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    Clinical Trial Results:
    A 12-Week, Randomized, Double-Blind, Placebo-Controlled, Efficacy and Safety Study of Fluticasone Propionate Multidose Dry Powder Inhaler Compared with Fluticasone Propionate/Salmeterol Multidose Dry Powder Inhaler in Patients Aged 4 Through 11 Years With Persistent Asthma

    Summary
    EudraCT number
    		 2016-003835-39
    Trial protocol
    		 HU  
    Global end of trial date
    13 Apr 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Oct 2019
    First version publication date
    24 Oct 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    FSS-AS-30003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02980133
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Teva Branded Pharmaceutical Products, R&D Inc.
    Sponsor organisation address
    41 Moores Road, Frazer, United States, 19355
    Public contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 8884838279, info.eraclinical@teva.de
    Scientific contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 8884838279, info.eraclinical@teva.de
    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
    14 May 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Apr 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the efficacy of fluticasone propionate (Fp) multidose dry powder inhaler (MDPI) and fluticasone propionate/salmetrol (FS) MDPI when administered over 12 weeks in participants of 4 through 11 years of age with persistent asthma.
    Protection of trial subjects
    This study was conducted in full accordance with the International Council for Harmonisation (ICH) Harmonised Tripartite Guideline for Good Clinical Practice (GCP) E6 and any applicable national and local laws and regulations (for example; Title 21 Code of Federal Regulations Parts 11, 50, 54, 56, 312, and 314, Directive 2001/20/EC of the European Parliament and of the Council 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).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Dec 2016
    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
    Georgia: 43
    Country: Number of subjects enrolled
    Hungary: 84
    Country: Number of subjects enrolled
    Russian Federation: 71
    Country: Number of subjects enrolled
    Ukraine: 150
    Country: Number of subjects enrolled
    United States: 493
    Worldwide total number of subjects
    841
    EEA total number of subjects
    84
    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)
    841
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 841 participants with persistent asthma were randomized in a 1:1:1:1 ratio to receive Fp MDPI 25 micrograms (mcg), Fp MDPI 50 mcg, FS MDPI 50/12.5 mcg, or placebo MDPI. Randomization was stratified by previous therapy (inhaled corticosteroid [ICS] or non-corticosteroid [NCS]).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo MDPI
    Arm description
    		 Participants received matching placebo via MDPI for 12 weeks.
    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
    Matching placebo was administered via MDPI per the schedule specified in the arm.

    Arm title
    		 Fp MDPI 25 mcg BID
    Arm description
    		 Participants received 1 inhalation of 25 mcg fluticasone propionate (Fp) via MDPI twice daily (BID) (total daily dose: 50 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 was administered via MDPI per the dose and schedule specified in the arm.

    Arm title
    		 Fp MDPI 50 mcg BID
    Arm description
    		 Participants received 1 inhalation of 50 mcg fluticasone propionate via MDPI BID (total daily dose: 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 was administered via MDPI per the dose and schedule specified in the arm.

    Arm title
    		 FS MDPI 50/12.5 mcg BID
    Arm description
    		 Participants received 1 inhalation of 50/12.5 mcg fluticasone propionate/salmeterol (FS) via MDPI BID (total daily dose: 100/25 mcg) for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fluticasone Propionate/Salmeterol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Fluticasone propionate/salmeterol was administered via MDPI per the dose and schedule specified in the arm.

    Number of subjects in period 1
    		Placebo MDPI Fp MDPI 25 mcg BID Fp MDPI 50 mcg BID FS MDPI 50/12.5 mcg BID
    Started
    209
    211
    210
    211
    Received at least 1 dose of study drug
    209
    211
    208
    211
    Completed
    202
    206
    203
    205
    Not completed
    7
    5
    7
    6
         Consent withdrawn by subject
    -
    -
    1
    -
         Other than specified
    1
    1
    2
    2
         Lost to follow-up
    -
    -
    1
    3
         Withdrawal by parent/guardian
    6
    3
    3
    1
         Protocol deviation
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo MDPI
    Reporting group description
    		 Participants received matching placebo via MDPI for 12 weeks.

    Reporting group title
    Fp MDPI 25 mcg BID
    Reporting group description
    		 Participants received 1 inhalation of 25 mcg fluticasone propionate (Fp) via MDPI twice daily (BID) (total daily dose: 50 mcg) for 12 weeks.

