107
    106
    107
    106
    106
    Efficacy population (Full Analysis Set)
    107
    106
    102
    107
    105
    103
    Completed
    82
    87
    75
    80
    58
    77
    Not completed
    25
    20
    31
    27
    48
    30
         Protocol deviation
    5
    4
    10
    6
    8
    12
         Sponsor requested subject to be withdrawn
    1
    -
    -
    -
    1
    -
         Physician decision
    1
    1
    1
    1
    -
    -
         Adverse event, non-fatal
    1
    1
    1
    1
    1
    -
         Noncompliance to study medication
    -
    -
    -
    -
    1
    1
         Met stopping criteria
    16
    13
    19
    16
    33
    15
         Consent withdrawn by subject
    1
    1
    -
    2
    4
    2
         Lost to follow-up
    -
    -
    -
    1
    -
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 889 patients were enrolled and received run-in placebo; 640 patients were randomized into the Treatment Period for which baseline characteristics are reported.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Fp MDPI 50 mcg
    Reporting group description
    Fluticasone propionate (Fp) 50 mcg per dose twice a day (for a total daily dose of 100 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner (investigator and subject blinded). During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.

    Reporting group title
    Fp MDPI 100 mcg
    Reporting group description
    Fluticasone propionate (Fp) 100 mcg per dose twice a day (for a total daily dose of 200 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner (investigator and subject blinded). During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.

    Reporting group title
    Fp MDPI 200 mcg
    Reporting group description
    Fluticasone propionate (Fp) 200 mcg per dose twice a day (for a total daily dose of 400 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner (investigator and subject blinded). During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.

    Reporting group title
    Fp MDPI 400 mcg
    Reporting group description
    Fluticasone propionate (Fp) 400 mcg per dose twice a day (for a total daily dose of 800 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner (investigator and subject blinded). During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.

    Reporting group title
    Placebo MDPI
    Reporting group description
    Placebo twice a day using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner (investigator and subject blinded). During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.

    Reporting group title
    Flovent Diskus
    Reporting group description
    Fluticasone propionate (Fp) 250 mcg per dose twice a day (for a total daily dose of 500 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in an open-label manner. During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.

    Reporting group values
    Fp MDPI 50 mcg Fp MDPI 100 mcg Fp MDPI 200 mcg Fp MDPI 400 mcg Placebo MDPI Flovent Diskus Total
    Number of subjects
    107 107 106 107 106 107 640
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    2 3 1 1 1 1 9
        Adults (18-64 years)
    94 99 90 90 94 96 563
        From 65-84 years
    11 5 15 16 11 10 68
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    47.9 ± 14.59 48.7 ± 12.48 47.7 ± 14.18 50.9 ± 13.32 49.8 ± 12.87 49.2 ± 13.26 -
    Gender categorical
    Units: Subjects
        Female
    63 55 66 72 65 58 379
        Male
    44 52 40 35 41 49 261
    Race
    Units: Subjects
        White
    96 94 93 91 96 95 565
        Black
    9 12 12 13 8 11 65
        Asian
    1 1 1 2 2 0 7
        American Indian or Alaskan Native
    0 0 0 0 0 1 1
        Pacific Islander
    1 0 0 0 0 0 1
        Other
    0 0 0 1 0 0 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    5 7 8 12 6 9 47
        Not Hispanic or Latino
    102 100 98 95 100 98 593
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    86.7 ± 23.73 86.6 ± 22.9 84.4 ± 21.89 84.4 ± 20.56 86.2 ± 25.19 83.3 ± 16.76 -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    169.4 ± 13.04 168.7 ± 9.14 168.4 ± 7.86 167.4 ± 9.67 168.1 ± 8.57 168 ± 8.33 -
    Body Mass Index
    Units: kg/m^2
        arithmetic mean (standard deviation)
    31.3 ± 17.88 30.4 ± 7.6 29.8 ± 8.12 30.1 ± 6.81 30.5 ± 8.83 29.6 ± 6.03 -
    Forced Expiratory Volume in 1 Second (FEV1)
    Units: liters
        arithmetic mean (standard deviation)
    2.108 ± 0.662 2.031 ± 0.551 1.999 ± 0.525 2.016 ± 0.636 1.984 ± 0.565 1.955 ± 0.529 -
    % Predicted Expiratory Volume In 1 Second
    Units: percent predicted FEV1
        arithmetic mean (standard deviation)
    63.7 ± 10.9 63.1 ± 9.5 63.4 ± 12.1 65.3 ± 11.4 63.1 ± 10 62.5 ± 12.1 -
    Qualifying Airway Reversibility
    Patients demonstrated a ≥12% reversibility of FEV1 within 30 minutes following 2-4 inhalations of albuterol/salbutamol inhalation aerosol at the screening visit. If subjects failed to demonstrate an increase in FEV1 ≥12% then subjects were not eligible for the study; however, based on investigator judgment, they were allowed to retest once within 7 days. Reversibility values of 11.50 through 11.99% were rounded to 12%. Documented historical reversibility of ≥12 % within 1 year was accepted.
    Units: percentage increase in FEV1
        arithmetic mean (standard deviation)
    31.6 ± 22.4 27.3 ± 14.7 30.4 ± 25.2 29.1 ± 19.5 28.9 ± 19.1 26.8 ± 15.7 -

    End points

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    End points reporting groups
    Reporting group title
    Fp MDPI 50 mcg
    Reporting group description
    Fluticasone propionate (Fp) 50 mcg per dose twice a day (for a total daily dose of 100 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner (investigator and subject blinded). During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.

    Reporting group title
    Fp MDPI 100 mcg
    Reporting group description
    Fluticasone propionate (Fp) 100 mcg per dose twice a day (for a total daily dose of 200 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner (investigator and subject blinded). During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.

    Reporting group title
    Fp MDPI 200 mcg
    Reporting group description
    Fluticasone propionate (Fp) 200 mcg per dose twice a day (for a total daily dose of 400 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner (investigator and subject blinded). During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.

    Reporting group title
    Fp MDPI 400 mcg
    Reporting group description
    Fluticasone propionate (Fp) 400 mcg per dose twice a day (for a total daily dose of 800 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner (investigator and subject blinded). During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.

    Reporting group title
    Placebo MDPI
    Reporting group description
    Placebo twice a day using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner (investigator and subject blinded). During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.

