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    Clinical Trial Results:
    A Multicenter, Randomized, Double-blind Phase 3 Study to Evaluate Tolerability and Pharmacokinetics of 500 µg Roflumilast Once Daily with an Up-titration Regimen in COPD, including an Open-label Down-titration Period Evaluating Tolerability and Pharmacokinetics of 250 µg Roflumilast Once Daily in Subjects not Tolerating 500 µg Roflumilast Once-daily

    Summary
    EudraCT number
    		 2013-001788-21
    Trial protocol
    		 GB   SK   DE   HU   RO   GR   BG  
    Global end of trial date
    21 Oct 2015

    Results information
    Results version number
    		 v1
    This version publication date
    16 Oct 2016
    First version publication date
    16 Oct 2016
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    RO-2455-302-RD
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02165826
    WHO universal trial number (UTN)
    		 U1111-1150-2477
    Other trial identifiers
    		 NRES: 14/NW/0138, Philippines: PHRR150519-001004, REec: REec-2014-0965
    Sponsors
    Sponsor organisation name
    Takeda Development Center Americas, Inc.
    Sponsor organisation address
    One Takeda Parkway, Deerfield, United States, 60015
    Public contact
    Director, Clinical Science, Takeda, +1 8778253327, clinicaltrialregistry@tpna.com
    Scientific contact
    Director, Clinical Science, Takeda, +1 8778253327, clinicaltrialregistry@tpna.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
    21 Oct 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Sep 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Oct 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to evaluate discontinuation rates of roflumilast 500 μg once daily (OD) using an up-titration regimen with either 250 μg OD or 500 μg every other day (EOD) for the first 4 weeks of treatment followed by 500 μg OD for 8 weeks compared with continuous treatment of 500 μg OD during the entire 12-week main period, and to evaluate if participants who do not tolerate roflumilast 500 μg OD have a drug exposure with 250 μg roflumilast OD similar to that observed in other participants with the 500 μg OD dose.
    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
    30 Apr 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 84
    Country: Number of subjects enrolled
    Germany: 52
    Country: Number of subjects enrolled
    Greece: 20
    Country: Number of subjects enrolled
    Hungary: 235
    Country: Number of subjects enrolled
    Korea, Republic of: 46
    Country: Number of subjects enrolled
    Philippines: 30
    Country: Number of subjects enrolled
    Poland: 199
    Country: Number of subjects enrolled
    Romania: 144
    Country: Number of subjects enrolled
    Russian Federation: 141
    Country: Number of subjects enrolled
    Slovakia: 106
    Country: Number of subjects enrolled
    South Africa: 61
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Thailand: 17
    Country: Number of subjects enrolled
    Ukraine: 168
    Country: Number of subjects enrolled
    United Kingdom: 15
    Worldwide total number of subjects
    1323
    EEA total number of subjects
    860
    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)
    668
    From 65 to 84 years
    653
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in the study at 161 investigative sites in Bulgaria, Germany, Greece, Hungary, Korea, Philippines, Poland, Romania, Russia, Slovakia, South Africa, Spain, Thailand, Ukraine and the United Kingdom from 30 April 2014 to 21 October 2015.

    Pre-assignment
    Screening details
    		 Participants with a diagnosis of Chronic Obstructive Pulmonary Disease (COPD) were enrolled equally in 1 of 3 treatment groups in the Main Treatment Period: roflumilast 250 μg then 500 μg once daily (OD), 500 μg every other day (EOD) then 500 μg OD and 500 μg OD. Participants who discontinued received 250 μg in the Down-Titration Period.

    Pre-assignment period milestones
    Number of subjects started
    		 1323
    Number of subjects completed
    		 1321

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Did Not Receive Study Drug: 2
    Period 1
    Period 1 title
    Main Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Roflumilast 250 μg OD then 500 μg OD
    Arm description
    		 Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Roflumilast
    Investigational medicinal product code
    Other name
    Daxas, Daliresp, Libertek
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Roflumilast tablets

    Arm title
    		 Roflumilast 500 μg EOD then 500 μg OD
    Arm description
    		 Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Roflumilast
    Investigational medicinal product code
    Other name
    Daxas, Daliresp, Libertek
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Roflumilast tablets

    Investigational medicinal product name
    Roflumilast Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Roflumilast placebo-matching tablets

    Arm title
    		 Roflumilast 500 μg OD
    Arm description
    		 Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Roflumilast
    Investigational medicinal product code
    Other name
    Daxas, Daliresp, Libertek
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Roflumilast tablets

    Number of subjects in period 1 [1]
    		Roflumilast 250 μg OD then 500 μg OD Roflumilast 500 μg EOD then 500 μg OD Roflumilast 500 μg OD
    Started
    441
    437
    443
    Safety Analysis Set: Received Study Drug
    441
    437
    443
    Completed
    360
    349
    334
    Not completed
    81
    88
    109
         Pre-treatment Event/Adverse Event
    44
    57
    68
         Major/Significant Protocol Deviation
    -
    1
    3
         Voluntary Withdrawal
    23
    23
    21
         Reason Not Specified
    8
    5
    16
         Lost to follow-up
    4
    2
    1
         Lack of efficacy
    2
    -
    -
    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: 2 participants were randomized but did not receive study treatment and are not included in the Baseline Period.
    Period 2
    Period 2 title
    Down-Titration Period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Roflumilast 250 μg OD then 500 μg OD
    Arm description
    		 Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Roflumilast
    Investigational medicinal product code
    Other name
    Daxas, Daliresp, Libertek
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Roflumilast tablets

    Arm title
    		 Roflumilast 500 μg EOD then 500 μg OD
    Arm description
    		 Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Roflumilast
    Investigational medicinal product code
    Other name
    Daxas, Daliresp, Libertek
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Roflumilast tablets

    Investigational medicinal product name
    Roflumilast Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Roflumilast placebo-matching tablets

    Arm title
    		 Roflumilast 500 μg OD
    Arm description
    		 Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Roflumilast
    Investigational medicinal product code
    Other name
    Daxas, Daliresp, Libertek
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Roflumilast tablets

    Number of subjects in period 2 [2]
    		Roflumilast 250 μg OD then 500 μg OD Roflumilast 500 μg EOD then 500 μg OD Roflumilast 500 μg OD
    Started
    27
    39
    38
    Safety Analysis Set: Received Study Drug
    27
    39
    38
    Completed
    20
    28
    31
    Not completed
    7
    11
    7
         Pre-treatment Event/Adverse Event
    4
    10
    3
         Voluntary Withdrawal
    2
    1
    2
         Reason Not Specified
    1
    -
    2
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Not all participants from the Main Treatment Period entered the Down-Titration Period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Roflumilast 250 μg OD then 500 μg OD
    Reporting group description
    		 Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.

    Reporting group title
    Roflumilast 500 μg EOD then 500 μg OD
    Reporting group description
    		 Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.

    Reporting group title
    Roflumilast 500 μg OD
    Reporting group description
    		 Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.

