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    Clinical Trial Results:
    A Phase 2, Randomized, Double-Blind, 4-week Crossover Trial to Investigate the Effect of a Once-Daily Combination of 500 μg Roflumilast Plus 10 mg Montelukast vs 10 mg Montelukast Alone on Pulmonary Function, Asthma Symptoms, and Inflammatory Markers in Subjects With Severe Asthma Not Adequately Controlled With a Combination of at Least Medium Dose Inhaled Corticosteroids and Long-Acting Beta Agonists Maintenance Therapy

    Summary
    EudraCT number
    		 2012-002064-27
    Trial protocol
    		 DE   HU  
    Global end of trial date
    24 Oct 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Mar 2016
    First version publication date
    05 Aug 2015
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ROF-ASTHMA_202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01765192
    WHO universal trial number (UTN)
    		 U1111-1132-3160
    Sponsors
    Sponsor organisation name
    Takeda Development Center Europe, Ltd.
    Sponsor organisation address
    61 Aldwych, London, United Kingdom, WC2B 4AE
    Public contact
    Medical Director , Takeda Development Center Europe, Ltd., +001 877-825-3327, trialdisclosures@takeda.com
    Scientific contact
    Medical Director , Takeda Development Center Europe, Ltd., +001 877-825-3327, trialdisclosures@takeda.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 Oct 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Oct 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study will evaluate the effect of roflumilast 500 μg once daily (QD) plus montelukast 10 mg QD versus 10 mg montelukast QD alone on predose (trough) prebronchodilator forced expiratory volume in the first second (FEV1).
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Feb 2013
    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
    Germany: 20
    Country: Number of subjects enrolled
    Hungary: 17
    Country: Number of subjects enrolled
    South Africa: 27
    Worldwide total number of subjects
    64
    EEA total number of subjects
    37
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    54
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants took part in the study at 12 investigative sites in Germany, Hungary, and South Africa from 15 February 2013 to 24 October 2013.

    Pre-assignment
    Screening details
    		 Participants with a historical diagnosis of severe asthma who were inadequately controlled while receiving a combination of at least medium dose inhaled corticosteroids and long-acting beta agonists maintenance therapy were enrolled in 1 of 2 treatment sequences, 500 µg roflumilast plus 10 mg montelukast once daily (QD) or 10 mg montelukast QD.

    Period 1
    Period 1 title
    Treatment period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Blinding was maintained using the interactive voice response system (IVRS), which could be accessed by the investigator or designee in an emergency.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Roflumilast Plus Montelukast, Then Placebo Plus Montelukast
    Arm description
    		 Participants in sequence 1 received roflumilast 500 μg plus montelukast 10 mg orally once daily for 4 weeks followed by a 4-week washout period and then received placebo plus montelukast 10 mg orally once daily for 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Roflumilast
    Investigational medicinal product code
    Other name
    Daxas, Daliresp
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500 µg once daily (QD)

    Investigational medicinal product name
    Montelukast
    Investigational medicinal product code
    Other name
    Singulair, Pluralair
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg once daily (QD)

    Arm title
    		 Placebo Plus Montelukast, Then Roflumilast Plus Montelukast
    Arm description
    		 Participants in sequence 2 received placebo plus montelukast 10 mg orally once daily for 4 weeks followed by a 4-week washout period and then received roflumilast 500 μg plus montelukast 10 mg orally once daily for 4 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Montelukast
    Investigational medicinal product code
    Other name
    Singulair, Pluralair
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg once daily (QD)

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo once daily (QD)