    Reporting group title
    Flovent Diskus
    Reporting group description
    Fluticasone propionate (Fp) 250 mcg per dose twice a day (for a total daily dose of 500 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in an open-label manner. During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.

    Primary: Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period

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    End point title
    Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period
    End point description
    Trough FEV1 was measured electronically by spirometry at morning (AM) investigational site visits, before administration of the AM dose of study drug, and before albuterol/salbutamol administration. The highest FEV1 value from 3 acceptable and 2 reproducible maneuvers was used. All FEV1 data were submitted to a central reading center for evaluation. The p-values for the treatment comparisons to placebo are from an MMRM model excluding FLOVENT DISKUS data: change from baseline = baseline FEV1 + sex + age + treatment + visit + treatment*visit with an unstructured covariance matrix assumed.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1 pre-dose), Weeks 1, 2, 3, 4, 6, 8, 10 and 12
    End point values
    Fp MDPI 50 mcg Fp MDPI 100 mcg Fp MDPI 200 mcg Fp MDPI 400 mcg Placebo MDPI Flovent Diskus
    Number of subjects analysed
    104 [1]
    102 [2]
    97 [3]
    103 [4]
    98 [5]
    0 [6]
    Units: liters
        least squares mean (standard error)
    0.059 ± 0.0269
    0.101 ± 0.0268
    0.109 ± 0.0278
    0.125 ± 0.0274
    0.053 ± 0.0283
    ±
    Notes
    [1] - Full analysis set
    [2] - Full analysis set
    [3] - Full analysis set
    [4] - Full analysis set
    [5] - Full analysis set
    [6] - Flovent Diskus data was used for confirmatory and exploratory endpoints and not in this endpoint.
    Statistical analysis title
    Change in FEV1 Linear Trend Test
    Statistical analysis description
    A linear in log-dose trend contrast was constructed to evaluate the time-averaged dose-response trend, where the logarithm of dose was defined as log(dose+1) to accommodate the case of a zero dose (placebo). A fixed-sequence testing procedure was employed to control the overall Type I error rate at the 0.05 level. Specifically, the 2-sided linear in log-dose time-averaged trend test was first performed at the 0.05 level of significance.
    Comparison groups
    Fp MDPI 50 mcg v Fp MDPI 100 mcg v Fp MDPI 200 mcg v Fp MDPI 400 mcg v Placebo MDPI
    Number of subjects included in analysis
    504
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0604 [7]
    Method
    Regression, Linear
    Confidence interval
    Notes
    [7] - If the Fp MDPI showed a significantly positive trend, then contrasts for pairwise comparisons of each Fp MDPI dose versus placebo were done in the sequence of highest to lowest Fp MDPI dose.
    Statistical analysis title
    Change in FEV1: Fp 400 - Placebo
    Statistical analysis description
    No explicit structure was assumed for the covariance among the repeated measures. Analyses for comparison of Fp MDPI to placebo did not contain FLOVENT DISKUS data.
    Comparison groups
    Fp MDPI 400 mcg v Placebo MDPI
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0637 [8]
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    0.072
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.004
         upper limit
    0.149
    Notes
    [8] - Significance at the 0.05 level
    Statistical analysis title
    Change in FEV1: Fp 200 - Placebo
    Statistical analysis description
    No explicit structure was assumed for the covariance among the repeated measures. Analyses for comparison of Fp MDPI to placebo did not contain FLOVENT DISKUS data.
    Comparison groups
    Fp MDPI 200 mcg v Placebo MDPI
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1585 [9]
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    0.056
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.022
         upper limit
    0.133
    Notes
    [9] - Significance at the 0.05 level
    Statistical analysis title
    Change in FEV1: Fp 100 - Placebo
    Statistical analysis description
    No explicit structure was assumed for the covariance among the repeated measures. Analyses for comparison of Fp MDPI to placebo did not contain FLOVENT DISKUS data.
    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
    = 0.2221 [10]
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    0.048
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.029
         upper limit
    0.124
    Notes
    [10] - Significance at the 0.05 level
    Statistical analysis title
    Change in FEV1: Fp 50 - Placebo
    Statistical analysis description
    No explicit structure was assumed for the covariance among the repeated measures. Analyses for comparison of Fp MDPI to placebo did not contain FLOVENT DISKUS data.
    Comparison groups
    Fp MDPI 50 mcg v Placebo MDPI
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8694 [11]
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    0.006
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.07
         upper limit
    0.083
    Notes
    [11] - Significance at the 0.05 level

    Secondary: Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Morning Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period