    Reporting group values
    		 Roflumilast 250 μg OD then 500 μg OD Roflumilast 500 μg EOD then 500 μg OD Roflumilast 500 μg OD Total
    Number of subjects
    		 441 437 443 1321
    Age, Customized
    Units: participants
        40-64 years
    		 242 202 224 668
        65-84 years
    		 199 235 217 651
        85 years and over
    		 0 0 2 2
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.2 ( 7.81 ) 65 ( 8.21 ) 64.6 ( 8.36 ) -
    Gender, Male/Female
    Units: participants
        Female
    		 121 112 105 338
        Male
    		 320 325 338 983
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    		 1 2 5 8
        Not Hispanic or Latino
    		 428 423 426 1277
        Missing
    		 12 12 12 36
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaskan Native
    		 0 1 0 1
        Asian
    		 32 30 32 94
        Black or African American
    		 3 3 3 9
        Native Hawaiian/Other Pacific Islander
    		 1 4 3 8
        White
    		 405 399 405 1209
    Smoking Classification
    Units: Subjects
        Current Smoker
    		 213 198 196 607
        Ex-smoker
    		 228 239 247 714
    Region of Enrollment
    Units: Subjects
        Bulgaria
    		 36 18 30 84
        Germany
    		 12 24 16 52
        Greece
    		 8 6 6 20
        Hungary
    		 82 74 79 235
        Korea, Republic Of
    		 22 11 13 46
        Philippines
    		 7 13 10 30
        Poland
    		 60 68 71 199
        Romania
    		 54 46 44 144
        Russia
    		 37 48 55 140
        Slovakia
    		 40 38 27 105
        South Africa
    		 17 18 26 61
        Spain
    		 2 2 1 5
        Thailand
    		 2 6 9 17
        Ukraine
    		 56 58 54 168
        United Kingdom
    		 6 7 2 15
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 169.1 ( 8.73 ) 168.8 ( 8.66 ) 169.1 ( 8.55 ) -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 75.59 ( 18.627 ) 74.31 ( 17.808 ) 75.68 ( 16.949 ) -
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 26.36 ( 5.957 ) 25.98 ( 5.614 ) 26.44 ( 5.888 ) -
    Number of Cigarette Pack-Years
    Number of pack-years = (number of cigarettes smoked per day/20) × number of years smoked
    Units: pack-years
        arithmetic mean (standard deviation)
    		 38.1 ( 17.49 ) 40.2 ( 19.22 ) 37.6 ( 17.7 ) -
    Pre-bronchodilator Forced Expiratory Volume in the First Second (FEV1)
    Pre-bronchodilator FEV1 data was available for 440, 436 and 443 participants in each treatment arm, respectively.
    Units: Liters
        arithmetic mean (standard deviation)
    		 1.022 ( 0.3177 ) 1.028 ( 0.3173 ) 1.018 ( 0.3289 ) -
    Pre-Bronchodilator Forced Vital Capacity (FVC)
    Pre-Bronchodilator FVC data was available for 440, 436 and 443 participants in each treatment arm, respectively.
    Units: Liters
        arithmetic mean (standard deviation)
    		 2.304 ( 0.7418 ) 2.303 ( 0.7091 ) 2.314 ( 0.6822 ) -

    End points

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    End points reporting groups
    Reporting group title
    Roflumilast 250 μg OD then 500 μg OD
    Reporting group description
    		 Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.

    Reporting group title
    Roflumilast 500 μg EOD then 500 μg OD
    Reporting group description
    		 Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.

    Reporting group title
    Roflumilast 500 μg OD
    Reporting group description
    		 Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.
    Reporting group title
    Roflumilast 250 μg OD then 500 μg OD
    Reporting group description
    		 Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.

    Reporting group title
    Roflumilast 500 μg EOD then 500 μg OD
    Reporting group description
    		 Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.

    Reporting group title
    Roflumilast 500 μg OD
    Reporting group description
    		 Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.

    Subject analysis set title
    Roflumilast 250 μg OD then 500 μg OD_Down Titration Period
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the roflumilast 250 μg once daily (OD) then 500 μg OD who were not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.

    Subject analysis set title
    Roflumilast 500 μg EOD_Down-Titration Period
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the roflumilast 500 μg, every other day (EOD) treatment arm who were not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.

    Subject analysis set title
    Roflumilast 500 μg OD_Down Titration Period
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the roflumilast 500 μg once daily (OD) treatment arm who were not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.

    Subject analysis set title
    Roflumilast 250 μg OD then 500 μg OD_Down Titration Period
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the roflumilast 250 μg once daily (OD) then 500 μg OD who were not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.

    Subject analysis set title
    All PK Participants_Roflumilast
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All PK participants who received any dose of roflumilast. Results for roflumilast.

    Subject analysis set title
    All PK Participants_Roflumilast N-oxide
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All PK participants who received any dose of rofumilast. Results for roflumilast N-oxide.

    Subject analysis set title
    Roflumilast 500 μg EOD
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Roflumilast 500 μg, tablets, orally, every other day (EOD) in the Main Period.

    Subject analysis set title
    Roflumilast 250 μg OD
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Roflumilast 250 μg tablets, orally, once daily in the Main Period.

    Subject analysis set title
    Roflumilast 250 µg Down-Titration
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.

    Subject analysis set title
    Roflumilast 250 μg OD
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Roflumilast 500 μg at least one dose in the Main Period followed by Roflumilast 250 μg tablets, orally, once daily in the Down -Titration Period.

    Subject analysis set title
    Roflumilast 250 μg OD
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Roflumilast 250 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.

    Subject analysis set title
    Roflumilast 500 μg EOD
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Roflumilast 500 μg, orally, every other day (EOD) at least 1 dose in the Main Period

    Subject analysis set title
    Roflumilast 500 μg OD_CFB in FEV1 @ Week 4
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Roflumilast 500 μg, tablets, orally, once daily (OD) for 12 weeks. Results for Change from Baseline in FEV1 at Week 4.

    Subject analysis set title
    Roflumilast 500 μg OD_CFB in FEV1 @ Week 12
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Roflumilast 500 μg, tablets, orally, once daily (OD) for 12 weeks. Results for Change from Baseline in FEV1 at Week 12.

    Subject analysis set title
    Roflumilast 500 μg OD
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.

    Subject analysis set title
    Roflumilast 500 μg OD
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Roflumilast 500 μg, tablets, orally, once daily (OD) at least 1 dose in the Main Period.

    Subject analysis set title
    Roflumilast 500 μg EOD then 500 μg OD
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.

    Primary: Percentage of Participants Prematurely Discontinuing Study Treatment due to any Reason