    Number of subjects in period 1
    		Roflumilast Plus Montelukast, Then Placebo Plus Montelukast Placebo Plus Montelukast, Then Roflumilast Plus Montelukast
    Started
    32
    32
    Completed
    32
    31
    Not completed
    0
    1
         Adverse event, non-fatal
    -
    1
    Period 2
    Period 2 title
    Washout period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Roflumilast Plus Montelukast, Then Placebo Plus Montelukast
    Arm description
    		 Participants in sequence 1 received roflumilast 500 μg plus montelukast 10 mg orally once daily for 4 weeks followed by a 4-week washout period and then received placebo plus montelukast 10 mg orally once daily for 4 weeks.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Placebo Plus Montelukast, Then Roflumilast Plus Montelukast
    Arm description
    		 Participants in sequence 2 received placebo plus montelukast 10 mg orally once daily for 4 weeks followed by a 4-week washout period and then received roflumilast 500 μg plus montelukast 10 mg orally once daily for 4 weeks.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Roflumilast Plus Montelukast, Then Placebo Plus Montelukast Placebo Plus Montelukast, Then Roflumilast Plus Montelukast
    Started
    32
    31
    Completed
    30
    30
    Not completed
    2
    1
         Reason not specified
    1
    -
         Voluntary withdrawal
    1
    1
    Period 3
    Period 3 title
    Treatment period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Blinding was maintained using the interactive voice response system (IVRS), which could be accessed by the investigator or designee in an emergency.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Roflumilast Plus Montelukast, Then Placebo Plus Montelukast
    Arm description
    		 Participants in sequence 1 received roflumilast 500 μg plus montelukast 10 mg orally once daily for 4 weeks followed by a 4-week washout period and then received placebo plus montelukast 10 mg orally once daily for 4 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Montelukast
    Investigational medicinal product code
    Other name
    Singulair, Pluralair
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg once daily (QD)

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo once daily (QD)

    Arm title
    		 Placebo Plus Montelukast, Then Roflumilast Plus Montelukast
    Arm description
    		 Participants in sequence 2 received placebo plus montelukast 10 mg orally once daily for 4 weeks followed by a 4-week washout period and then received roflumilast 500 μg plus montelukast 10 mg orally once daily for 4 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Montelukast
    Investigational medicinal product code
    Other name
    Singulair, Pluralair
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg once daily (QD)

    Investigational medicinal product name
    Roflumilast
    Investigational medicinal product code
    Other name
    Daxas, Daliresp
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500 µg once daily (QD)

    Number of subjects in period 3
    		Roflumilast Plus Montelukast, Then Placebo Plus Montelukast Placebo Plus Montelukast, Then Roflumilast Plus Montelukast
    Started
    30
    30
    Completed
    30
    28
    Not completed
    0
    2
         Reason not specified
    -
    2
    Period 4
    Period 4 title
    End of treatment period 2 to final visit
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Roflumilast Plus Montelukast, Then Placebo Plus Montelukast
    Arm description
    		 Participants in sequence 1 received roflumilast 500 μg plus montelukast 10 mg orally once daily for 4 weeks followed by a 4-week washout period and then received placebo plus montelukast 10 mg orally once daily for 4 weeks
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Placebo Plus Montelukast, Then Roflumilast Plus Montelukast
    Arm description
    		 Participants in sequence 2 received placebo plus montelukast 10 mg orally once daily for 4 weeks followed by a 4-week washout period and then received roflumilast 500 μg plus montelukast 10 mg orally once daily for 4 weeks.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 4
    		Roflumilast Plus Montelukast, Then Placebo Plus Montelukast Placebo Plus Montelukast, Then Roflumilast Plus Montelukast
    Started
    30
    28
    Completed
    30
    27
    Not completed
    0
    1
         Adverse event, non-fatal
    -
    1

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Roflumilast Plus Montelukast, Then Placebo Plus Montelukast
    Reporting group description
    		 Participants in sequence 1 received roflumilast 500 μg plus montelukast 10 mg orally once daily for 4 weeks followed by a 4-week washout period and then received placebo plus montelukast 10 mg orally once daily for 4 weeks.

    Reporting group title
    Placebo Plus Montelukast, Then Roflumilast Plus Montelukast
    Reporting group description
    		 Participants in sequence 2 received placebo plus montelukast 10 mg orally once daily for 4 weeks followed by a 4-week washout period and then received roflumilast 500 μg plus montelukast 10 mg orally once daily for 4 weeks.