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    End point title
    Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Morning Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period
    End point description
    Peak expiratory flow was determined in the AM and in the PM, before administration of study or rescue medications using a handheld electronic peak flow meter. The highest value of triplicate measurements obtained was recorded by the subject’s diary device. On mornings for which a treatment visit was scheduled (TV1 through TV9), the PEF was measured and recorded at the investigational site visit. Baseline trough AM PEF was defined as the average of recorded (nonmissing) trough AM PEF assessments over the 7 days directly preceding first study drug intake. The p-values for the treatment comparisons to placebo are from an MMRM model excluding FLOVENT DISKUS data: change from baseline = baseline PEF + sex + age + treatment + visit + treatment*visit with an unstructured covariance matrix assumed.
    End point type
    Secondary
    End point timeframe
    Baseline (Days -6 to Day 1 pre-dose), Weeks 1, 2, 3, 4, 6, 8, 10 and 12
    End point values
    Fp MDPI 50 mcg Fp MDPI 100 mcg Fp MDPI 200 mcg Fp MDPI 400 mcg Placebo MDPI Flovent Diskus
    Number of subjects analysed
    101 [12]
    101 [13]
    96 [14]
    101 [15]
    98 [16]
    0 [17]
    Units: liters/minute
        least squares mean (standard error)
    10.48 ± 4.299
    9.34 ± 4.245
    10.03 ± 4.42
    9.61 ± 4.307
    2.24 ± 4.507
    ±
    Notes
    [12] - Full analysis set
    [13] - Full analysis set
    [14] - Full analysis set
    [15] - Full analysis set
    [16] - Full analysis set
    [17] - Flovent Diskus data was used for confirmatory and exploratory endpoints and not in this endpoint.
    Statistical analysis title
    Change in AM PEF Linear Trend Test
    Statistical analysis description
    A linear in log-dose trend contrast was constructed to evaluate the time-averaged dose-response trend, where the logarithm of dose was defined as log(dose+1) to accommodate the case of a zero dose (placebo). A fixed-sequence testing procedure was employed to control the overall Type I error rate at the 0.05 level. Specifically, the 2-sided linear in log-dose time-averaged trend test was first performed at the 0.05 level of significance.
    Comparison groups
    Fp MDPI 50 mcg v Fp MDPI 100 mcg v Fp MDPI 200 mcg v Fp MDPI 400 mcg v Placebo MDPI
    Number of subjects included in analysis
    497
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1512 [18]
    Method
    Regression, Linear
    Confidence interval
    Notes
    [18] - If the Fp MDPI showed a significantly positive trend, then contrasts for pairwise comparisons of each Fp MDPI dose versus placebo were done in the sequence of highest to lowest Fp MDPI dose.
    Statistical analysis title
    Change in AM PEF: Fp 400 - Placebo
    Statistical analysis description
    No explicit structure was assumed for the covariance among the repeated measures. Analyses for comparison of Fp MDPI to placebo did not contain FLOVENT DISKUS data.
    Comparison groups
    Fp MDPI 400 mcg v Placebo MDPI
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2361 [19]
    Method
    Regression, Linear
    Parameter type
    LSM difference
    Point estimate
    7.36
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.83
         upper limit
    19.56
    Notes
    [19] - Significance at the 0.05 level
    Statistical analysis title
    Change in AM PEF: Fp 200 - Placebo
    Statistical analysis description
    No explicit structure was assumed for the covariance among the repeated measures. Analyses for comparison of Fp MDPI to placebo did not contain FLOVENT DISKUS data.
    Comparison groups
    Fp MDPI 200 mcg v Placebo MDPI
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2169 [20]
    Method
    Regression, Linear
    Parameter type
    LSM difference
    Point estimate
    7.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.59
         upper limit
    20.15
    Notes
    [20] - Significance at the 0.05 level
    Statistical analysis title
    Change in AM PEF: Fp 100 - Placebo
    Statistical analysis description
    No explicit structure was assumed for the covariance among the repeated measures. Analyses for comparison of Fp MDPI to placebo did not contain FLOVENT DISKUS data.
    Comparison groups
    Fp MDPI 100 mcg v Placebo MDPI
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2523 [21]
    Method
    Regression, Linear
    Parameter type
    LSM difference
    Point estimate
    7.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.07
         upper limit
    19.26
    Notes
    [21] - Significance at the 0.05 level
    Statistical analysis title
    Change in AM PEF: Fp 50 - Placebo
    Statistical analysis description
    No explicit structure was assumed for the covariance among the repeated measures. Analyses for comparison of Fp MDPI to placebo did not contain FLOVENT DISKUS data.
    Comparison groups
    Fp MDPI 50 mcg v Placebo MDPI
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1858 [22]
    Method
    Regression, Linear
    Parameter type
    LSM difference
    Point estimate
    8.23
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.98
         upper limit
    20.45
    Notes
    [22] - Significance at the 0.05 level

    Secondary: Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period

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    End point title
    Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period
    End point description
    Peak expiratory flow was determined in the AM and in the PM, before administration of study or rescue medications using a handheld electronic peak flow meter. The highest value of triplicate measurements obtained was recorded by the subject’s diary device. PM PEF baseline was defined as the average of recorded (nonmissing) PM PEF assessments over the 7 days directly preceding first study drug intake. The p-values for the treatment comparisons to placebo are from an MMRM model excluding FLOVENT DISKUS data: change from baseline = baseline PEF + sex + age + treatment + visit + treatment*visit with an unstructured covariance matrix assumed.
    End point type
    Secondary
    End point timeframe
    Baseline (Days -6 to Day 1 pre-dose), Weeks 1, 2, 3, 4, 6, 8, 10 and 12
    End point values
    Fp MDPI 50 mcg Fp MDPI 100 mcg Fp MDPI 200 mcg Fp MDPI 400 mcg Placebo MDPI Flovent Diskus
    Number of subjects analysed
    103 [23]
    99 [24]
    96 [25]
    102 [26]
    96 [27]
    0 [28]
    Units: liters/minute
        least squares mean (standard error)
    3.81 ± 4.183
    6.41 ± 4.209
    7.45 ± 4.335
    10.97 ± 4.208
    3.42 ± 4.462
    ±
    Notes
    [23] - Full analysis set
    [24] - Full analysis set
    [25] - Full analysis set
    [26] - Full analysis set
    [27] - Full analysis set
    [28] - Flovent Diskus data was used for confirmatory and exploratory endpoints and not in this endpoint.
    Statistical analysis title
    Change in PM PEF Linear Trend Test
    Statistical analysis description
    A linear in log-dose trend contrast was constructed to evaluate the time-averaged dose-response trend, where the logarithm of dose was defined as log(dose+1) to accommodate the case of a zero dose (placebo). A fixed-sequence testing procedure was employed to control the overall Type I error rate at the 0.05 level. Specifically, the 2-sided linear in log-dose time-averaged trend test was first performed at the 0.05 level of significance.
    Comparison groups
    Fp MDPI 50 mcg v Fp MDPI 100 mcg v Fp MDPI 200 mcg v Fp MDPI 400 mcg v Placebo MDPI
    Number of subjects included in analysis
    496
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2879 [29]
    Method
    Regression, Linear
    Confidence interval
    Notes
    [29] - If the Fp MDPI showed a significantly positive trend, then contrasts for pairwise comparisons of each Fp MDPI dose versus placebo were done in the sequence of highest to lowest Fp MDPI dose.
    Statistical analysis title
    Change in PM PEF: Fp 400 - Placebo
    Statistical analysis description
    No explicit structure was assumed for the covariance among the repeated measures. Analyses for comparison of Fp MDPI to placebo did not contain FLOVENT DISKUS data.
    Comparison groups
    Fp MDPI 400 mcg v Placebo MDPI
    Number of subjects included in analysis
    198
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2166 [30]
    Method
    Regression, Linear
    Parameter type
    LSM difference
    Point estimate
    7.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.45
         upper limit
    19.56
    Notes
    [30] - Significance at the 0.05 level
    Statistical analysis title
    Change in PM PEF: Fp 200 - Placebo
    Statistical analysis description
    No explicit structure was assumed for the covariance among the repeated measures. Analyses for comparison of Fp MDPI to placebo did not contain FLOVENT DISKUS data.
    Comparison groups
    Fp MDPI 200 mcg v Placebo MDPI
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5167 [31]
    Method
    Regression, Linear
    Parameter type
    LSM difference
    Point estimate
    4.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.17
         upper limit
    16.23
    Notes
    [31] - Significance at the 0.05 level
    Statistical analysis title
    Change in PM PEF: Fp 100 - Placebo
    Statistical analysis description
    No explicit structure was assumed for the covariance among the repeated measures. Analyses for comparison of Fp MDPI to placebo did not contain FLOVENT DISKUS data.
    Comparison groups
    Fp MDPI 100 mcg v Placebo MDPI
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6258 [32]
    Method
    Regression, Linear
    Parameter type
    LSM difference
    Point estimate
    2.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.06
         upper limit
    15.05
    Notes
    [32] - Significance at the 0.05 level
    Statistical analysis title
    Change in PM PEF: Fp 50 - Placebo
    Statistical analysis description
    No explicit structure was assumed for the covariance among the repeated measures. Analyses for comparison of Fp MDPI to placebo did not contain FLOVENT DISKUS data.
    Comparison groups
    Fp MDPI 50 mcg v Placebo MDPI
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9487 [33]
    Method
    Regression, Linear
    Parameter type
    LSM difference
    Point estimate
    0.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11.6
         upper limit
    12.39
    Notes
    [33] - Significance at the 0.05 level