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    End point title
    		 Percentage of Participants Prematurely Discontinuing Study Treatment due to any Reason
    End point description
    The primary endpoint is the percentage of participants prematurely discontinuing study treatment for any reason during the Main Period from Visit 1 (V1) to Last Visit (Vend). Discontinuation is defined as permanently stopping randomized treatment; participants who resume randomized treatment after an interval will not be counted as having discontinued. The analysis used discontinuations occurring during the Main Period, irrespective of whether a participant subsequently entered into the Down-Titration Period. Safety Analysis Set (SAS) included all randomized participants who took at least one dose of study medication.
    End point type
    Primary
    End point timeframe
    Baseline to Week 12 (Main Period)
    End point values
    		 Roflumilast 250 μg OD then 500 μg OD Roflumilast 500 μg EOD then 500 μg OD Roflumilast 500 μg OD
    Number of subjects analysed
    441
    437
    443
    Units: percentage of participants
        number (not applicable)
    18.4
    20.1
    24.6
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analyses were performed using a hierarchical testing procedure.
    Comparison groups
    Roflumilast 250 μg OD then 500 μg OD v Roflumilast 500 μg OD
    Number of subjects included in analysis
    884
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.017 [1]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 0.93
    Notes
    [1] - Study treatment, country and baseline forced expiratory volume in the first second (FEV1) as explanatory variables.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Analyses were performed using a hierarchical testing procedure.
    Comparison groups
    Roflumilast 250 μg OD then 500 μg OD v Roflumilast 500 μg OD
    Number of subjects included in analysis
    884
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 0.92
    Notes
    [2] - Cox proportional hazards model with study treatment and country as class effects, and baseline FEV1 as a continuous variable.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Analyses were performed using a hierarchical testing procedure.
    Comparison groups
    Roflumilast 500 μg EOD then 500 μg OD v Roflumilast 500 μg OD
    Number of subjects included in analysis
    880
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.114 [3]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 1.07
    Notes
    [3] - Study treatment, country and baseline forced expiratory volume in the first second (FEV1) as explanatory variables.
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Analyses were performed using a hierarchical testing procedure.
    Comparison groups
    Roflumilast 500 μg EOD then 500 μg OD v Roflumilast 500 μg OD
    Number of subjects included in analysis
    880
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 1.02
    Notes
    [4] - Cox proportional hazards model with study treatment and country as class effects, and baseline FEV1 as a continuous variable.

    Secondary: Percentage of Participants with Adverse Events of Interest

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    End point title
    		 Percentage of Participants with Adverse Events of Interest
    End point description
    Adverse events (AEs) of interest to evaluate tolerability are defined as diarrhea, nausea, headache, decreased appetite, insomnia and abdominal pain. SAS included all randomized participants who took at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12 (Main Period)
    End point values
    		 Roflumilast 250 μg OD then 500 μg OD Roflumilast 500 μg EOD then 500 μg OD Roflumilast 500 μg OD
    Number of subjects analysed
    441
    437
    443
    Units: percentage of participants
        number (not applicable)
    45.4
    48.3
    54.2
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analyses were performed using a hierarchical testing procedure.
    Comparison groups
    Roflumilast 250 μg OD then 500 μg OD v Roflumilast 500 μg OD
    Number of subjects included in analysis
    884
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.001 [5]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 0.83
    Notes
    [5] - Study treatment, country and baseline forced expiratory volume in the first second (FEV1) as explanatory variables.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Analyses were performed using a hierarchical testing procedure.
    Comparison groups
    Roflumilast 500 μg EOD then 500 μg OD v Roflumilast 500 μg OD
    Number of subjects included in analysis
    880
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.091 [6]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 1.04
    Notes
    [6] - Study treatment, country and baseline forced expiratory volume in the first second (FEV1) as explanatory variables.

    Secondary: Change from Baseline (V0DT) in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) to Final Visit of the Down-Titration Period

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    End point title
    		 Change from Baseline (V0DT) in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) to Final Visit of the Down-Titration Period
    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. Pulmonary function testing was performed using spirometry prior to taking study medication A positive change from Baseline indicates improvement. Participants from the Down-Titration Period Full Analysis Set (FAS), all randomized participants who entered this period, regardless of whether they took study medication, with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (V0DT) [assessment at end of main period] and Final Visit of Down-Titration Period (Up to Day 56)
    End point values
    		 Roflumilast 250 μg OD then 500 μg OD_Down Titration Period Roflumilast 500 μg EOD_Down-Titration Period Roflumilast 500 μg OD_Down Titration Period
    Number of subjects analysed
    26
    39
    38
    Units: Liters
        arithmetic mean (standard deviation)
    0.03 ( 0.2294 )
    0.055 ( 0.417 )
    0.007 ( 0.3555 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants Prematurely Discontinuing Study Treatment due to Any Reason During Down-Titration Period

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    End point title
    		 Percentage of Participants Prematurely Discontinuing Study Treatment due to Any Reason During Down-Titration Period
    End point description
    Down-Titration Period Full Analysis Set (FAS) included all randomized participants who entered this period, regardless of whether they took study medication.
    End point type
    Secondary
    End point timeframe
    Baseline DT (Day 1 of Down-Titration Period) to Week 8 (Down-Titration Period)
    End point values
    		 Roflumilast 500 μg EOD_Down-Titration Period Roflumilast 500 μg OD_Down Titration Period Roflumilast 250 μg OD then 500 μg OD_Down Titration Period
    Number of subjects analysed
    39
    38
    27
    Units: percentage of participants
        number (not applicable)
    28.2
    18.4
    25.9
    No statistical analyses for this end point

    Secondary: Change from Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) during the Down-Titration Period

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    End point title
    		 Change from Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) during the Down-Titration Period
    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. Pulmonary function testing was performed using spirometry prior to taking study medication. A positive change from Baseline indicates improvement. Participants from the Down-Titration Period Full Analysis Set (FAS), all randomized participants who entered this period, regardless of whether they took study medication, with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline DT (Day 1 of Down-Titration Period) to Days 14, 28 and 56 (Down-Titration Period)
    End point values
    		 Roflumilast 250 μg OD then 500 μg OD_Down Titration Period Roflumilast 500 μg EOD_Down-Titration Period Roflumilast 500 μg OD_Down Titration Period
    Number of subjects analysed
    27
    39
    38
    Units: Liters
    arithmetic mean (standard deviation)
        Day 14 (n=20, 32, 34)
    0.128 ( 0.3708 )
    0.223 ( 0.4101 )
    0.097 ( 0.2532 )
        Day 28 (n=20, 29, 31)
    0.162 ( 0.4274 )
    0.218 ( 0.4443 )
    0.07 ( 0.2067 )
        Day 56 (n=26, 39, 38)
    0.162 ( 0.3311 )
    0.261 ( 0.4616 )
    0.127 ( 0.3334 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) during the Main Period

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    End point title
    		 Change from Baseline in Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1) during the Main Period [7]
    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. Pulmonary function testing was performed using spirometry prior to taking study medication. A positive change from Baseline indicates improvement. Main Period FAS included all randomized participants, regardless of whether they took study medication. "n" in each of the categories is the number of participants with data available at the given time-point.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1 of Main Period) to Days 15, 29, 57 and 84 (Main Period)
    Notes
    [7] - 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: Not all Baseline period arms are applicable to this endpoint.
    End point values
    		 Roflumilast 250 μg OD then 500 μg OD Roflumilast 500 μg OD Roflumilast 500 μg EOD then 500 μg OD
    Number of subjects analysed
    441
    443
    439
    Units: Liters
    arithmetic mean (standard deviation)
        Day 15 (n=409, 406, 386)
    0.067 ( 0.2299 )
    0.094 ( 0.2566 )
    0.094 ( 0.2573 )
        Day 29 (n=402, 389, 365)
    0.099 ( 0.2605 )
    0.116 ( 0.244 )
    0.115 ( 0.2629 )
        Day 57 (n=376, 367, 352)
    0.104 ( 0.2659 )
    0.133 ( 0.2705 )
    0.161 ( 0.2765 )
        Day 84 (n=402, 411, 409)
    0.117 ( 0.269 )
    0.122 ( 0.2705 )
    0.141 ( 0.2882 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) during the Main Period