    Reporting group values
    		 Roflumilast Plus Montelukast, Then Placebo Plus Montelukast Placebo Plus Montelukast, Then Roflumilast Plus Montelukast Total
    Number of subjects
    		 32 32 64
    Age categorical
    Units: Subjects
        < 65 years
    		 27 27 54
        ≥ 65 years
    		 5 5 10
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 50.3 ( 13.8 ) 50 ( 14.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 21 20 41
        Male
    		 11 12 23
    Country of enrollement
    Units: Subjects
        Germany
    		 8 12 20
        South Africa
    		 16 11 27
        Hungary
    		 8 9 17
    Race/Ethnicity
    Units: Subjects
        White
    		 29 32 61
        Black or African American
    		 3 0 3
    Smoking Classification
    Units: Subjects
        Participant has never smoked
    		 22 21 43
        Participant is a current smoker
    		 0 0 0
        Participant is an ex-smoker
    		 10 11 21
    Body Mass Index (BMI)
    Units: kilogram/metre^2
        arithmetic mean (standard deviation)
    		 29.53 ( 7.105 ) 30.06 ( 5.605 ) -
    Height
    Units: centimetre(s)
        arithmetic mean (standard deviation)
    		 163.7 ( 8.47 ) 168.3 ( 10.68 ) -
    Weight
    Units: kilograms
        arithmetic mean (standard deviation)
    		 79.06 ( 18.708 ) 85.16 ( 17.491 ) -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Roflumilast Plus Montelukast, Then Placebo Plus Montelukast
    Reporting group description
    		 Participants in sequence 1 received roflumilast 500 μg plus montelukast 10 mg orally once daily for 4 weeks followed by a 4-week washout period and then received placebo plus montelukast 10 mg orally once daily for 4 weeks.

    Reporting group title
    Placebo Plus Montelukast, Then Roflumilast Plus Montelukast
    Reporting group description
    		 Participants in sequence 2 received placebo plus montelukast 10 mg orally once daily for 4 weeks followed by a 4-week washout period and then received roflumilast 500 μg plus montelukast 10 mg orally once daily for 4 weeks.
    Reporting group title
    Roflumilast Plus Montelukast, Then Placebo Plus Montelukast
    Reporting group description
    		 Participants in sequence 1 received roflumilast 500 μg plus montelukast 10 mg orally once daily for 4 weeks followed by a 4-week washout period and then received placebo plus montelukast 10 mg orally once daily for 4 weeks.

    Reporting group title
    Placebo Plus Montelukast, Then Roflumilast Plus Montelukast
    Reporting group description
    		 Participants in sequence 2 received placebo plus montelukast 10 mg orally once daily for 4 weeks followed by a 4-week washout period and then received roflumilast 500 μg plus montelukast 10 mg orally once daily for 4 weeks.
    Reporting group title
    Roflumilast Plus Montelukast, Then Placebo Plus Montelukast
    Reporting group description
    		 Participants in sequence 1 received roflumilast 500 μg plus montelukast 10 mg orally once daily for 4 weeks followed by a 4-week washout period and then received placebo plus montelukast 10 mg orally once daily for 4 weeks.

    Reporting group title
    Placebo Plus Montelukast, Then Roflumilast Plus Montelukast
    Reporting group description
    		 Participants in sequence 2 received placebo plus montelukast 10 mg orally once daily for 4 weeks followed by a 4-week washout period and then received roflumilast 500 μg plus montelukast 10 mg orally once daily for 4 weeks.
    Reporting group title
    Roflumilast Plus Montelukast, Then Placebo Plus Montelukast
    Reporting group description
    		 Participants in sequence 1 received roflumilast 500 μg plus montelukast 10 mg orally once daily for 4 weeks followed by a 4-week washout period and then received placebo plus montelukast 10 mg orally once daily for 4 weeks

    Reporting group title
    Placebo Plus Montelukast, Then Roflumilast Plus Montelukast
    Reporting group description
    		 Participants in sequence 2 received placebo plus montelukast 10 mg orally once daily for 4 weeks followed by a 4-week washout period and then received roflumilast 500 μg plus montelukast 10 mg orally once daily for 4 weeks.