    Secondary: The Kaplan-Meier Estimate Of The Probability Of Remaining In The Study At Week 12

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    End point title
    The Kaplan-Meier Estimate Of The Probability Of Remaining In The 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. Worsening asthma was defined as: - clinic visit FEV1 below the FEV1 stability limit value calculated on Day 1. -any 7-day run-in or treatment window (using information from the patient diary), the subject experienced:  3 or more days in which the highest PEF has fallen below the PEF stability limit calculated on Day 1  3 or more days in which ≥12 inhalations/day of albuterol/salbutamol was used  2 or more days in which the subject experienced a nighttime asthma symptom score of >2 - clinical asthma exacerbation, defined as worsening asthma requiring any treatment other than study drug or rescue albuterol/salbutamol including the use of systemic corticosteroids and/or ER visit or hospitalization. Patients 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
    Day 1 to Week 12
    End point values
    Fp MDPI 50 mcg Fp MDPI 100 mcg Fp MDPI 200 mcg Fp MDPI 400 mcg Placebo MDPI Flovent Diskus
    Number of subjects analysed
    107 [34]
    106 [35]
    102 [36]
    107 [37]
    105 [38]
    103 [39]
    Units: probability
        number (confidence interval 95%)
    0.6872 (0.5891 to 0.7665)
    0.633 (0.5307 to 0.7188)
    0.5852 (0.4796 to 0.6766)
    0.6109 (0.5093 to 0.6977)
    0.4722 (0.3712 to 0.5665)
    0.5657 (0.4617 to 0.6571)
    Notes
    [34] - Full analysis set
    [35] - Full analysis set
    [36] - Full analysis set
    [37] - Full analysis set
    [38] - Full analysis set
    [39] - Full analysis set
    Statistical analysis title
    Probability 12 Weeks: Fp 400 - Placebo
    Comparison groups
    Fp MDPI 400 mcg v Placebo MDPI
    Number of subjects included in analysis
    212
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0341 [40]
    Method
    Logrank
    Confidence interval
    Notes
    [40] - Significance level of 0.05.
    Statistical analysis title
    Probability 12 Weeks: Fp 200 - Placebo
    Comparison groups
    Fp MDPI 200 mcg v Placebo MDPI
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.034 [41]
    Method
    Logrank
    Confidence interval
    Notes
    [41] - Significance level of 0.05.
    Statistical analysis title
    Probability 12 Weeks: Fp 100 - Placebo
    Comparison groups
    Fp MDPI 100 mcg v Placebo MDPI
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0058 [42]
    Method
    Logrank
    Confidence interval
    Notes
    [42] - Significance level of 0.05.
    Statistical analysis title
    Probability 12 Weeks: Fp 50 - Placebo
    Comparison groups
    Fp MDPI 50 mcg v Placebo MDPI
    Number of subjects included in analysis
    212
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0018 [43]
    Method
    Logrank
    Confidence interval
    Notes
    [43] - Significance level of 0.05.
    Statistical analysis title
    Probability 12 Weeks: FLOVENT DISKUS - Placebo
    Comparison groups
    Flovent Diskus v Placebo MDPI
    Number of subjects included in analysis
    208
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1006 [44]
    Method
    Logrank
    Confidence interval
    Notes
    [44] - Significance level of 0.05.