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    End point title
    		 Change from Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) during the Main Period [8]
    End point description
    Forced vital capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. Pulmonary function testing was performed using spirometry prior to taking study medication. A positive change from Baseline indicates improvement. Main Period FAS included all randomized participants, regardless of whether they took study medication. "n" in each of the categories is the number of participants with data available at the given time-point.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1 of Main Period) to Days 15, 29, 57 and 84 (Main Period)
    Notes
    [8] - 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: Not all Baseline period arms are applicable to this endpoint.
    End point values
    		 Roflumilast 250 μg OD then 500 μg OD Roflumilast 500 μg OD Roflumilast 500 μg EOD then 500 μg OD
    Number of subjects analysed
    441
    443
    439
    Units: Liters
    arithmetic mean (standard deviation)
        Day 15 (n=409, 406, 386)
    0.096 ( 0.4053 )
    0.104 ( 0.4166 )
    0.112 ( 0.4168 )
        Day 29 (n=402, 389, 365)
    0.139 ( 0.3826 )
    0.149 ( 0.4173 )
    0.143 ( 0.4172 )
        Day 57 (n=376, 367, 352)
    0.156 ( 0.4346 )
    0.162 ( 0.4341 )
    0.194 ( 0.4974 )
        Day 84 (n=402, 411, 409)
    0.157 ( 0.4746 )
    0.147 ( 0.4555 )
    0.207 ( 0.4925 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) during the Down-Titration Period

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    End point title
    		 Change from Baseline in Pre-bronchodilator Forced Vital Capacity (FVC) during the Down-Titration Period
    End point description
    Forced vital capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. Pulmonary function testing was performed using spirometry prior to taking study medication. A positive change from Baseline indicates improvement. Down-Titration Period Full Analysis Set (FAS) included all randomized participants who entered this period, regardless of whether they took study medication.
    End point type
    Secondary
    End point timeframe
    Baseline DT (Day 1 of Down-Titration Period) to Days 14, 28 and 56 (Down-Titration Period)
    End point values
    		 Roflumilast 250 μg OD then 500 μg OD_Down Titration Period Roflumilast 500 μg EOD_Down-Titration Period Roflumilast 500 μg OD_Down Titration Period
    Number of subjects analysed
    27
    39
    38
    Units: Liters
    arithmetic mean (standard deviation)
        Day 14 (n=20, 32, 34)
    0.087 ( 0.5392 )
    0.303 ( 0.5103 )
    0.104 ( 0.4568 )
        Day 28 (n=20, 29, 31)
    0.125 ( 0.6151 )
    0.191 ( 0.478 )
    0.067 ( 0.3522 )
        Day 56 (n=26, 39, 38)
    0.167 ( 0.5492 )
    0.133 ( 0.51 )
    0.029 ( 0.4628 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Treatment Satisfaction Scores during the Main Period

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    End point title
    		 Change from Baseline in Treatment Satisfaction Scores during the Main Period [9]
    End point description
    Participants will be asked to assess their satisfaction with their COPD therapy at each visit. The participants will rate their treatment satisfaction on a 7-point scale where 0=very satisfied, 1=satisfied, 2=somewhat satisfied, 3=neither satisfied nor dissatisfied, 4=somewhat dissatisfied, 5=dissatisfied and 6=very dissatisfied. A negative change from Baseline indicates improvement. Main Period FAS included all randomized participants, regardless of whether they took study medication. "n" in each of the categories is the number of participants with data available at the given time-point.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1 of Main Period) to Days 15, 29, 57 and 84 (Main Period)
    Notes
    [9] - 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: Not all Baseline period arms are applicable to this endpoint.
    End point values
    		 Roflumilast 250 μg OD then 500 μg OD Roflumilast 500 μg OD Roflumilast 500 μg EOD then 500 μg OD
    Number of subjects analysed
    441
    443
    439
    Units: score on a scale
    arithmetic mean (standard deviation)
        Day 15 (n=410, 408, 386)
    -0.4 ( 1.12 )
    -0.3 ( 1.07 )
    -0.3 ( 1.15 )
        Day 29 (n=403, 390, 366)
    -0.5 ( 1.23 )
    -0.5 ( 1.22 )
    -0.5 ( 1.16 )
        Day 57 (n=375, 369, 351)
    -0.6 ( 1.24 )
    -0.5 ( 1.29 )
    -0.6 ( 1.26 )
        Day 84 (n=407, 416, 412)
    -0.5 ( 1.43 )
    -0.3 ( 1.52 )
    -0.5 ( 1.51 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Treatment Satisfaction Scores during the Down-Titration Period

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    End point title
    		 Change from Baseline in Treatment Satisfaction Scores during the Down-Titration Period
    End point description
    Participants will be asked to assess their satisfaction with their COPD therapy at each visit. The participants will rate their treatment satisfaction on a 7-point scale where 0=very satisfied, 1=satisfied, 2=somewhat satisfied, 3=neither satisfied nor dissatisfied, 4=somewhat dissatisfied, 5=dissatisfied and 6=very dissatisfied. A negative change from Baseline indicates improvement. Down-Titration Period Full Analysis Set (FAS) included all randomized participants who entered this period, regardless of whether they took study medication. "n" in each of the categories is the number of participants with data available at the given time-point.
    End point type
    Secondary
    End point timeframe
    Baseline DT (Day 1 of Down-Titration Period) to Days 14, 28 and 56 (Down-Titration Period)
    End point values
    		 Roflumilast 250 μg OD then 500 μg OD_Down Titration Period Roflumilast 500 μg EOD_Down-Titration Period Roflumilast 500 μg OD_Down Titration Period
    Number of subjects analysed
    27
    39
    38
    Units: Liters
    arithmetic mean (standard deviation)
        Day 14 (n=20, 32, 34)
    -1.1 ( 1.85 )
    -0.8 ( 1.57 )
    -0.8 ( 1.84 )
        Day 28 (n=20, 29, 31)
    -1.2 ( 2.01 )
    -0.8 ( 1.75 )
    -0.9 ( 1.81 )
        Day 56 (n=26, 39, 38)
    -0.8 ( 2.23 )
    -0.3 ( 2.15 )
    -0.4 ( 2.26 )
    No statistical analyses for this end point

    Secondary: Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide

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    End point title
    		 Population PK Model Point Estimate for Absorption Rate Constant (Ka) of Roflumilast and Roflumilast N-oxide
    End point description
    PK model point estimates for Ka are calculated using all available PK data for all doses of roflumilast combined and are presented for roflumilast and metabolite roflumilast N-oxide. Results are reported for the overall population as well as for the subgroups defined according to the covariates (weight, age, smoking status and sex) included in the final model. Pharmacokinetic (PK) Set included all participants who had at least 1 quantifiable PK concentration.
    End point type
    Secondary
    End point timeframe
    Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours at weeks 2 or 8
    End point values
    		 All PK Participants_Roflumilast All PK Participants_Roflumilast N-oxide
    Number of subjects analysed
    1238
    1238
    Units: units per hour (1/h)
    number (not applicable)
        Weight=33.5 kg
    0.9
    0.57
        Weight=70 kg
    0.9
    0.57
        Weight=160 kg
    0.9
    0.57
        Age=40
    0.9
    0.57
        Age=60
    0.9
    0.57
        Age=92
    0.9
    0.57
        Smoking=former
    0.9
    0.57
        Smoking=current
    0.9
    0.57
        Sex=female
    0.9
    0.57
        Sex=male
    0.9
    0.57
    No statistical analyses for this end point