    Subject analysis set title
    Roflumilast Plus Montelukast
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received roflumilast 500 μg plus montelukast 10 mg once daily for 4 weeks.

    Subject analysis set title
    Placebo Plus Montelukast
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received placebo plus montelukast 10 mg once daily for 4 weeks.

    Primary: Change From Baseline in Pre-dose (Trough) Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1)

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    End point title
    		 Change From Baseline in Pre-dose (Trough) Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1)
    End point description
    FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. FEV1 will be measured using spirometry in accordance with the American Thoracic Society / European Respiratory Society (ATS/ERS) consensus guidelines. An ANCOVA model with treatment sequence, treatment period, and study treatment as fixed factors with Baseline FEV1 measurement as the covariate was used for analysis.
    End point type
    Primary
    End point timeframe
    Baseline (Days 1 and 56) and after 4 weeks of treatment (Days 28 and 84)
    End point values
    		 Roflumilast Plus Montelukast Placebo Plus Montelukast
    Number of subjects analysed
    58
    61
    Units: litre(s)
        least squares mean (standard error)
    0.18 ( 0.028 )
    0.08 ( 0.027 )
    Statistical analysis title
    		 Change from Baseline in FEV1
    Statistical analysis description
    The primary endpoint was analyzed using an analysis of covariance model adapted for the crossover design. The following fixed factors and covariates were included in the model: Treatment, sequence, period, and baseline FEV1 measurement of the respective treatment period. The reported analysis results are for the 2 crossover treatment periods combined.
    Comparison groups
    Placebo Plus Montelukast v Roflumilast Plus Montelukast
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.013
    Method
    		 ANCOVA
    Parameter type
    		 Least squares (LS) mean difference
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.0219
         upper limit
    		 0.1795
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.039

    Secondary: Change From Baseline in Pre-dose (Trough) Pre-bronchodilator Forced Vital Capacity (FVC)

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    End point title
    		 Change From Baseline in Pre-dose (Trough) Pre-bronchodilator Forced Vital Capacity (FVC)
    End point description
    FVC is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. FVC will be measured using spirometry in accordance with ATS/ERS consensus guidelines. An ANCOVA model with treatment sequence, treatment period, and study treatment as fixed factors with Baseline FVC measurement as the covariate was used for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Days 1 and 56) and after 4 weeks of treatment (Days 28 and 84)
    End point values
    		 Roflumilast Plus Montelukast Placebo Plus Montelukast
    Number of subjects analysed
    58
    61
    Units: liters
        least squares mean (standard error)
    0.12 ( 0.029 )
    0.06 ( 0.027 )
    Statistical analysis title
    		 Change from Baseline to Week 4 in FVC
    Statistical analysis description
    An ANCOVA model with treatment sequence, treatment period, and study treatment as fixed factors with Baseline FVC measurement as the covariate was used for analysis.
    Comparison groups
    Roflumilast Plus Montelukast v Placebo Plus Montelukast
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.129 [1]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0185
         upper limit
    		 0.1422
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.04
    Notes
    [1] - P-values were obtained using an ANCOVA model with treatment sequence, treatment period, and study treatment as fixed factors with Baseline pre-bronchodilator FVC measurement as the covariate.