    Secondary: Change From Baseline In The Percentage Of Rescue-Free 24-Hour Periods

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    End point title
    Change From Baseline In The Percentage Of Rescue-Free 24-Hour Periods
    End point description
    The change from baseline in the percentage of rescue-free 24-hour periods was analyzed with a marginal (also called population averaged) logistic model, with the response being the proportion of rescue-free 24-hour periods. The model included 2 time points of measurement for each subject: the baseline (the last 7 days before the treatment period) and the treatment period. The model contained covariates for sex, age, and treatment. Rescue-free days were as indicated in patient diaries. Data values are estimated means.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -6 to Day 1 predose), Treatment (Day 1 to Week 12)
    End point values
    Fp MDPI 50 mcg Fp MDPI 100 mcg Fp MDPI 200 mcg Fp MDPI 400 mcg Placebo MDPI Flovent Diskus
    Number of subjects analysed
    96 [45]
    90 [46]
    91 [47]
    99 [48]
    93 [49]
    95 [50]
    Units: percentage of total 24 hour periods
        arithmetic mean (standard error)
    22.78 ± 4.016
    26.41 ± 4.013
    16.18 ± 3.662
    28.05 ± 3.951
    27.15 ± 4.475
    15.87 ± 3.75
    Notes
    [45] - Full analysis set
    [46] - Full analysis set
    [47] - Full analysis set
    [48] - Full analysis set
    [49] - Full analysis set
    [50] - Full analysis set
    Statistical analysis title
    % Change in Rescue-Free 24 Hrs: Fp 400 - Placebo
    Statistical analysis description
    Estimates computed from a generalized linear logistic model with gender and age as covariates and allows correlation between estimates on the same subject. Interpretation of the estimates is that they are the average over the population at the average level of continuous covariate (age) averaged over discrete covariate (gender).
    Comparison groups
    Fp MDPI 400 mcg v Placebo MDPI
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.88116 [51]
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11.12
         upper limit
    12.91
    Notes
    [51] - Significance at the 0.05 level
    Statistical analysis title
    % Change in Rescue-Free 24 Hrs: Fp 200 - Placebo
    Statistical analysis description
    Estimates computed from a generalized linear logistic model with gender and age as covariates and allows correlation between estimates on the same subject. Interpretation of the estimates is that they are the average over the population at the average level of continuous covariate (age) averaged over discrete covariate (gender).
    Comparison groups
    Fp MDPI 200 mcg v Placebo MDPI
    Number of subjects included in analysis
    184
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.05977 [52]
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    -10.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -22.64
         upper limit
    0.68
    Notes
    [52] - Significance at the 0.05 level
    Statistical analysis title
    % Change in Rescue-Free 24 Hrs: Fp 100 - Placebo
    Statistical analysis description
    Estimates computed from a generalized linear logistic model with gender and age as covariates and allows correlation between estimates on the same subject. Interpretation of the estimates is that they are the average over the population at the average level of continuous covariate (age) averaged over discrete covariate (gender).
    Comparison groups
    Fp MDPI 100 mcg v Placebo MDPI
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.90426 [53]
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.02
         upper limit
    11.54
    Notes
    [53] - Significance at the 0.05 level
    Statistical analysis title
    % Change in Rescue-Free 24 Hrs: Fp 50 - Placebo
    Statistical analysis description
    Estimates computed from a generalized linear logistic model with gender and age as covariates and allows correlation between estimates on the same subject. Interpretation of the estimates is that they are the average over the population at the average level of continuous covariate (age) averaged over discrete covariate (gender).
    Comparison groups
    Fp MDPI 50 mcg v Placebo MDPI
    Number of subjects included in analysis
    189
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4731 [54]
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    -4.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.57
         upper limit
    7.82
    Notes
    [54] - Significance at the 0.05 level

    Secondary: Area Under The Plasma Concentration-Time Curve From Time Zero To The Time Of The Last Measurable Concentration (AUC0-t)

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    End point title
    Area Under The Plasma Concentration-Time Curve From Time Zero To The Time Of The Last Measurable Concentration (AUC0-t) [55]
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 predose (within 10 minutes of treatment administration), and 5, 10, 15, 30, and 45 minutes, 1 hour, 1 hour 15 minutes, 1 hour 30 minutes, and 2, 4, 8, and 12 hours postdose
    Notes
    [55] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: PK assessments not reported for placebo arm.
    End point values
    Fp MDPI 50 mcg Fp MDPI 100 mcg Fp MDPI 200 mcg Fp MDPI 400 mcg Flovent Diskus
    Number of subjects analysed
    18 [56]
    16 [57]
    18 [58]
    20 [59]
    16 [60]
    Units: pg*hr/mL
        arithmetic mean (standard deviation)
    117.6 ± 145.79
    126.8 ± 33.73
    292 ± 162.28
    462.8 ± 262.45
    162.3 ± 74.79
    Notes
    [56] - Pharmacokinetics Analysis set
    [57] - Pharmacokinetics Analysis set; two patients did not have AUC data.
    [58] - Pharmacokinetics Analysis set
    [59] - Pharmacokinetics Analysis set
    [60] - Pharmacokinetics Analysis set
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax)

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    End point title
    Maximum Observed Plasma Concentration (Cmax) [61]
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 predose (within 10 minutes of treatment administration), and 5, 10, 15, 30, and 45 minutes, 1 hour, 1 hour 15 minutes, 1 hour 30 minutes, and 2, 4, 8, and 12 hours postdose
    Notes
    [61] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: PK assessments not reported for placebo arm.
    End point values
    Fp MDPI 50 mcg Fp MDPI 100 mcg Fp MDPI 200 mcg Fp MDPI 400 mcg Flovent Diskus
    Number of subjects analysed
    18 [62]
    16 [63]
    18 [64]
    20 [65]
    16 [66]
    Units: pg/mL
        arithmetic mean (standard deviation)
    19.1 ± 15.53
    26.5 ± 6.18
    55.2 ± 29.12
    83 ± 44.32
    32.5 ± 13.92
    Notes
    [62] - Pharmacokinetics Analysis set
    [63] - Pharmacokinetics Analysis set; two patients did not have Cmax data
    [64] - Pharmacokinetics Analysis set
    [65] - Pharmacokinetics Analysis set
    [66] - Pharmacokinetics Analysis set
    No statistical analyses for this end point

    Secondary: Time Of Maximum Observed Plasma Concentration (tmax)

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    End point title
    Time Of Maximum Observed Plasma Concentration (tmax) [67]
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 predose (within 10 minutes of treatment administration), and 5, 10, 15, 30, and 45 minutes, 1 hour, 1 hour 15 minutes, 1 hour 30 minutes, and 2, 4, 8, and 12 hours postdose
    Notes
    [67] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: PK assessments not reported for placebo arm.
    End point values
    Fp MDPI 50 mcg Fp MDPI 100 mcg Fp MDPI 200 mcg Fp MDPI 400 mcg Flovent Diskus
    Number of subjects analysed
    18 [68]
    16 [69]
    18 [70]
    20 [71]
    16 [72]
    Units: hour
        arithmetic mean (standard deviation)
    1 ± 0.54
    1.2 ± 1.85
    2.2 ± 3.58
    1.4 ± 2.6
    1.8 ± 2.75
    Notes
    [68] - Pharmacokinetics Analysis set
    [69] - Pharmacokinetics Analysis set; two patients do not have Tmax data
    [70] - Pharmacokinetics Analysis set
    [71] - Pharmacokinetics Analysis set
    [72] - Pharmacokinetics Analysis set
    No statistical analyses for this end point