    Secondary: Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide

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    End point title
    		 Population PK Model Point Estimate for Apparent Oral Clearance (CL/F) of Roflumilast and Roflumilast N-oxide
    End point description
    PK model point estimates for CL/F are calculated using all available PK data for all doses of roflumilast combined and are presented for roflumilast and metabolite roflumilast N-oxide. Results are reported for the overall population as well as for the subgroups defined according to the covariates (weight, age, smoking status and sex) included in the final model. Pharmacokinetic (PK) Set included all participants who had at least 1 quantifiable PK concentration.
    End point type
    Secondary
    End point timeframe
    Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours at weeks 2 or 8
    End point values
    		 All PK Participants_Roflumilast All PK Participants_Roflumilast N-oxide
    Number of subjects analysed
    1238
    1238
    Units: liters per hour (L/h)
    number (not applicable)
        Weight=33.5 kg
    5.64
    0.73
        Weight=70 kg
    5.64
    0.89
        Weight=160 kg
    5.64
    1.12
        Age=40
    7.23
    1.11
        Age=60
    5.64
    0.89
        Age=92
    4.35
    0.71
        Smoking=former
    5.64
    0.89
        Smoking=current
    6.5
    1.03
        Sex=female
    5.64
    0.89
        Sex=male
    5.64
    0.79
    No statistical analyses for this end point

    Secondary: Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide

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    End point title
    		 Population PK Model Point Estimate for Apparent Central Volume (Vc/F) of Roflumilast and Roflumilast N-oxide
    End point description
    PK model point estimates for Vc/F are calculated using all available PK data for all doses of roflumilast combined and are presented for roflumilast and metabolite roflumilast N-oxide. Results are reported for the overall population as well as for the subgroups defined according to the covariates (weight, age, smoking status and sex) included in the final model. Pharmacokinetic (PK) Set included all participants who had at least 1 quantifiable PK concentration.
    End point type
    Secondary
    End point timeframe
    Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours at weeks 2 or 8
    End point values
    		 All PK Participants_Roflumilast All PK Participants_Roflumilast N-oxide
    Number of subjects analysed
    1238
    1238
    Units: liters (L)
    number (not applicable)
        Weight=33.5 kg
    26
    4.5
        Weight=70 kg
    63.9
    11
        Weight=160 kg
    175.2
    30.2
        Age=40
    63.9
    11
        Age=60
    63.9
    11
        Age=92
    63.9
    11
        Smoking=former
    63.9
    11
        Smoking=current
    63.9
    11
        Sex=female
    63.9
    11
        Sex=male
    63.9
    11
    No statistical analyses for this end point

    Secondary: Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide

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    End point title
    		 Population PK Model Point Estimate for Apparent Peripheral Volume (Vp/F) of Roflumilast and Roflumilast N-oxide
    End point description
    PK model point estimates for Vp/F are calculated using all available PK data for all doses of roflumilast combined and are presented for roflumilast and metabolite roflumilast N-oxide. Results are reported for the overall population as well as for the subgroups defined according to the covariates (weight, age, smoking status and sex) included in the final model. Pharmacokinetic (PK) Set included all participants who had at least 1 quantifiable PK concentration.
    End point type
    Secondary
    End point timeframe
    Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours at weeks 2 or 8
    End point values
    		 All PK Participants_Roflumilast All PK Participants_Roflumilast N-oxide
    Number of subjects analysed
    1238
    1238
    Units: Liters
    number (not applicable)
        Weight=33.5 kg
    69.6
    5
        Weight=70 kg
    171
    12.4
        Weight=160 kg
    468.8
    34
        Age=40
    171
    12.4
        Age=60
    171
    12.4
        Age=92
    171
    12.4
        Smoking=former
    171
    12.4
        Smoking=current
    171
    12.4
        Sex=female
    171
    12.4
        Sex=male
    171
    12.4
    No statistical analyses for this end point

    Secondary: Total PDE4 Inhibitory Activity (tPDE4i)

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    End point title
    		 Total PDE4 Inhibitory Activity (tPDE4i) [10]
    End point description
    tPDE4i of roflumilast and roflumilast N-oxide was derived using in-vitro constants for protein binding and biochemical activity (IC50). tPDE4i is reported for a set of reference participants defined according to the covariates included in the final model. Participants from the PK Set, all participants who had at least 1 quantifiable PK concentration, with data available. Measured values are predicted values reported as median and 90% prediction interval.
    End point type
    Secondary
    End point timeframe
    Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours post-dose at Days 15 and 57. Down-titration: Pre-dose and 1,2,3,4,6 hours post-dose at Days 1 and 14 and pre-dose at Days 28 and 56.
    Notes
    [10] - 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: Not all Baseline period arms are applicable to this endpoint.
    End point values
    		 Roflumilast 500 μg OD Roflumilast 500 μg EOD Roflumilast 250 μg OD Roflumilast 250 µg Down-Titration
    Number of subjects analysed
    392
    399
    404
    101
    Units: unitless
    median (confidence interval 90%)
        Overall
    1.17 (0.366 to 2.05)
    0.608 (0.227 to 1.03)
    0.563 (0.157 to 1.01)
    0.583 (0.21 to 1.24)
        Age < 65 (n=198,187,229,45)
    1.06 (0.323 to 1.85)
    0.559 (0.237 to 0.998)
    0.518 (0.16 to 0.958)
    0.511 (0.205 to 0.984)
        Age ≥ 65 to < 75 (n=146,159,136,39)
    1.24 (0.55 to 2.08)
    0.66 (0.177 to 1.04)
    0.614 (0.138 to 1.1)
    0.683 (0.207 to 1.23)
        Age ≥ 75 (n=48,53,39,17)
    1.24 (0.318 to 2.31)
    0.676 (0.188 to 1.12)
    0.616 (0.195 to 1.01)
    0.712 (0.3 to 1.32)
        Weight < 60 kg (n=56,78,73,17)
    1.34 (0.591 to 2.64)
    0.755 (0.258 to 1.22)
    0.653 (0.156 to 1.12)
    0.934 (0.325 to 1.39)
        Weight ≥ 60 kg (n=336,321,331,84)
    1.12 (0.339 to 1.99)
    0.592 (0.223 to 1.01)
    0.552 (0.158 to 0.971)
    0.538 (0.202 to 1.02)
        Males (n=300,297,290,66)
    1.12 (0.363 to 1.96)
    0.585 (0.226 to 0.994)
    0.558 (0.145 to 0.998)
    0.575 (0.213 to 1.14)
        Females (n=92,102,114,35)
    1.29 (0.468 to 2.38)
    0.696 (0.26 to 1.15)
    0.618 (0.189 to 1.01)
    0.626 (0.217 to 1.25)
        Current Smoker (n=179,183,200,45)
    1.04 (0.327 to 1.88)
    0.568 (0.247 to 0.976)
    0.514 (0.101 to 0.949)
    0.554 (0.228 to 1.21)
        Former Smoker (n=213,216,204,56)
    1.25 (0.416 to 2.15)
    0.632 (0.186 to 1.09)
    0.626 (0.196 to 1.1)
    0.624 (0.207 to 1.3)
    No statistical analyses for this end point

    Secondary: Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i)