    Reporting group title
    Fp MDPI 50 mcg BID
    Reporting group description
    		 Participants received 1 inhalation of 50 mcg fluticasone propionate via MDPI BID (total daily dose: 100 mcg) for 12 weeks.

    Reporting group title
    FS MDPI 50/12.5 mcg BID
    Reporting group description
    		 Participants received 1 inhalation of 50/12.5 mcg fluticasone propionate/salmeterol (FS) via MDPI BID (total daily dose: 100/25 mcg) for 12 weeks.

    Reporting group values
    		 Placebo MDPI Fp MDPI 25 mcg BID Fp MDPI 50 mcg BID FS MDPI 50/12.5 mcg BID Total
    Number of subjects
    		 209 211 210 211 841
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 209 211 210 211 841
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 8.5 ± 1.98 8.7 ± 1.83 8.5 ± 1.94 8.4 ± 2.05 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 79 74 80 91 324
        Male
    		 130 137 130 120 517
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 172 168 171 172 683
        Black or African American
    		 33 41 32 29 135
        Asian
    		 1 0 2 3 6
        American Indian or Alaska Native
    		 0 1 2 0 3
        Native Hawaiian or Other Pacific Islander
    		 1 0 0 0 1
        Other
    		 2 1 3 7 13
    Percent Predicted Forced Expiratory Volume in 1 Second (FEV1)
    FEV1 is the volume of air exhaled in the first second of a forced expiration as measured by spirometer. Baseline trough morning percent predicted FEV1 was defined as the average value of recorded (nonmissing) morning assessments 5 out of the last 7 days prior to randomization. 'Number of participants analyzed' for this parameter are 209, 211, 209, and 211 for each arm respectively.
    Units: percent predicted of FEV1
        arithmetic mean (standard deviation)
    		 68.8 ± 9.70 69.6 ± 9.68 69.6 ± 9.47 69.9 ± 9.15 -
    1-Hour Postdose Percent Predicted Morning FEV1
    FEV1 is the volume of air exhaled in the first second of a forced expiration as measured by spirometer. The baseline 1-hour trough morning percent predicted FEV1 was defined as the predose trough morning percent predicted FEV1 measurement at the randomization visit (Baseline [Day 1]) at the investigational center. 'Number of participants analyzed' for this parameter are 205, 209, 207, and 211 for each arm respectively.
    Units: percent predicted of FEV1
        arithmetic mean (standard deviation)
    		 81.1 ± 16.92 79.3 ± 14.60 80.2 ± 15.87 87.3 ± 18.72 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo MDPI
    Reporting group description
    		 Participants received matching placebo via MDPI for 12 weeks.

    Reporting group title
    Fp MDPI 25 mcg BID
    Reporting group description
    		 Participants received 1 inhalation of 25 mcg fluticasone propionate (Fp) via MDPI twice daily (BID) (total daily dose: 50 mcg) for 12 weeks.

    Reporting group title
    Fp MDPI 50 mcg BID
    Reporting group description
    		 Participants received 1 inhalation of 50 mcg fluticasone propionate via MDPI BID (total daily dose: 100 mcg) for 12 weeks.

    Reporting group title
    FS MDPI 50/12.5 mcg BID
    Reporting group description
    		 Participants received 1 inhalation of 50/12.5 mcg fluticasone propionate/salmeterol (FS) via MDPI BID (total daily dose: 100/25 mcg) for 12 weeks.

    Primary: For FS MDPI Versus Fp MDPI: Change From Baseline in 1-Hour Postdose Percent Predicted Morning Forced Expiratory Volume in 1 Second (FEV1) at Week 12

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    End point title
    		 For FS MDPI Versus Fp MDPI: Change From Baseline in 1-Hour Postdose Percent Predicted Morning Forced Expiratory Volume in 1 Second (FEV1) at Week 12 [1]
    End point description
    FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer. The baseline 1-hour trough morning percent predicted FEV1 was defined as the predose trough morning percent predicted FEV1 measurement at the randomization visit (Baseline [Day 1]) at the investigational center. The IMP dose was administered right after the predose FEV1 measurement (within a 10 minute window). Participant then performed 1-hour (±10 minutes) postdose lung function assessments on Week 12 at the investigational center. ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' signifies participants evaluable for this endpoint. Missing data was imputed using missing not at random (MNAR) methodology for prematurely discontinue participants or missing at random (MAR) for completers with implausible data.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    Notes
    [1] - 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: The endpoint is reporting statistics for the specified arms only.
    End point values
    		 Fp MDPI 25 mcg BID Fp MDPI 50 mcg BID FS MDPI 50/12.5 mcg BID
    Number of subjects analysed
    211
    209
    211
    Units: percent predicted of FEV1
        least squares mean (standard error)
    16.8 ± 1.32
    16.4 ± 1.32
    18.2 ± 1.29
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using an analysis of covariance (ANCOVA) model with effects due to baseline trough morning percent predicted FEV1, sex, age, (pooled) investigational center, previous therapy (inhaled corticosteroid [ICS] or noncorticosteroid [NCS]), and investigational medicinal product (IMP) treatment group.
    Comparison groups
    Fp MDPI 50 mcg BID v FS MDPI 50/12.5 mcg BID
    Number of subjects included in analysis
    420
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.285 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Least square (LS) mean difference
    Point estimate
    1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 5.3
    Notes
    [2] - Threshold for significance at 0.05 level.