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

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    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
    End point values
    Fp MDPI 50 mcg Fp MDPI 100 mcg Fp MDPI 200 mcg Fp MDPI 400 mcg Placebo MDPI Flovent Diskus
    Number of subjects analysed
    107 [73]
    107 [74]
    106 [75]
    107 [76]
    106 [77]
    106 [78]
    Units: patients
        Any adverse event
    31
    27
    34
    41
    33
    27
        Severe AE
    3
    1
    1
    1
    1
    0
        Treatment-related AE
    4
    1
    6
    9
    5
    2
        Deaths
    0
    0
    0
    0
    0
    0
        Other serious AE
    1
    1
    1
    0
    1
    0
        Withdrawn from treatment due to AE
    1
    1
    1
    1
    1
    0
    Notes
    [73] - Safety analysis set
    [74] - Safety analysis set
    [75] - Safety analysis set
    [76] - Safety analysis set
    [77] - Safety analysis set
    [78] - Safety analysis set
    No statistical analyses for this end point

    Secondary: Patients with Positive Swab Test Results for Oral Candidiasis

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    End point title
    Patients with Positive Swab Test Results for Oral Candidiasis
    End point description
    Oropharyngeal examinations for visual evidence of oral candidiasis were conducted at each visit. Any visual evidence of oral candidiasis during the oropharyngeal exam was evaluated by obtaining and analyzing a swab of the suspect area. This outcomes indicates who many patients had positive swab test results. The total number of patients who had oropharyngeal exams at each timepoint are specified in the timepoint field. Appropriate therapy was to be initiated immediately at the discretion of the investigator and was not to be delayed for culture confirmation. Subjects with a culture-positive infection could continue participation in the study on appropriate anti-infective therapy, provided this therapy was not prohibited by the protocol.
    End point type
    Secondary
    End point timeframe
    Screening (Days -21 to -14), Randomization (Day 1), Weeks 1, 2, 3, 4, 6, 8, 10, 12
    End point values
    Fp MDPI 50 mcg Fp MDPI 100 mcg Fp MDPI 200 mcg Fp MDPI 400 mcg Placebo MDPI Flovent Diskus
    Number of subjects analysed
    107 [79]
    107 [80]
    106 [81]
    107 [82]
    106 [83]
    106 [84]
    Units: patients
        Screening (n=107, 106, 106, 107, 106, 104)
    0
    0
    0
    0
    0
    0
        Day 1 (n=107. 107, 106, 107, 106, 106)
    0
    0
    1
    0
    1
    1
        Week 1 (n=102, 103, 98, 97, 96, 99)
    0
    0
    0
    0
    1
    1
        Week 2 (n=99, 101, 94, 95, 84, 92)
    0
    0
    1
    2
    0
    0
        Week 3 (n=91, 98, 92, 93, 80, 87)
    0
    0
    0
    4
    0
    0
        Week 4 (n=91, 95, 88, 87, 75, 87)
    1
    0
    1
    1
    0
    0
        Week 6 (n=86, 92, 86, 86, 68, 85)
    0
    0
    0
    1
    0
    0
        Week 8 (n=83, 90, 81, 83, 64, 82)
    0
    0
    1
    0
    0
    1
        Week 10 (n=83, 87, 77, 82, 60, 79)
    0
    0
    0
    1
    0
    0
        Week 12 (n=104, 104, 103, 106, 102, 100)
    0
    0
    0
    1
    0
    1
    Notes
    [79] - Safety Analysis set
    [80] - Safety Analysis set
    [81] - Safety Analysis set
    [82] - Safety Analysis set
    [83] - Safety Analysis set
    [84] - Safety Analysis set
    No statistical analyses for this end point

    Secondary: 24-Hour Urinary Cortisol Excretion at Baseline, Week 12 and Endpoint

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    End point title
    24-Hour Urinary Cortisol Excretion at Baseline, Week 12 and Endpoint
    End point description
    24-hour urinary cortisol excretion was determined from 24-hour pooled-urine samples; urine was refrigerated until return to the investigational site after each 24-hour collection period. Urine was collected within 7 days of Day 1 and within 7 days of Week 12. Urine cortisol sample collection was not required at endpoint visit for subjects who terminated early from the study.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Week 12, Endpoint
    End point values
    Fp MDPI 50 mcg Fp MDPI 100 mcg Fp MDPI 200 mcg Fp MDPI 400 mcg Placebo MDPI Flovent Diskus
    Number of subjects analysed
    62 [85]
    72 [86]
    56 [87]
    68 [88]
    43 [89]
    59 [90]
    Units: nmol/day
    arithmetic mean (standard deviation)
        Baseline (n=62, 70, 55, 68, 41, 59)
    65.3 ± 42.69
    63.8 ± 44.7
    66.6 ± 45.53
    57.4 ± 34.68
    74.3 ± 43.54
    66.2 ± 42.68
        Week 12 (n=61, 70, 53, 65, 38, 57)
    71.8 ± 48.37
    61.5 ± 45.73
    66.8 ± 53.96
    46.2 ± 38.67
    69.2 ± 49.56
    58.5 ± 43.75
        Endpoint (n=62, 70, 55, 68, 41, 59)
    71 ± 48.31
    61.5 ± 45.73
    65.8 ± 53.33
    45 ± 38.33
    74.4 ± 54.97
    58.4 ± 43.49
    Notes
    [85] - Urine Cortisol Analysis set
    [86] - Urine Cortisol Analysis set
    [87] - Urine Cortisol Analysis set
    [88] - Urine Cortisol Analysis set
    [89] - Urine Cortisol Analysis set
    [90] - Urine Cortisol Analysis set
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period (Including the Flovent Diskus treatment arm)