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    End point title
    		 Summary Statistics of Predicted Total PDE4 Inhibitory Activity (tPDE4i)
    End point description
    tPDE4i of roflumilast and roflumilast N-oxide was derived using in-vitro constants for protein binding and biochemical activity (IC50). An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A treatment-emergent adverse event (TEAE) is defined as an AE with an onset that occurs after receiving study drug. Adverse Events of Interest (AEI) for PK analyses included: headache, diarrhea, nausea, vomiting, abdominal pain, appetite disorders, sleep disorders, angioedema, psychiatric disorders (anxiety, nervousness), psychiatric disorders (depression,suicidal ideation,behaviour) and weight loss. 99999=NA (no participants analyzed). Measured values are predicted values reported as median and 90% prediction interval. PK Set . "n" in the category is the number of participants with available data.
    End point type
    Secondary
    End point timeframe
    Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours post-dose at Days 15 and 57. Down-titration: Pre-dose and 1,2,3,4,6 hours post-dose at Days 1 and 14 and pre-dose at Days 28 and 56.
    End point values
    		 Roflumilast 250 μg OD Roflumilast 500 μg OD
    Number of subjects analysed
    76
    1114
    Units: unitless
    median (confidence interval 90%)
        All Participants (n=76,1114)
    0.611 (0.197 to 1.243)
    1.17 (0.352 to 2.03)
        Discontinuation due to Any AEI=Yes (n=62,67)
    0.647 (0.201 to 1.239)
    1.28 (0.427 to 2.22)
        Discontinuation due to Any AEI=No (n=14,1047)
    0.436 (0.212 to 1.069)
    1.16 (0.339 to 2.02)
        Discontinuation due to Any AE=Yes (n=64,77)
    0.647 (0.204 to 1.237)
    1.29 (0.464 to 2.1)
        Discontinuation due to Any AE=No (n=12,1037)
    0.408 (0.209 to 1.006)
    1.16 (0.337 to 2.02)
        Discontinuation Due to Any Reason=Yes (n=75,106)
    0.6 (0.197 to 1.243)
    1.23 (0.416 to 2.06)
        Discontinuation Due to Any Reason=No (n=1,1008)
    0.626 (0.626 to 0.626)
    1.16 (0.332 to 2.02)
        At Least 1 AEI=Yes (n=75,536)
    0.6 (0.197 to 1.243)
    1.23 (0.453 to 2.09)
        At Least 1 AEI=No (1,578)
    0.929 (0.929 to 0.929)
    1.12 (0.297 to 1.98)
        At Least 1 AE=Yes (n=76,693)
    0.611 (0.197 to 1.243)
    1.22 (0.416 to 2.07)
        At Least 1 AE=No (n=0,421)
    99999 (99999 to 99999)
    1.08 (0.294 to 1.97)
    No statistical analyses for this end point

    Secondary: Median Predicted Percentage of Participants with Adverse Events of Interest

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    End point title
    		 Median Predicted Percentage of Participants with Adverse Events of Interest
    End point description
    The PK model predicted the total PDE4 inhibitory activity and the median percentage of participants with Adverse Events of Interest during 12 weeks of treatment based on 1000 participants simulated. Results are reported for the set of reference participants defined according to the covariates [weight, smoking status, sex, age and long acting muscarinic antagonist (LAMA)] included in the final model and tPDE4i. Adverse Events of Interest (AEI) for PK analyses included: headache, diarrhea, nausea, vomiting, abdominal pain, appetite disorders, sleep disorders, angioedema, psychiatric disorders (anxiety, nervousness), psychiatric disorders (depression,suicidal ideation,behaviour) and weight loss. PK Set included all participants who had at least 1 quantifiable PK concentration. Number of participants analyzed is the number of participants simulated. Measured values are predicted values.
    End point type
    Secondary
    End point timeframe
    Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours post-dose at Days 15 and 57.
    End point values
    		 Roflumilast 250 μg OD Roflumilast 500 μg EOD Roflumilast 500 μg OD
    Number of subjects analysed
    1000
    1000
    1000
    Units: percentage of participants
    number (not applicable)
        Weight=48 kg (tPDE4i=0.72,0.72,1.45)
    53.2
    53.2
    61.8
        Weight=74 kg (tPDE4i=0.65,0.65,1.30)
    52.3
    52.3
    60.1
        Weight=105 kg (tPDE4i=0.60.0.60,1.19)
    51.7
    51.7
    58.8
        Former Smoker (tPDE4i=0.65,0.65,1.30)
    52.3
    52.3
    60.1
        Current Smoker (tPDE4i=0.56,0.56,1.13)
    42.5
    42.5
    49.2
        Male (tPDE4i=0.65,0.65,1.30)
    52.3
    52.3
    60.1
        Female (tPDE4i=0.72,0.72,1.45)
    53.2
    53.2
    61.8
        Age=51 (tPDE4i=0.58,0.58,1.15)
    51.4
    51.4
    58.4
        Age=64 (tPDE4i=0.65,0.65,1.30)
    52.3
    52.3
    60.1
        Age=77 (tPDE4i=0.72,0.72,1.44)
    53.2
    53.2
    61.7
        With LAMA (tPDE4i=0.65,0.65,1.30)
    52.3
    52.3
    60.1
        Without LAMA (tPDE4i=0.65,0.65,1.30)
    43.5
    43.5
    51.4
    No statistical analyses for this end point

    Secondary: Median Predicted Absolute Change from Baseline in FEV1 at Weeks 4 and 12

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    End point title
    		 Median Predicted Absolute Change from Baseline in FEV1 at Weeks 4 and 12
    End point description
    The PK model predicted the total PDE4 inhibitory activity and the median Change from Baseline (CFB) in FEV1 at Week 4 and the Change from Baseline in FEV1 at Week 12 during 12 weeks of treatment with roflumilast 500 μg OD based on 1000 participants simulated. Results are reported for the set of reference participants defined according to the covariates [weight, smoking status, sex, age, race, COPD severity, concomitant long acting muscarinic antagonist (LAMA) and Percent FEV1 reversibility] included in the final model and tPDE4i. FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Pulmonary function testing was performed using spirometry prior to taking study medication. A positive change from Baseline indicates improvement. PK Set included all participants who had at least 1 quantifiable PK concentration. The number of participants analyzed is the number of participants simulated. Measured values are predicted values.
    End point type
    Secondary
    End point timeframe
    Main period: Pre-dose and 1,2,3,4,6 hours post-dose or pre-dose and 2 hours post-dose at Days 15 and 57.
    End point values
    		 Roflumilast 500 μg OD_CFB in FEV1 @ Week 4 Roflumilast 500 μg OD_CFB in FEV1 @ Week 12
    Number of subjects analysed
    1000
    1000
    Units: milliliters (mL)
    number (not applicable)
        Weight=33.5 kg (tPDE4i=1.012,1.012)
    50
    32
        Weight=70 kg (tPDE4i=0.839,0.839)
    60.5
    56
        Weight=160 kg (tPDE4i=0.681,0.681)
    108
    157
        Current Smoker (tPDE4i=0.729,0.729)
    99.5
    96.5
        Former/Never Smoker (tPDE4i=0.839,0.839)
    60.5
    56
        Male (tPDE4i=0.839,0.839)
    60.5
    56
        Female (tPDE4i=0.937,0.937)
    53.2
    49.8
        Age=40 years (tPDE4i=0.675,0.675)
    57.6
    52.2
        Age=60 years (tPDE4i=0.839,0.839)
    60.5
    56
        Age=92 years (tPDE4i=1.06,1.06)
    56.4
    53.3
        Asian (tPDE4i=0.839,0.839)
    56.1
    52
        non-Asian (tPDE4i=0.839,0.839)
    60.5
    56
        COPD_Not Very Severe (tPDE4i=0.839,0.839)
    60.5
    56
        COPD_Very Severe (tPDE4i=0.839,0.839)
    42.2
    39.1
        LAMA=Yes (tPDE4i=0.839,0.839)
    60.5
    56
        LAMA=No (tPDE4i=0.839,0.839)
    63.5
    58.8
        %FEV1 Reversibility=-28% (tPDE4i=0.839,0.839)
    68.1
    63.1
        %FEV1 Reversibility=10% (tPDE4i=0.839,0.839)
    60.5
    56
        %FEV1 Reversibility=147% (tPDE4i=0.839,0.839)
    32.9
    30.5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Main Treatment Period: First dose of study drug to 30 days past last dose or first dose in the Down-Titration Period (Up to 114 Days). Down-Titration Period: First dose of study drug to 30 days past the last dose of study drug (Up to 86 Days).
    Adverse event reporting additional description
    Due to the design of the study, the most common (≥ 2%) non-serious adverse events were determined separately for each period, the blinded Main Treatment Period and the open-label Down-Titration Period. A result of 0 means that the event did not meet the ≥ 2% threshold for that study period but did meet the threshold for the other study period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Roflumilast 250 μg OD then 500 μg OD_Main Treatment Period
    Reporting group description
    		 Roflumilast 250 μg, tablets, orally, once daily (OD) for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.