    Primary: For Fp MDPI Versus Placebo: Change From Baseline in Weekly Average of the Percent Predicted Trough Morning FEV1 at Week 12

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    End point title
    		 For Fp MDPI Versus Placebo: Change From Baseline in Weekly Average of the Percent Predicted Trough Morning FEV1 at Week 12 [3]
    End point description
    Baseline trough morning percent predicted FEV1: the average value of recorded morning assessments 5 out of the last 7 days prior to randomization. First day before randomization consisted of electronic diary entry at home on the morning of randomization visit (Baseline [Day 1]) and the first day postrandomization consisted of electronic diary entry at home on the morning of the day after the randomization visit. For postdose weekly average of trough morning percent predicted FEV1 measurements, values were the averages based on the available data for that week. Averages were calculated as the sum of morning FEV1 values divided by number of nonmissing assessments. ITT analysis set: all randomized participants. Here, 'Overall number of participants analyzed' signifies participants evaluable for this endpoint. Missing data was imputed using MNAR methodology for prematurely discontinue participants or MAR for completers with implausible data.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    Notes
    [3] - 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: The endpoint is reporting statistics for the specified arms only.
    End point values
    		 Placebo MDPI Fp MDPI 25 mcg BID Fp MDPI 50 mcg BID
    Number of subjects analysed
    209
    211
    209
    Units: percent predicted of FEV1
        least squares mean (standard error)
    7.3 ± 1.10
    13.3 ± 1.09
    14.2 ± 1.10
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using an ANCOVA model with effects due to baseline trough morning percent predicted FEV1, sex, age, (pooled) investigational center, previous therapy (ICS or NCS), and IMP treatment group.
    Comparison groups
    Placebo MDPI v Fp MDPI 25 mcg BID
    Number of subjects included in analysis
    420
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [4]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.2
         upper limit
    		 8.8
    Notes
    [4] - Threshold for significance at 0.05 level.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Analysis was performed using an ANCOVA model with effects due to baseline trough morning percent predicted FEV1, sex, age, (pooled) investigational center, previous therapy (ICS or NCS), and IMP treatment group.
    Comparison groups
    Placebo MDPI v Fp MDPI 50 mcg BID
    Number of subjects included in analysis
    418
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [5]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.1
         upper limit
    		 9.8
    Notes
    [5] - Threshold for significance at 0.05 level.

    Secondary: Change From Baseline in the Weekly Average of Daily Trough Morning (Predose and Pre-Rescue Bronchodilator) Peak Expiratory Flow (PEF) Over the 12 Week Treatment Period

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    End point title
    		 Change From Baseline in the Weekly Average of Daily Trough Morning (Predose and Pre-Rescue Bronchodilator) Peak Expiratory Flow (PEF) Over the 12 Week Treatment Period
    End point description
    Morning PEF was determined in the morning, before administration of IMP or rescue medications. Baseline trough morning PEF was defined as the average value of recorded (nonmissing) morning assessments 5 out of the last 7 days prior to randomization. The first day before randomization consisted of the electronic participant diary entry at home on the morning of the randomization visit (Baseline [Day 1]) and the first day postrandomization consisted of the electronic participant diary entry at home on the morning of the day after the randomization visit (Baseline [Day 1]). For postdose weekly average of trough morning PEF measurements, the values were the averages based on the available data for that week. The averages were calculated as the sum of morning PEF values divided by the number of nonmissing assessments. ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' signifies participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1 to 12
    End point values
    		 Placebo MDPI Fp MDPI 25 mcg BID Fp MDPI 50 mcg BID FS MDPI 50/12.5 mcg BID
    Number of subjects analysed
    208
    210
    208
    211
    Units: liters/minute
        least squares mean (standard error)
    12.3 ± 2.65
    28.9 ± 2.62
    26.3 ± 2.64
    32.0 ± 2.61
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Weekly Average of Total Daily (24 Hour) Use of Albuterol/Salbutamol Inhalation Aerosol (Number of Inhalations) Over Weeks 1 Through 12