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    End point title
    Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period (Including the Flovent Diskus treatment arm)
    End point description
    Peak expiratory flow was determined in the AM and in the PM, before administration of study or rescue medications using a handheld electronic peak flow meter. The highest value of triplicate measurements obtained was recorded by the subject’s diary device. On mornings for which a treatment visit was scheduled (TV1 through TV9), the PEF was measured and recorded at the investigational site visit. Baseline trough AM PEF was defined as the average of recorded (nonmissing) trough AM PEF assessments over the 7 days directly preceding first study drug intake. The p-values for the treatment comparisons to Flovent Diskus are from an MMRM model which includes data from all treatments: change from baseline = baseline PEF + sex + age + treatment + visit + treatment*visit with an unstructured covariance matrix assumed.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Day 1 pre-dose), Weeks 1, 2, 3, 4, 6, 8, 10 and 12
    End point values
    Fp MDPI 50 mcg Fp MDPI 100 mcg Fp MDPI 200 mcg Fp MDPI 400 mcg Placebo MDPI Flovent Diskus
    Number of subjects analysed
    104 [91]
    102 [92]
    97 [93]
    103 [94]
    98 [95]
    100 [96]
    Units: liters
        least squares mean (standard error)
    0.063 ± 0.027
    0.102 ± 0.0269
    0.113 ± 0.0279
    0.129 ± 0.0274
    0.057 ± 0.0284
    0.11 ± 0.0274
    Notes
    [91] - Full analysis set
    [92] - Full analysis set
    [93] - Full analysis set
    [94] - Full analysis set
    [95] - Full analysis set
    [96] - Full analysis set
    Statistical analysis title
    Change in FEV1: Fp 400 - Flovent Diskus
    Comparison groups
    Fp MDPI 400 mcg v Flovent Diskus
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6161
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    0.019
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.057
         upper limit
    0.096
    Statistical analysis title
    Change in FEV1: Fp 200 - Flovent Diskus
    Comparison groups
    Fp MDPI 200 mcg v Flovent Diskus
    Number of subjects included in analysis
    197
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9245
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    0.004
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.973
         upper limit
    0.08
    Statistical analysis title
    Change in FEV1: Fp 100 - Flovent Diskus
    Comparison groups
    Fp MDPI 100 mcg v Flovent Diskus
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8434
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    -0.008
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.083
         upper limit
    0.068
    Statistical analysis title
    Change in FEV1: Fp 50 - Flovent Diskus
    Comparison groups
    Fp MDPI 50 mcg v Flovent Diskus
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2241
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    -0.047
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.122
         upper limit
    0.029
    Statistical analysis title
    Change in FEV1: Placebo - Flovent Diskus
    Comparison groups
    Placebo MDPI v Flovent Diskus
    Number of subjects included in analysis
    198
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1822
    Method
    mixed model for repeated measures
    Parameter type
    LSM difference
    Point estimate
    -0.053
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.13
         upper limit
    0.025

    Other pre-specified: Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Morning Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period (Including the Flovent Diskus treatment arm)

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    End point title
    Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Morning Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period (Including the Flovent Diskus treatment arm)
    End point description
    Peak expiratory flow was determined in the AM and in the PM, before administration of study or rescue medications using a handheld electronic peak flow meter. The highest value of triplicate measurements obtained was recorded by the subject’s diary device. On mornings for which a treatment visit was scheduled (TV1 through TV9), the PEF was measured and recorded at the investigational site visit. Baseline trough AM PEF was defined as the average of recorded (nonmissing) trough AM PEF assessments over the 7 days directly preceding first study drug intake. The p-values for the treatment comparisons to Flovent Diskus are from an MMRM model that included data for all treatments: change from baseline = baseline PEF + sex + age + treatment + visit + treatment*visit with an unstructured covariance matrix assumed.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Days -6 to Day 1 pre-dose), Weeks 1, 2, 3, 4, 6, 8, 10 and 12
    End point values
    Fp MDPI 50 mcg Fp MDPI 100 mcg Fp MDPI 200 mcg Fp MDPI 400 mcg Placebo MDPI Flovent Diskus
    Number of subjects analysed
    101 [97]
    101 [98]
    96 [99]
    101 [100]
    98 [101]
    99 [102]
    Units: liters/minute
        least squares mean (standard error)
    10.85 ± 4.245
    9.39 ± 4.193
    10.29 ± 4.362
    10.4 ± 4.254
    2.52 ± 4.453
    15.97 ± 4.283
    Notes
    [97] - Full analysis set
    [98] - Full analysis set
    [99] - Full analysis set
    [100] - Full analysis set
    [101] - Full analysis set
    [102] - Full analysis set
    Statistical analysis title
    Change in AM PEF: Fp 400 - Flovent Diskus
    Comparison groups
    Fp MDPI 400 mcg v Flovent Diskus
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3568
    Method
    Regression, Linear
    Parameter type
    LSM difference
    Point estimate
    -5.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17.42
         upper limit
    6.29
    Statistical analysis title
    Change in AM PEF: Fp 200 - Flovent Diskus
    Comparison groups
    Fp MDPI 200 mcg v Flovent Diskus
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3531
    Method
    Regression, Linear
    Parameter type
    LSM difference
    Point estimate
    -5.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17.67
         upper limit
    6.32
    Statistical analysis title
    Change in AM PEF: Fp 100 - Flovent Diskus
    Comparison groups
    Fp MDPI 100 mcg v Flovent Diskus
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2724
    Method
    Regression, Linear
    Parameter type
    LSM difference
    Point estimate
    -6.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18.35
         upper limit
    5.19
    Statistical analysis title
    Change in AM PEF: Fp 50 - Flovent Diskus
    Comparison groups
    Fp MDPI 50 mcg v Flovent Diskus
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3964
    Method
    Regression, Linear
    Parameter type
    LSM difference
    Point estimate
    -5.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.95
         upper limit
    6.72
    Statistical analysis title
    Change in AM PEF: Placebo - Flovent Diskus
    Comparison groups
    Placebo MDPI v Flovent Diskus
    Number of subjects included in analysis
    197
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0296
    Method
    Regression, Linear
    Parameter type
    LSM difference
    Point estimate
    -13.45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -25.57
         upper limit
    -1.33

    Other pre-specified: Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period (Including the Flovent Diskus treatment arm)