    Secondary: Change From Baseline in Pre-dose (Trough) Pre-bronchodilator Forced Expiratory Flow (FEF) 25-75%

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    End point title
    		 Change From Baseline in Pre-dose (Trough) Pre-bronchodilator Forced Expiratory Flow (FEF) 25-75%
    End point description
    FEF is a measure of how much air can be exhaled from the lungs. It is an indicator of obstruction of the smaller airways. FEF25-75% is the mid-flow rate or forced expiratory flow occurring in the middle 50% of the patient's exhaled volume, and will be measured using spirometry in accordance with ATS/ERS consensus guidelines. An ANCOVA model with treatment sequence, treatment period, and study treatment as fixed factors with Baseline FEF measurement as the covariate was used for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Days 1 and 56) and after 4 weeks of treatment (Days 28 and 84)
    End point values
    		 Roflumilast Plus Montelukast Placebo Plus Montelukast
    Number of subjects analysed
    54
    55
    Units: liters/second
        least squares mean (standard error)
    0.23 ( 0.039 )
    0.11 ( 0.039 )
    Statistical analysis title
    		 Change from Baseline in FEF
    Comparison groups
    Roflumilast Plus Montelukast v Placebo Plus Montelukast
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.032 [2]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.0113
         upper limit
    		 0.2364
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.056
    Notes
    [2] - P-values were obtained using an ANCOVA model with treatment sequence, treatment period, and study treatment as fixed factors with Baseline pre-bronchodilator FEF measurement as the covariate.

    Secondary: Change From Baseline in Pre-dose (Trough) Pre-bronchodilator Peak Expiratory Flow (PEF)

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    End point title
    		 Change From Baseline in Pre-dose (Trough) Pre-bronchodilator Peak Expiratory Flow (PEF)
    End point description
    PEF is a person's maximum speed of expiration. It measures the airflow through the bronchi and thus the degree of obstruction in the airways. PEF will be measured using spirometry in accordance with ATS/ERS consensus guidelines. An ANCOVA model with treatment sequence, treatment period, and study treatment as fixed factors with Baseline PEF measurement as the covariate was used for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Days 1 and 56) and after 4 weeks of treatment (Days 28 and 84)
    End point values
    		 Roflumilast Plus Montelukast Placebo Plus Montelukast
    Number of subjects analysed
    58
    61
    Units: liters/minute (L/min)
        least squares mean (standard error)
    15.05 ( 10.616 )
    7.85 ( 10.401 )
    Statistical analysis title
    		 Change from Baseline in PEF
    Comparison groups
    Roflumilast Plus Montelukast v Placebo Plus Montelukast
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.635 [3]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    7.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.0531
         upper limit
    		 37.466
    Variability estimate
    Standard error of the mean
    Dispersion value
    15.105
    Notes
    [3] - P-values were obtained using an ANCOVA model with treatment sequence, treatment period, and study treatment as fixed factors with Baseline pre-bronchodilator PEF measurement as the covariate.

    Secondary: Change From Baseline in Morning Peak Expiratory Flow (PEF)

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    End point title
    		 Change From Baseline in Morning Peak Expiratory Flow (PEF)
    End point description
    PEF will be measured at home using portable electronic peak flow meter. The participant will record PEF daily in the morning immediately after getting up. An ANCOVA model with treatment sequence, treatment period, and study treatment as fixed factors with Baseline PEF measurement as the covariate was used for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Days 1 and 56) and after 4 weeks of treatment (Days 28 and 84)
    End point values
    		 Roflumilast Plus Montelukast Placebo Plus Montelukast
    Number of subjects analysed
    60
    61
    Units: L/min
        least squares mean (standard error)
    20.85 ( 3.708 )
    7.23 ( 3.646 )
    Statistical analysis title
    		 Change from Baseline in Morning PEF
    Comparison groups
    Roflumilast Plus Montelukast v Placebo Plus Montelukast
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.011 [4]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    13.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.1896
         upper limit
    		 24.0553
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.206
    Notes
    [4] - P-values were obtained using an ANCOVA model with treatment sequence, treatment period, and study treatment as fixed factors with Baseline pre-bronchodilator PEF measurement as the covariate.