    Reporting group title
    Roflumilast 500 μg EOD then 500 μg OD_Main Treatment Period
    Reporting group description
    		 Roflumilast 500 μg, tablets, orally, every other day (EOD), and roflumilast placebo-matching tablets, orally, every other day on non-treatment days, for 4 weeks, followed by roflumilast 500 μg, tablets, orally, once daily, for 8 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.

    Reporting group title
    Roflumilast 500 μg OD_Main Treatment Period
    Reporting group description
    		 Roflumilast 500 μg tablets, orally, once daily for 12 weeks in the Main Treatment Period. Any participants not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.

    Reporting group title
    Roflumilast 250 μg OD then 500 μg OD_Down Titration Period
    Reporting group description
    		 Participants in the roflumilast 250 μg once daily (OD) then 500 μg OD who were not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.

    Reporting group title
    Roflumilast 500 μg EOD_Down-Titration Period
    Reporting group description
    		 Participants in the roflumilast 500 μg, every other day (EOD) treatment arm who were not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.

    Reporting group title
    Roflumilast 500 μg OD_Down Titration Period
    Reporting group description
    		 Participants in the roflumilast 500 μg once daily (OD) treatment arm who were not tolerating study treatment were prematurely discontinued and received roflumilast 250 μg, tablets, orally, once daily for 8 weeks in the open-label Down-Titration Period.