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    End point title
    Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period (Including the Flovent Diskus treatment arm)
    End point description
    Peak expiratory flow was determined in the AM and in the PM, before administration of study or rescue medications using a handheld electronic peak flow meter. The highest value of triplicate measurements obtained was recorded by the subject’s diary device. PM PEF baseline was defined as the average of recorded (nonmissing) PM PEF assessments over the 7 days directly preceding first study drug intake. The p-values for the treatment comparisons to Flovent Diskus are from an MMRM model that included data for all treatments: change from baseline = baseline PEF + sex + age + treatment + visit + treatment*visit with an unstructured covariance matrix assumed.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Days -6 to Day 1 pre-dose), Weeks 1, 2, 3, 4, 6, 8, 10 and 12
    End point values
    Fp MDPI 50 mcg Fp MDPI 100 mcg Fp MDPI 200 mcg Fp MDPI 400 mcg Placebo MDPI Flovent Diskus
    Number of subjects analysed
    103 [103]
    99 [104]
    96 [105]
    102 [106]
    96 [107]
    99 [108]
    Units: liters/minute
        least squares mean (standard error)
    4.22 ± 4.245
    6.52 ± 4.275
    7.89 ± 4.397
    11.72 ± 4.271
    3.35 ± 4.518
    12.4 ± 4.309
    Notes
    [103] - Full analysis set
    [104] - Full analysis set
    [105] - Full analysis set
    [106] - Full analysis set
    [107] - Full analysis set
    [108] - Full analysis set
    Statistical analysis title
    Change in PM PEF: Fp 400 - Flovent Diskus
    Comparison groups
    Fp MDPI 400 mcg v Flovent Diskus
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9101
    Method
    Regression, Linear
    Parameter type
    LSM difference
    Point estimate
    -0.69
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.59
         upper limit
    11.22
    Statistical analysis title
    Change in PM PEF: Fp 200 - Flovent Diskus
    Comparison groups
    Fp MDPI 200 mcg v Flovent Diskus
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4634
    Method
    Regression, Linear
    Parameter type
    LSM difference
    Point estimate
    -4.51
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -16.6
         upper limit
    7.57
    Statistical analysis title
    Change in PM PEF: Fp 100 - Flovent Diskus
    Comparison groups
    Fp MDPI 100 mcg v Flovent Diskus
    Number of subjects included in analysis
    198
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3333
    Method
    Regression, Linear
    Parameter type
    LSM difference
    Point estimate
    -5.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17.8
         upper limit
    6.05
    Statistical analysis title
    Change in PM PEF: Fp 50 - Flovent Diskus
    Comparison groups
    Fp MDPI 50 mcg v Flovent Diskus
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1763
    Method
    Regression, Linear
    Parameter type
    LSM difference
    Point estimate
    -8.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -20.06
         upper limit
    3.69
    Statistical analysis title
    Change in PM PEF: Placebo - Flovent Diskus
    Comparison groups
    Placebo MDPI v Flovent Diskus
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1469
    Method
    Regression, Linear
    Parameter type
    LSM difference
    Point estimate
    -9.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -21.3
         upper limit
    3.19

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 to Week 16
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Fp MDPI 50 mcg
    Reporting group description
    Fluticasone propionate (Fp) 50 mcg per dose twice a day (for a total daily dose of 100 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner (investigator and subject blinded). During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.

    Reporting group title
    Fp MDPI 100 mcg
    Reporting group description
    Fluticasone propionate (Fp) 100 mcg per dose twice a day (for a total daily dose of 200 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner (investigator and subject blinded). During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.

    Reporting group title
    Fp MDPI 200 mcg
    Reporting group description
    Fluticasone propionate (Fp) 200 mcg per dose twice a day (for a total daily dose of 400 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner (investigator and subject blinded). During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.

    Reporting group title
    Fp MDPI 400 mcg
    Reporting group description
    Fluticasone propionate (Fp) 400 mcg per dose twice a day (for a total daily dose of 800 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner (investigator and subject blinded). During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.

    Reporting group title
    Placebo MDPI
    Reporting group description
    Placebo twice a day using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner (investigator and subject blinded). During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.

    Reporting group title
    Flovent Diskus
    Reporting group description
    Fluticasone propionate (Fp) 250 mcg per dose twice a day (for a total daily dose of 500 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in an open-label manner. During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms.

    Serious adverse events
    Fp MDPI 50 mcg Fp MDPI 100 mcg Fp MDPI 200 mcg Fp MDPI 400 mcg Placebo MDPI Flovent Diskus
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 107 (0.93%)
    1 / 106 (0.94%)
    0 / 107 (0.00%)
    1 / 106 (0.94%)
    0 / 106 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 107 (0.00%)
    0 / 106 (0.00%)
    0 / 107 (0.00%)
    0 / 106 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 107 (0.00%)
    1 / 106 (0.94%)
    0 / 107 (0.00%)
    0 / 106 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 107 (0.00%)
    0 / 107 (0.00%)
    0 / 106 (0.00%)
    0 / 107 (0.00%)
    1 / 106 (0.94%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Kidney infection
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 107 (0.93%)
    0 / 106 (0.00%)
    0 / 107 (0.00%)
    0 / 106 (0.00%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Fp MDPI 50 mcg Fp MDPI 100 mcg Fp MDPI 200 mcg Fp MDPI 400 mcg Placebo MDPI Flovent Diskus
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 107 (4.67%)
    4 / 107 (3.74%)
    5 / 106 (4.72%)
    7 / 107 (6.54%)
    6 / 106 (5.66%)
    4 / 106 (3.77%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 107 (4.67%)
    4 / 107 (3.74%)
    5 / 106 (4.72%)
    7 / 107 (6.54%)
    6 / 106 (5.66%)
    4 / 106 (3.77%)
         occurrences all number
    5
    10
    6
    9
    9
    4

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Apr 2011
    Amendment 1 to the protocol was issued before any subjects were enrolled into the study (first patient in [FPI] = 30 April 2012). Amendment 1 was made in 2 parts (leading to protocol versions 2.0 and 3.0) and involved changing study design to double-dummy (this protocol amendment was not implemented) and correcting a format error in Section 7.0 of the protocol.
    15 Aug 2011
    Amendment 2 to the protocol was issued before any subjects were enrolled into the study. In this amendment, study design reverted to the design presented in the original protocol and minor formatting and administrative changes were made.
    10 Feb 2012
    Amendment 3 to the protocol was issued before any subjects were enrolled into the study. In this amendment, the study visit schedule was revised to provide additional safety monitoring of subjects, and inclusion/exclusion criteria were modified to better define the study population. A total of 3 subjects were randomized to the study under this version of the protocol.
    30 Apr 2012
    Amendment 4 modified inclusion/exclusion criteria to clarify the study population. A total of 23 subjects were randomized to the study under this version of the protocol.
    30 Jul 2012
    Amendment 5 to the protocol modified inclusion criteria to clarify the study population. Changes to the protocol were considered to have no negative impact on the safety of subjects already enrolled into the study. A total of 84 subjects were randomized to the study under this version of the protocol.
    20 Dec 2012
    Amendment 6 modified inclusion criteria to allow retesting and rescreening and the dosage for permitted ICS was updated. Changes to the protocol were considered to have no negative impact on the safety of subjects already enrolled into the study. A total of 530 subjects were randomized to the study under this version of the protocol.

    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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