    Secondary: Change From Baseline in Daytime Asthma Symptoms

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    End point title
    		 Change From Baseline in Daytime Asthma Symptoms
    End point description
    Patients will assess their daily day-time asthma symptoms according to the following scale: 0: Very well, no symptoms. 1: One episode of wheezing, cough, or breathlessness. 2: More than 1 episode of wheezing, cough, or breathlessness without interference with normal activities. 3: Wheezing, cough, or short of breath most of the day which interfered to some extent with normal activities. 4: Asthma very bad. Unable to carry out daily activities, as usual. An ANCOVA model with treatment sequence, treatment period, and study treatment as fixed factors with Baseline Daytime Asthma Symptoms measurement as the covariate was used for analysis. A negative change from Baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline (Days 1 and 56) and after 4 weeks of treatment (Days 28 and 84)
    End point values
    		 Roflumilast Plus Montelukast Placebo Plus Montelukast
    Number of subjects analysed
    60
    61
    Units: units on a scale
        least squares mean (standard error)
    -0.39 ( 0.061 )
    -0.18 ( 0.063 )
    Statistical analysis title
    		 Change from Baseline in Daytime Asthma Symptoms
    Comparison groups
    Roflumilast Plus Montelukast v Placebo Plus Montelukast
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.025 [5]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.385
         upper limit
    		 -0.0271
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.089
    Notes
    [5] - P-values were obtained using an ANCOVA model with treatment sequence, treatment period, and study treatment as fixed factors with Baseline Daytime Asthma Symptom Score as the covariate.

    Secondary: Change From Baseline in Nighttime Asthma Symptoms

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    End point title
    		 Change From Baseline in Nighttime Asthma Symptoms
    End point description
    Patients will assess their daily night-time asthma symptoms according to the following scale: 0: No symptoms, slept through the night. 1: Slept well but some complaints in the morning. 2: Woke up once because of asthma (inclusive early awakening). 3: Woke up several times because of asthma (inclusive early awakening). 4: Bad night, awake most of the night because of asthma. An ANCOVA model with treatment sequence, treatment period, and study treatment as fixed factors with Baseline Nighttime Asthma Symptoms measurement as the covariate was used for analysis. A negative change from Baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline (Days 1 and 56) and after 4 weeks of treatment (Days 28 and 84)
    End point values
    		 Roflumilast Plus Montelukast Placebo Plus Montelukast
    Number of subjects analysed
    60
    61
    Units: units on a scale
        least squares mean (standard error)
    -0.27 ( 0.053 )
    -0.17 ( 0.052 )
    Statistical analysis title
    		 Change from Baseline in Nighttime Asthma
    Comparison groups
    Roflumilast Plus Montelukast v Placebo Plus Montelukast
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.217 [6]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2426
         upper limit
    		 0.0563
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.075
    Notes
    [6] - P-values were obtained using an ANCOVA model with treatment sequence, treatment period, and study treatment as fixed factors with Baseline Nighttime Asthma Symptoms measurement as the covariate.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to the end of the study (Days 1-105)
    Adverse event reporting additional description
    Safety analysis set: All randomized participants who received at least 1 dose of study drug. Adverse events are reported for 61 and 62 participants in the roflumilast + montelukast (R+M) and placebo + montelukast (P+M) treatment groups, respectively, as 3 participants discontinued prior to receiving R+M and 2 participants discontinued prior to rec
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Roflumilast Plus Montelukast
    Reporting group description
    		 Participants received roflumilast 500 μg plus montelukast 10 mg once daily for 4 weeks.

    Reporting group title
    Placebo Plus Montelukast
    Reporting group description
    		 Participants received placebo plus montelukast 10 mg once daily for 4 weeks.

    Serious adverse events
    		 Roflumilast Plus Montelukast Placebo Plus Montelukast
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 61 (0.00%)
    0 / 62 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Roflumilast Plus Montelukast Placebo Plus Montelukast
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 61 (8.20%)
    0 / 62 (0.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 61 (8.20%)
    0 / 62 (0.00%)
         occurrences all number
    5
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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