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    End point title
    		 Change From Baseline in the Weekly Average of Total Daily (24 Hour) Use of Albuterol/Salbutamol Inhalation Aerosol (Number of Inhalations) Over Weeks 1 Through 12
    End point description
    Participants recorded the number of inhalations of rescue medication (albuterol/salbutamol HFA MDI) each morning and evening in the electronic participant diary. An entry of 0 inhalations indicated no rescue medication was needed. To calculate the total daily use of albuterol/salbutamol inhalation aerosol (number of inhalations), the electronic participant diary entry on randomization visit (Baseline [Day 1]) was defined as the first day of analysis. The weekly average of the total daily inhalations was the average based on the available data for that week. The average was calculated as the sum of total daily inhalations over the 7 days for each analysis week divided by the number of nonmissing assessments. LS mean and standard error (SE) were obtained using mixed model for repeated measures (MMRM). ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' signifies participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1 to 12
    End point values
    		 Placebo MDPI Fp MDPI 25 mcg BID Fp MDPI 50 mcg BID FS MDPI 50/12.5 mcg BID
    Number of subjects analysed
    208
    210
    209
    211
    Units: inhalations
        least squares mean (standard error)
    -0.2 ± 0.05
    -0.4 ± 0.05
    -0.5 ± 0.05
    -0.4 ± 0.05
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Weekly Average of the Total Daily Asthma Symptom Score Over Weeks 1 Through 12

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    End point title
    		 Change From Baseline in the Weekly Average of the Total Daily Asthma Symptom Score Over Weeks 1 Through 12
    End point description
    Each participant assessed the asthma symptoms of cough, wheeze, shortness of breath, and chest tightness and entered a single score that was inclusive of all symptoms. Daytime Symptom Score (determined in the evening) ranged from 0=No symptoms to 5=Symptoms so severe that I could not go to work or perform normal daily activities. Nighttime Symptom Score (determined in the morning) ranged from 0=No symptoms to 4=Symptoms so severe that I did not sleep at all. Total daily asthma symptom score was average of daytime and nighttime scores. Total daily asthma symptom score ranged from 0 - 9 with 0=no symptoms and 9=severe symptoms. Weekly average was calculated as the sum of total daily asthma symptom scores over the 7 days for each analysis week divided by the number of nonmissing assessments. LS mean and SE were obtained using MMRM. ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' signifies participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1 to 12
    End point values
    		 Placebo MDPI Fp MDPI 25 mcg BID Fp MDPI 50 mcg BID FS MDPI 50/12.5 mcg BID
    Number of subjects analysed
    208
    210
    209
    211
    Units: units on a scale
        least squares mean (standard error)
    -0.1 ± 0.02
    -0.2 ± 0.02
    -0.2 ± 0.02
    -0.2 ± 0.02
    No statistical analyses for this end point

    Secondary: Change From Baseline in Asthma Control (Measured by Childhood Asthma Control Test [C-ACT] Score) Over the 12 Week Treatment Period

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    End point title
    		 Change From Baseline in Asthma Control (Measured by Childhood Asthma Control Test [C-ACT] Score) Over the 12 Week Treatment Period
    End point description
    C-ACT was a simple, participant-completed tool used for the assessment of overall asthma control. The first 4 items of the test were completed by the participant, while the last 3 items were completed by the participant’s parents/legal guardians/caregivers. A total sum score based upon responses to all items was calculated to provide an overall measure of asthma control. The derived C-ACT score ranging from 0 to 27. These scores spanned the continuum of poor control of asthma (score ≤5) to complete control of asthma (score ≥25), with a cut off score of 19 indicating participants with poorly controlled asthma. LS mean and SE were obtained using MMRM. ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' signifies participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1 to 12
    End point values
    		 Placebo MDPI Fp MDPI 25 mcg BID Fp MDPI 50 mcg BID FS MDPI 50/12.5 mcg BID
    Number of subjects analysed
    204
    208
    205
    209
    Units: units on a scale
        least squares mean (standard error)
    4.5 ± 0.21
    5.1 ± 0.21
    5.5 ± 0.21
    5.4 ± 0.21
    No statistical analyses for this end point