    Serious adverse events
    		 Roflumilast 250 μg OD then 500 μg OD_Main Treatment Period Roflumilast 500 μg EOD then 500 μg OD_Main Treatment Period Roflumilast 500 μg OD_Main Treatment Period Roflumilast 250 μg OD then 500 μg OD_Down Titration Period Roflumilast 500 μg EOD_Down-Titration Period Roflumilast 500 μg OD_Down Titration Period
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 441 (4.31%)
    22 / 437 (5.03%)
    20 / 443 (4.51%)
    1 / 27 (3.70%)
    0 / 39 (0.00%)
    0 / 38 (0.00%)
         number of deaths (all causes)
    3
    1
    2
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung adenocarcinoma
    Additional description: One treatment-emergent death occurred during treatment with roflumilast 500 μg OD and is not related (previous AE included concurrent moderate haemoptysis).
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    1 / 443 (0.23%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (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 / 1
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    1 / 443 (0.23%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (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
    Prostate cancer
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    1 / 443 (0.23%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (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
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 437 (0.23%)
    0 / 443 (0.00%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (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
    Injury, poisoning and procedural complications
    Lower limb fracture
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 437 (0.23%)
    0 / 443 (0.00%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (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
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    1 / 443 (0.23%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (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
    Hypertensive crisis
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 437 (0.23%)
    0 / 443 (0.00%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (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
    Vasculitis
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 437 (0.23%)
    0 / 443 (0.00%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (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
    Cardiac disorders
    Myocardial infarction
    Additional description: One treatment-emergent death occurred during treatment with roflumilast 500 μg OD and is not related (previous AE included severe syncope).
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 437 (0.00%)
    1 / 443 (0.23%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 437 (0.23%)
    1 / 443 (0.23%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Atrial fibrillation
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 437 (0.23%)
    0 / 443 (0.00%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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 failure
    Additional description: One treatment-emergent death occurred during treatment with roflumilast 250 μg OD then 500 μg OD and is not related (previous AE included moderate COPD).
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 437 (0.00%)
    0 / 443 (0.00%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (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 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiopulmonary failure
    Additional description: One treatment-emergent death occurred during treatment with roflumilast 250 μg OD then 500 μg OD and is not related (previous AE included moderate COPD).
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 437 (0.00%)
    0 / 443 (0.00%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (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 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Sciatica
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    1 / 443 (0.23%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (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
    Syncope
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    1 / 443 (0.23%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (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
    Transient ischaemic attack
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 437 (0.23%)
    0 / 443 (0.00%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (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
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 437 (0.00%)
    0 / 443 (0.00%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    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
    Gastrointestinal disorders
    Abdominal mass
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 437 (0.00%)
    0 / 443 (0.00%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (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
    Colitis ulcerative
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 437 (0.00%)
    0 / 443 (0.00%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    Femoral hernia incarcerated
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    1 / 443 (0.23%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (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
    Small intestinal obstruction
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    1 / 443 (0.23%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (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
    Chronic obstructive pulmonary disease
    Additional description: One treatment-emergent death occurred during treatment with roflumilast 250 μg OD then 500 μg OD and is not related (previous AE included concurrent moderate pneumonia).
         subjects affected / exposed
    8 / 441 (1.81%)
    13 / 437 (2.97%)
    7 / 443 (1.58%)
    1 / 27 (3.70%)
    0 / 39 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 8
    1 / 14
    0 / 8
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 441 (0.68%)
    0 / 437 (0.00%)
    3 / 443 (0.68%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 437 (0.23%)
    0 / 443 (0.00%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (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
    Haemoptysis
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    1 / 443 (0.23%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (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
    Pleural effusion
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 437 (0.23%)
    0 / 443 (0.00%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (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
    Pneumothorax spontaneous
    Additional description: One treatment-emergent death occurred during treatment with roflumilast 500 µg EOD then 500 µg OD and is not related.
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 437 (0.23%)
    0 / 443 (0.00%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (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 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 437 (0.00%)
    0 / 443 (0.00%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (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
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 437 (0.23%)
    0 / 443 (0.00%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (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
    Musculoskeletal and connective tissue disorders
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 437 (0.23%)
    0 / 443 (0.00%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (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
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 441 (0.45%)
    1 / 437 (0.23%)
    1 / 443 (0.23%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 437 (0.00%)
    1 / 443 (0.23%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    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
    Acute sinusitis
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 437 (0.23%)
    0 / 443 (0.00%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (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
    Appendicitis
         subjects affected / exposed
    1 / 441 (0.23%)
    0 / 437 (0.00%)
    0 / 443 (0.00%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Bronchopneumonia
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    1 / 443 (0.23%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (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 tract infection
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 437 (0.23%)
    0 / 443 (0.00%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (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
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 441 (0.00%)
    1 / 437 (0.23%)
    0 / 443 (0.00%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (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
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    1 / 443 (0.23%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 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
    Gout
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    1 / 443 (0.23%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (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
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Roflumilast 250 μg OD then 500 μg OD_Main Treatment Period Roflumilast 500 μg EOD then 500 μg OD_Main Treatment Period Roflumilast 500 μg OD_Main Treatment Period Roflumilast 250 μg OD then 500 μg OD_Down Titration Period Roflumilast 500 μg EOD_Down-Titration Period Roflumilast 500 μg OD_Down Titration Period
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    239 / 441 (54.20%)
    248 / 437 (56.75%)
    272 / 443 (61.40%)
    13 / 27 (48.15%)
    21 / 39 (53.85%)
    25 / 38 (65.79%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 441 (0.91%)
    10 / 437 (2.29%)
    5 / 443 (1.13%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    4
    10
    9
    0
    0
    1
    Feeling hot
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    0 / 443 (0.00%)
    1 / 27 (3.70%)
    0 / 39 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Malaise
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    0 / 443 (0.00%)
    1 / 27 (3.70%)
    0 / 39 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Reproductive system and breast disorders
    Postmenopausal haemorrhage
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    0 / 443 (0.00%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    34 / 441 (7.71%)
    39 / 437 (8.92%)
    38 / 443 (8.58%)
    3 / 27 (11.11%)
    3 / 39 (7.69%)
    1 / 38 (2.63%)
         occurrences all number
    38
    41
    45
    3
    3
    1
    Dyspnoea
         subjects affected / exposed
    15 / 441 (3.40%)
    13 / 437 (2.97%)
    11 / 443 (2.48%)
    1 / 27 (3.70%)
    0 / 39 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    15
    13
    11
    1
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    97 / 441 (22.00%)
    100 / 437 (22.88%)
    106 / 443 (23.93%)
    2 / 27 (7.41%)
    10 / 39 (25.64%)
    6 / 38 (15.79%)
         occurrences all number
    253
    252
    234
    4
    15
    10
    Investigations
    Weight decreased
         subjects affected / exposed
    10 / 441 (2.27%)
    9 / 437 (2.06%)
    17 / 443 (3.84%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    10
    9
    17
    0
    0
    2
    Blood glucose increased
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    0 / 443 (0.00%)
    0 / 27 (0.00%)
    1 / 39 (2.56%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Procedural dizziness
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    0 / 443 (0.00%)
    1 / 27 (3.70%)
    0 / 39 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Skin abrasion
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    0 / 443 (0.00%)
    1 / 27 (3.70%)
    0 / 39 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    107 / 441 (24.26%)
    115 / 437 (26.32%)
    115 / 443 (25.96%)
    2 / 27 (7.41%)
    7 / 39 (17.95%)
    10 / 38 (26.32%)
         occurrences all number
    278
    279
    271
    2
    9
    21
    Dizziness
         subjects affected / exposed
    16 / 441 (3.63%)
    20 / 437 (4.58%)
    14 / 443 (3.16%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    16
    20
    18
    0
    0
    0
    Tremor
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    0 / 443 (0.00%)
    2 / 27 (7.41%)
    1 / 39 (2.56%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    2
    1
    0
    Amnesia
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    0 / 443 (0.00%)
    1 / 27 (3.70%)
    0 / 39 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    0 / 443 (0.00%)
    0 / 27 (0.00%)
    1 / 39 (2.56%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Eye disorders
    Chalazion
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    0 / 443 (0.00%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    107 / 441 (24.26%)
    113 / 437 (25.86%)
    134 / 443 (30.25%)
    3 / 27 (11.11%)
    6 / 39 (15.38%)
    11 / 38 (28.95%)
         occurrences all number
    216
    233
    259
    4
    8
    18
    Nausea
         subjects affected / exposed
    87 / 441 (19.73%)
    92 / 437 (21.05%)
    110 / 443 (24.83%)
    1 / 27 (3.70%)
    5 / 39 (12.82%)
    8 / 38 (21.05%)
         occurrences all number
    183
    201
    192
    1
    8
    11
    Abdominal pain
         subjects affected / exposed
    69 / 441 (15.65%)
    58 / 437 (13.27%)
    64 / 443 (14.45%)
    0 / 27 (0.00%)
    6 / 39 (15.38%)
    5 / 38 (13.16%)
         occurrences all number
    145
    126
    141
    0
    10
    6
    Abdominal pain upper
         subjects affected / exposed
    19 / 441 (4.31%)
    15 / 437 (3.43%)
    27 / 443 (6.09%)
    0 / 27 (0.00%)
    3 / 39 (7.69%)
    3 / 38 (7.89%)
         occurrences all number
    29
    27
    34
    0
    4
    5
    Bowel movement irregularity
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    0 / 443 (0.00%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Duodenitis
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    0 / 443 (0.00%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Dyspepsia
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    0 / 443 (0.00%)
    1 / 27 (3.70%)
    0 / 39 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    20 / 441 (4.54%)
    21 / 437 (4.81%)
    20 / 443 (4.51%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    24
    23
    23
    0
    0
    0
    Arthralgia
         subjects affected / exposed
    8 / 441 (1.81%)
    7 / 437 (1.60%)
    9 / 443 (2.03%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    8
    7
    10
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 441 (1.59%)
    11 / 437 (2.52%)
    12 / 443 (2.71%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    3 / 38 (7.89%)
         occurrences all number
    8
    11
    12
    0
    0
    3
    Pharyngitis
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    0 / 443 (0.00%)
    1 / 27 (3.70%)
    0 / 39 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    Candida infection
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    0 / 443 (0.00%)
    1 / 27 (3.70%)
    0 / 39 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    0 / 443 (0.00%)
    1 / 27 (3.70%)
    0 / 39 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Viral pharyngitis
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    0 / 443 (0.00%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Bronchitis
         subjects affected / exposed
    6 / 441 (1.36%)
    4 / 437 (0.92%)
    9 / 443 (2.03%)
    0 / 27 (0.00%)
    0 / 39 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    7
    4
    9
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    100 / 441 (22.68%)
    105 / 437 (24.03%)
    129 / 443 (29.12%)
    3 / 27 (11.11%)
    8 / 39 (20.51%)
    9 / 38 (23.68%)
         occurrences all number
    201
    204
    251
    4
    12
    15
    Hypokalaemia
         subjects affected / exposed
    0 / 441 (0.00%)
    0 / 437 (0.00%)
    0 / 443 (0.00%)
    0 / 27 (0.00%)
    1 / 39 (2.56%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Aug 2014
    Amendment 1: • All procedures outlined in the V(end) visit were to be performed at V(0DT) for participants continuing into the open label Down-Titration Period of the study. • Clarified that the ‘Liver Function Test (LFT) Abnormalities’ were not be a separate participant discontinuation/withdrawal category. • Clarified that an additional dose of study drug was not to be provided at Vend for participants discontinuing prematurely from the Main Period without continuing into the Down-Titration Period, and that only 1 PK sample was to be taken at this visit.

    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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