    Secondary: Time to First Onset of Effect

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    End point title
    		 Time to First Onset of Effect
    End point description
    The time to first onset of effect, defined as the first decrease from baseline in daily rescue medication use, was calculated based on the number of inhalations of rescue medication (albuterol/salbutamol hydrofluoroalkane metered-dose inhaler [HFA MDI] [90 mcg ex actuator] or equivalent) recorded by the participant each morning and evening in the participant diary built into the handheld device. ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' signifies participants evaluable for this endpoint. Here, '99999' signifies data could not be calculated due to smaller number of participants with an event.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    		 Placebo MDPI Fp MDPI 25 mcg BID Fp MDPI 50 mcg BID FS MDPI 50/12.5 mcg BID
    Number of subjects analysed
    208
    210
    208
    211
    Units: days
        median (confidence interval 95%)
    20.0 (5.0 to 99999)
    99999 (3.0 to 99999)
    2.0 (2.0 to 2.0)
    6.0 (2.0 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Participants who Discontinued From Investigational Medicinal Product (IMP) for Asthma Exacerbation During the 12 Week Treatment Period

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    End point title
    		 Percentage of Participants who Discontinued From Investigational Medicinal Product (IMP) for Asthma Exacerbation During the 12 Week Treatment Period
    End point description
    ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' signifies participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    		 Placebo MDPI Fp MDPI 25 mcg BID Fp MDPI 50 mcg BID FS MDPI 50/12.5 mcg BID
    Number of subjects analysed
    208
    210
    208
    211
    Units: percentage of participants
        number (not applicable)
    6
    2
    1
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Week 13
    Adverse event reporting additional description
    Safety analysis set included all randomized participants who received at least 1 dose of IMP.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Placebo MDPI
    Reporting group description
    		 Participants received matching placebo via MDPI for 12 weeks.

    Reporting group title
    Fp MDPI 25 mcg BID
    Reporting group description
    		 Participants received 1 inhalation of 25 mcg fluticasone propionate via MDPI BID (total daily dose: 50 mcg) for 12 weeks.

    Reporting group title
    Fp MDPI 50 mcg BID
    Reporting group description
    		 Participants received 1 inhalation of 50 mcg fluticasone propionate via MDPI BID (total daily dose: 100 mcg) for 12 weeks.

    Reporting group title
    FS MDPI 50/12.5 mcg BID
    Reporting group description
    		 Participants received 1 inhalation of 50/12.5 mcg fluticasone propionate/salmeterol via MDPI BID (total daily dose: 100/25 mcg) for 12 weeks.

    Serious adverse events
    		 Placebo MDPI Fp MDPI 25 mcg BID Fp MDPI 50 mcg BID FS MDPI 50/12.5 mcg BID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 209 (0.48%)
    2 / 211 (0.95%)
    1 / 208 (0.48%)
    4 / 211 (1.90%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    0 / 208 (0.00%)
    1 / 211 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    0 / 208 (0.00%)
    1 / 211 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphadenitis
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    0 / 208 (0.00%)
    1 / 211 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    0 / 208 (0.00%)
    1 / 211 (0.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 209 (0.48%)
    1 / 211 (0.47%)
    0 / 208 (0.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Disruptive mood dysregulation disorder
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 211 (0.00%)
    1 / 208 (0.48%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia mycoplasmal
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 211 (0.47%)
    0 / 208 (0.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 211 (0.00%)
    0 / 208 (0.00%)
    0 / 211 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo MDPI Fp MDPI 25 mcg BID Fp MDPI 50 mcg BID FS MDPI 50/12.5 mcg BID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 209 (5.26%)
    8 / 211 (3.79%)
    11 / 208 (5.29%)
    9 / 211 (4.27%)
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    11 / 209 (5.26%)
    8 / 211 (3.79%)
    11 / 208 (5.29%)
    9 / 211 (4.27%)
         occurrences all number
    12
    9
    11
    9

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Jun 2018
    The following major procedural changes (not all-inclusive) were made to the protocol: • An unplanned blinded data quality evaluation and sample size reassessment was conducted. Based on the observed blinded 410 completed participants, the initial assumptions for SD and power calculation and the sample size were revised. Increase in number of participants enrolled. • Treatment compliance was assessed on both data from the dose counter and the diary. • “2-Dimensional tipping point” multiple imputation 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
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